Library Resources - Results from #160

Malignant Renal Tumors

Renal cancers are common, accounting for an estimated 65,340 new diagnoses and 14,970 attributable deaths in 2018 in the United States.¹ In the article, "Epidemiology and Etiology of Kidney Cancer" both topics are discussed at great length. Despite a large number of histologic tumors which may occur in the kidney, renal cell carcinoma (RCC) is the most prevalent histology.

Tumor biology

Research into the molecular genetics of hereditary RCC has yielded many insights which contribute to the treatment of sporadic RCCs. An understanding of the function of the von Hippel Lindau protein led to the identification of the importance of vascular endothelial growth factor (VEGF) and the mammalian target of rapamycin (mTOR) pathways. Identification of the importance of VEGF aided in both explaining the significant neovascularity associated with ccRCC and providing a therapeutic target for systemic therapy.

Other molecular insights have significant clinical implications as well. First, RCC expresses multi-drug resistance proteins, energy-dependent efflux pumps. These pumps prevent the intracellular accumulation of chemotherapeutics and contribute to the chemotherapy-resistance of RCC. Second, based on observations of tumor-infiltrating immune cells and neoantigens, RCC is highly immunogenic. Thus, immunotherapies beginning with interleukins and interferon and now immune checkpoint inhibitors are efficacious in RCC.

Unfortunately, none of these insights have to lead to validated diagnostic, prognostic, or predictive biomarkers to date.

Pathology

Renal cell carcinoma tends to form relatively spherical tumors with a surrounding pseudo capsule of compressed adjacent parenchyma and fibrosis. With rare exceptions (collecting duct carcinoma and sarcomatoid variants), RCC tends to be relatively well circumscribed without gross infiltrative features. This allows for local treatment, radiographically-guided approaches such as partial nephrectomy and tumor ablation (see linked article on non-surgical focal therapy of renal tumors). Grading of RCC is undertaken using Fuhrman’s system. While this approach was developed for ccRCC,² more recent evidence suggests that it is prognostic in papillary RCC as well.³ Fuhrman’s grading system relies on the size and shape of the nucleus and the presence or absence of nucleoli.

A relatively unique pathological characteristic of RCC is its propensity for the involvement of the venous system. This occurs in nearly 10% of all RCCs, at least in historical series, which is much higher than other tumor types.⁴

Histologic subgroups

A number of histological subtypes have been recognized including conventional clear cell RCC (ccRCC), papillary RCC, chromophobe RCC, collecting duct carcinoma, renal medullary carcinoma, unclassified RCC, RCC associated with Xp11.² translocations/TFE3 gene fusions, post-neuroblastoma RCC, and mucinous tubular and spindle cell carcinoma. Conventional ccRCC comprises approximately 70-80% of all RCCs while papillary RCC comprises 10-15%, chromophobe 3-5%, collecting duct carcinoma <1%, unclassified RCC 1-3%, and the remainder are very uncommon.

Clear cell RCC is formerly described as “conventional” RCC. These tumors, as mentioned prior, are highly vascular and thus tend to respond well to vascular-targeted agents when systemic therapy is indicated. In general, ccRCC is more aggressive than papillary RCC or chromophobe RCC, even after accounting for stage and grade.⁵

Papillary RCC, formerly known as “chromophilic” RCC, may be subdivided into type 1 and type 2. Type 1 papillary RCC histologically is characterized by basophilic cells with low-grade nuclei. In contrast, type 2 papillary RCC has eosinophilic cells with high-grade nuclei. Correspondingly, type 1 papillary RCC is less aggressive and portends a more favourable prognosis than type 2 papillary RCC. Papillary RCC exhibits a predilection for multifocality.

Chromophobe RCC is histologically characterized by a perinuclear halo. While chromophobe RCC typically have a good prognosis, those with sarcomatoid features are associated with a poor outcome.⁶

Collecting duct carcinoma and renal medullary carcinoma are relatively rare variants of RCC which exhibit aggressive behaviour and have poor to dismal prognosis. Renal medullary carcinoma is notably found in patients with sickle cell trait.

Finally, rather than its prior classification as a distinct subtype, sarcomatoid differentiation is now noted as a feature accompanying an underlying histologic characterization.

Clinical presentation of RCC

Historically, RCC was diagnosed on the basis of a classic triad of flank pain, gross hematuria, and a palpable flank mass. However, nowadays most RCCs are diagnosed incidentally during abdominal imaging for a variety of nonspecific abdominal complaints.⁷ Symptoms may arise due to local tumor growth, hemorrhage, paraneoplastic syndromes, or metastatic disease.

While paraneoplastic syndromes are relatively uncommon in other tumors, these occur in 10-20% of patients with RCC. A wide variety of clinical manifestations due to endocrinologically-active compounds may occur including hypertension, electrolyte dysregulation, and cytokine-driven effects such as weight loss, fever, and anemia.

Screening for RCC

Due in large part to the relatively low incidence of RCC, widespread screening is not advocated.

However, certain populations at a much higher risk of RCC warrant screening. This including patients with end-stage renal disease and acquired renal cystic disease, those with tuberous sclerosis, and those with familial RCC syndromes. Patients with end-stage renal disease are generally recommended to undergo RCC screening upon reaching their third year on dialysis assuming that they do not have other major comorbidities which would be life-limiting.

Staging of RCC

Robson’s staging system was widely used until the 1990s. However, there are numerous limitations including the amalgamation of tumors with lymph node metastases and those with venous involvement as stage III and the omission of tumor size. Thus, the TNM (tumor, node, metastasis) system is now widely used.

Notably, the involvement of the ipsilateral adrenal gland may be classified at T4 if contiguous or M1 if metastatic. Historically, lymph node involvement had been sub-stratified. However, this did not show the prognostic value. Thus, a single present/absent classification is now used.

As may be implied from the characteristics used in the staging schema, clinical staging involves a thorough history, physical examination, radiographic investigation and laboratory investigations (including liver function tests). Contrast-enhanced abdominal computed tomography and chest radiograph are considered standard imaging approaches.⁸ MRI may be indicated in patients with locally advanced disease, those with unclear venous involvement, and those for whom CT is contraindicated.⁸ For patients with suspected inferior vena cava involvement, MRI or multiplanar CT are reasonable imaging approaches.⁸ Doppler ultrasonography is an alternative. Venacavography is rarely utilized today. In patients with suspected metastatic disease, bone scintigraphy is indicated among those with elevated serum alkaline phosphate, bony pain, or poor performance status.⁹ Similarly, CT chest is indicated in patients with pulmonary symptoms or an abnormal chest radiograph.

A number of prognostic factors have been described for patients with RCC:¹⁰

Clinical characteristics:
1. Performance status
2. Systemic symptoms
3. Symptomatic (vs. incidental) presentation
4. Anemia
5. Thrombocytosis
6. Hypercalcemia
7. Elevated lactate dehydrogenase
8. Elevated erythrocyte sedimentation rate
9. Elevated C-reactive protein
10. Elevated alkaline phosphatase
Tumor anatomic characteristics:
1. Tumor size
2. Venous extension
3. Contiguous invasion of adjacent organs (i.e. T4 stage)
4. Adrenal involvement (i.e. T4 or M1 stage)
5. Lymph node metastasis (i.e. N1 stage)
6. Presence and burden of metastatic disease (i.e. M1 stage)
Tumor histologic characteristics:
1. Histologic subtype
2. Presence of sarcomatoid differentiation
3. Nuclear grade
4. Presence of histologic necrosis
5. Vascular invasion
6. Invasion of perinephric or sinus fat
7. Invasion of collecting system
8. (post-operative) surgical margin status

Pathologic stage is the single most important prognostic factor in RCC.¹⁰ Interestingly, tumor size has additional independent prognostic value, beyond that which is conveyed in the tumor stage.¹¹ Among patients with IVC thrombus, direct invasion into the caval wall appears to portend a worse prognosis.¹²

To date, no biomarkers have been adopted in clinical practice for prognostic or predictive purposes. However, a number of nomograms relying on clinical data have been proposed for risk prediction. They may be useful in predicting tumor histology, recurrence rates, and survival.

Treatment of RCC (localized)

There are a number of accepted treatment options for patients diagnosed with localized RCC. These include radical nephrectomy (whether open, laparoscopic or robotic), partial nephrectomy (whether open, laparoscopic, or robotic), surgical or non-surgical ablation, and active surveillance. The most appropriate treatment strategy will depend on the patient (host) and tumor characteristics.

The ability to distinguish between benign and malignant renal masses is relatively limited on the basis of clinical characteristics. The renal mass biopsy may, therefore, be indicated where the results of this test would modify treatment choices.

Radical nephrectomy was historically the treatment of choice for localized RCC. Partial nephrectomy was initially indicated for patients with imperative indications. However, today, partial nephrectomy is the standard of care for small renal masses. Radical nephrectomy remains indicated for patients with larger tumors and those where partial nephrectomy is not feasible (for example, a tumor in a very central location).¹³ The primary concern regarding radical nephrectomy is the loss of nephron mass and the corresponding risk of surgically induced chronic kidney disease (CKD). Such CKD may predispose to cardiovascular events and premature mortality. However, the only randomized controlled trial to compare radical and partial nephrectomy (EORTC 30904) demonstrated improved overall survival among patients undergoing radical nephrectomy and decreased rates of cardiovascular events.¹⁴ These results have proven controversial and have not dissuaded enthusiasm for partial nephrectomy.

A more fulsome discussion regarding nonsurgical renal mass ablation may be found entitled “Focal therapy for renal tumors.”

Finally, active surveillance has gained acceptance. This approach was first employed among asymptomatic elderly patients who were poor surgical candidates with small, incidentally detected RCCs.¹⁵ Subsequent follow-up has demonstrated that small renal masses grow quite slowly (0.1-0.3cm/year). AUA guidelines recommend serial abdominal imaging to both ascertain the growth and monitor for progression.¹⁶ Biopsy may be considered in order to inform surveillance strategies. For patients found to have biopsy-proven RCC, a chest radiograph may be added to the annual surveillance testing.

The American Urological Association offers a helpful algorithm to guide treatment decision making in patients with small renal masses

Published Date: April 16th, 2019

References:

Siegel RL, Miller KD, Jemal A. Cancer statistics, 2018. CA: a cancer journal for clinicians 2018;68:7-30.
Fuhrman SA, Lasky LC, Limas C. Prognostic significance of morphologic parameters in renal cell carcinoma. Am J Surg Pathol 1982;6:655-63.
Sukov WR, Lohse CM, Leibovich BC, Thompson RH, Cheville JC. Clinical and pathological features associated with prognosis in patients with papillary renal cell carcinoma. The Journal of urology 2012;187:54-9.
Skinner DG, Pfister RF, Colvin R. Extension of renal cell carcinoma into the vena cava: the rationale for aggressive surgical management. The Journal of urology 1972;107:711-6.
Deng FM, Melamed J. Histologic variants of renal cell carcinoma: does tumor type influence outcome? The Urologic clinics of North America 2012;39:119-32.
Klatte T, Han KR, Said JW, et al. Pathobiology and prognosis of chromophobe renal cell carcinoma. Urologic oncology 2008;26:604-9.
Almassi N, Gill BC, Rini B, Fareed K. Management of the small renal mass. Transl Androl Urol 2017;6:923-30.
Ng CS, Wood CG, Silverman PM, Tannir NM, Tamboli P, Sandler CM. Renal cell carcinoma: diagnosis, staging, and surveillance. AJR Am J Roentgenol 2008;191:1220-32.
Shvarts O, Lam JS, Kim HL, Han KR, Figlin R, Belldegrun A. Eastern Cooperative Oncology Group performance status predicts bone metastasis in patients presenting with renal cell carcinoma: implication for preoperative bone scans. The Journal of urology 2004;172:867-70.
Lane BR, Kattan MW. Prognostic models and algorithms in renal cell carcinoma. The Urologic clinics of North America 2008;35:613-25; vii.
Kattan MW, Reuter V, Motzer RJ, Katz J, Russo P. A postoperative prognostic nomogram for renal cell carcinoma. The Journal of urology 2001;166:63-7.
Zini L, Destrieux-Garnier L, Leroy X, et al. Renal vein ostium wall invasion of renal cell carcinoma with an inferior vena cava tumor thrombus: prediction by renal and vena caval vein diameters and prognostic significance. The Journal of urology 2008;179:450-4; discussion 4.
Nguyen CT, Campbell SC, Novick AC. Choice of operation for clinically localized renal tumor. The Urologic clinics of North America 2008;35:645-55; vii.
Van Poppel H, Da Pozzo L, Albrecht W, et al. A prospective, randomised EORTC intergroup phase 3 study comparing the oncologic outcome of elective nephron-sparing surgery and radical nephrectomy for low-stage renal cell carcinoma. European urology 2011;59:543-52.
Abouassaly R, Lane BR, Novick AC. Active surveillance of renal masses in elderly patients. The Journal of urology 2008;180:505-8; discussion 8-9.
Donat SM, Diaz M, Bishoff JT, et al. Follow-up for Clinically Localized Renal Neoplasms: AUA Guideline. The Journal of urology 2013;190:407-16.

Epidemiology and Etiology of Bladder Cancer

Epidemiology

Bladder cancer is the most common malignancy of the urinary tract and second only to the prostate in the entire genitourinary system. The most updated available global estimate, based on registry data collected through the year 2012, found approximately 430,000 new diagnoses worldwide, making it the 9th most common malignancy overall (6th in men and 17th in women) while being the 13th leading cause of cancer mortality (Figure 1).¹ A more recent estimate available for the United States population based on Surveillance, Epidemiology, and End Results (SEER) data estimates the annual incidence will be 81,000 for the year 2018 corresponding to the 4th and 11th most common cancer among men and women, respectively.² In the decade between 2006 and 2015 the annual incidence of bladder cancer per 100,000 persons has declined by 1.3% annually, however, the mortality rate has remained nearly unchanged.³ By comparison, the mortality rates of the other top malignancies, lung, colon, and prostate, have declined by 2.6%, 2.4%, and 2.9% over the same period of time, respectively.

figure-1b-epidemiology-bladder-cancer@2x.jpg

Figure 1. Age-standardized rates (ASR) of incidence (gold) and mortality (blue) from the World Health Organization International Agency for Research on Cancer GLOBOCAN 2012 dataset. (A) Worldwide ASR for the top 20 cancers, divided by sex. Bladder cancer incidence is the 6th most common among men and 17th among women. (B) Bladder cancer ASR incidence and mortality by WHO reporting region. More developed regions have 2-3 times higher incidence than less developed regions.

The gender disparity in bladder cancer risk is readily evident considering men represent slightly more than 75% of new diagnoses each year.2 Perhaps the most obvious explanation for this difference is the inequality in exposure to bladder carcinogens, namely tobacco smoke. This topic has undergone close examination but higher rates of smoking and tobacco use among males fails to entirely account for the increased bladder cancer risk.4,5 Sex hormones may play a key role in the development and progression of bladder cancer, with increased androgen receptor expression noted in lower stage/grade tumors while higher stage disease is associated with increased expression of the estrogen receptor β isoform (Figure 2).^6-9 This may point to an explanation for the poorer stage-adjusted cancer-specific mortality in women compared to men (HR 1.17-4.47) in spite of a male to female incidence ratio of 4 to 1.^10-14

figure-2-epidemiology-bladder-cancer@2x.jpg

Internationally, gender differences in bladder cancer mirrors the trends seen in the US population but incidences vary widely from region to region. For instance, the lowest age-standardized rates (ASR) in men are seen in Africa (Uganda ASR = 2.6 per 100,000) while the highest are found in North America (ASR = 19.5 per 100,000) and Europe (ASR = 17.7 per 100,000), including Spain with its ASR of 36.7 per 100,000 men.¹ In an analysis of the WHO cancer databases, Antoni et al. made several notable observations regarding worldwide bladder cancer incidence and mortality.¹⁵ The ASR of more developed regions is approximately 3-times higher than the developing world and is likely explained by the high prevalence of cigarette smoking among the former population during the preceding three to four decades. Case-in-point, nearly 2 in 3 Spanish adult males actively smoked in the late 1970s, and while smoking rates have certainly declined among the developed world, it will take many more years to see the attendant decline in the disease burden of bladder cancer.15-17 Egypt – and the Northern African region as a whole – are worth highlighting given the abnormally high incidence when compared to the continent overall (ASR = 19.0, 15.1, and 6.3 per 100,000, respectively).¹⁵ Endemic parasitic infection with Schistoma haematobium has traditionally been associated with the increased prevalence of disease among the Egyptian population, especially squamous cell carcinoma (SCC) which accounted for up to 81% of all bladder cancers diagnosed before the turn of the century.¹⁸ More recently, bilharzial infection rates have fallen and SCC now accounts for less than 30% of bladder cancer pathology, but the overall incidence is holding steady due to smoking rates among the male population that has increased to over 50%.^18,19

Racial disparity among the US population is skewed towards a 2-fold higher incidence of bladder cancer among Caucasian men, however, tumor stage and grade are higher at the presentation in African American men.²⁰ Several researchers have noted worse disease-specific outcomes for African Americans and hypothesize that this is probably due to socioeconomic factors and poor access to healthcare, but a recent evaluation of a Florida cancer registry actually found significantly better overall survival among blacks (HR=0.35, p=0.045) when controlling for patient and disease factors.^21-25

Etiology

Risk Factors

The urothelium is exposed to the outside environment, not unlike the skin or the lung epithelium, making it susceptible to damage from environmental toxins. Once filtered by the kidney and concentrated in the urine, these toxins remain in continuous contact with the urothelium of the bladder until expelled during urination. The result is DNA damage caused by several carcinogenic compounds (aromatic amines, polycyclic aromatic hydrocarbons, etc.) which leads to accumulation of oncogenic mutations over the course of decades and explains why bladder cancer carries one of the highest mutational burdens of all cancers.^26,27

The most strongly attributable risk factor for bladder cancer is cigarette smoking, which causes approximate 50% of cases annually across both sexes.28 Since the overall rate of smoking in the US has dropped in the past several decades, one would expect to see a commensurate decline in the incidence of bladder cancer, but this has not been the case. Instead, it appears that the strength of association between bladder cancer and smoking has increased, likely due to the enrichment of carcinogenic agents found in cigarette tobacco over time – specifically nitrates, which become metabolized into carcinogenic N-nitrosamines.^28,29

E-cigarettes are a popular “safe” alternative to cigarette smoking, but the vaporized liquid, comprised of nicotine and flavoring, contains several carcinogenic compounds found in tobacco smoke, such as polycyclic aromatic hydrocarbons, phenols, nitrosamines, and aldehydes, among others.³⁰ It is too early to make a causal link between e-cigarettes and bladder cancer, however, studies have discovered, while less than cigarette smokers, levels of carcinogenic metabolites in the urine of e-cigarette smokers are significantly higher than non-smoking controls.^31,32 Furthermore, pre-clinical work with mouse models demonstrated DNA damage induced by nitrosamines from e-cigarettes in the murine lungs, heart, and bladder.³³

Other environmental toxins, aside from tobacco smoke, that are known to cause bladder cancer are often found in industrial settings where workers are subjected to repeated daily exposure. In a contemporary analysis of bladder cancer risk from occupational exposures, workers in tobacco, dye, rubber, printing, leather, and hairdressing industries as well as chimney sweeps, firefighters, aluminum workers, and oil workers were at highest risk for bladder cancer secondary to environmental presence of aromatic amines and polycyclic aromatic hydrocarbons (Table).^26,34-37 The inorganic form of arsenic found both naturally and as a contaminant in the environment, has been strongly linked to urothelial malignancy, especially when the concentration in drinking water is over 150-300 µg/L.^38,39

Innumerable dietary risk factors have been associated with cancer risk in general and even a few with particular emphasis on bladder cancer.⁴⁰ Meat consumption at the population level appears to be positively correlated with bladder cancer risk for both red meat and processed meats, but the quality of evidence is generally poor.^41,42 Likewise, artificial sweeteners are a frequent suspect for dietary carcinogenesis while lacking any clear link to cancer of the urinary tract, only conflicting results from case-control studies.^43-45

The most commonly cited hereditary links to bladder cancer are not tumor suppressor or proto-oncogene mutations, but rather related to the manner in which an individual metabolizes the carcinogens from the environment, especially in the form of cigarette smoke. Two isoforms of the N-acetyltransferase enzyme (NAT1 and NAT2) that are responsible for inactivating the carcinogenic aromatic and heterocyclic amine compounds can be associated with an increased risk of developing bladder cancer when certain germline polymorphisms are present that correlate with “slow” enzyme activity.^46,47 Enzymes in the glutathione S-transferase (GST) family also carry a detoxifying function, and bladder cancer risk is increased in the GSTM1-null genotype, however, the effect in this population is more pronounced among never smokers over former or current smokers through an as of yet unknown mechanism.^48,49

Chronic inflammation contributes to bladder cancer formation through a process by which immune cells (neutrophils, monocytes, and macrophages) generate reactive oxygen species that induce DNA damage as well as stimulate cellular proliferation through cell-signaling pathways. ⁵⁰ Urinary tract infections and urothelial irritants, such as calculi and indwelling catheters, are associated with increased risk of bladder cancer overall, as well as an increased proportion of squamous cell carcinoma.^51,52 This is particularly evident among spinal cord injury patients and populations with endemic Schistosomiasis, and though the exact mechanism is unknown, urothelial to squamous metaplasia appears to precede the development of invasive carcinoma in these patients.^50,53

Iatrogenic causes of bladder cancer include systemic agents (i.e. chemotherapy) and pelvic irradiation for other malignancies. The popular class of anti-diabetic medications known as thiazolidinediones (TZD), which includes the specific drugs pioglitazone and rosiglitazone, have been implicated in urothelial carcinoma carcinogenesis via activation of the peroxisome proliferator-activated receptors gamma (PPARγ). Large cohort studies have reported conflicting results regarding an increased incidence of bladder cancer that increases with duration of TZD therapy, especially pioglitazone, prompting the FDA to include a warning label regarding the increased risk and recommend ongoing re-evaluation of the data.^54-58 Bladder cancer risk is also associated with systemic cyclophosphamide chemotherapy, due to either direct effect of toxic metabolites in the urine (acrolein and phosphoramide) or severe urothelial inflammation.^59,60 Radiotherapy of the pelvis may lead to at least 30% increased risk, though this effect is seen only with the external beam but not brachytherapy.⁶¹

Prevention

Given the role of inflammation in carcinogenesis, it makes sense that inhibiting enzymes within the pro-inflammatory pathways (i.e. cyclooxygenase-2 [COX-2] or 3-hydroxy-3-mehylglutaryl-coenzyme A [HMGCoA] reductase) might be useful for disease prevention. Laboratory models of nonsteroidal anti-inflammatories (NSAIDs) have demonstrated promising results related to bladder cancer prevention, however, a randomized controlled trial of the COX-2 inhibitor celecoxib failed significantly reduce NMIBC recurrences in humans.^62-64 Likewise, results from case-control studies suggest that HMGCoA reductase inhibitors do not offer a significant benefit.^65,66

Smoking cessation, on the other hand, can help to erase some of the tobacco-associated bladder cancer risks, especially when the user quits prior to disease onset. The risk of developing bladder cancer in former smokers decreases with time since quitting but they still maintain a higher risk when compared to never smokers, though, this is approximately 50% less than that of current smokers.^37,67-69 Smoking status remains important even after bladder cancer has developed, as former smokers who quit at least 1 year prior to bladder cancer diagnosis appear to have a lower recurrence risk when compared to more recent former smokers and current smokers, but some studies have only found a difference for patients who quit more than 10 years before.^70,71

Cannabis may possess antineoplastic properties based on inhibition of tumor growth and pro-apoptotic effects seen in the laboratory, but supporting clinical data is currently lacking.^72-74 A slightly higher incidence of bladder cancer was noted in non-smokers (neither tobacco nor cannabis) when compared to cannabis users (0.4% v. 0.3%, respectively) in one large cohort study, translating into a relative risk of 0.55 (p=0.048) on multivariate analysis, though only age, race, and BMI were used as co-variables.⁷⁵ Conversely, a much smaller case-control study of Vietnam-era veterans found increased rates of habitual marijuana use among bladder cancer patients (88.5%) when compared to matched controls (69.2%), though tobacco use was equal among both groups.⁷⁶

Proposed dietary factors offering a protective effect include increased fluid intake, fruits, vegetables, vitamin supplements (A, C, & D), selenium, and other antioxidants.⁶⁷ Randomized controlled trials are lacking in this arena and systematic reviews of retrospective, case-control studies have yielded mixed results, so no definitive conclusions can be drawn at this time.^40,77,78

Summary/Conclusions:

Bladder cancer is a leading malignancy worldwide but incidence is disproportionately higher among more developed nations, including the US.
The most important recognized risk factor is cigarette smoking, but despite declining rates of smoking, bladder cancer incidence has declined only slightly, owing to the long lead time and potentially increased carcinogenicity of modern tobacco products.
Men continue to have a 3-4 fold higher lifetime risk even though the gender gap for smoking has narrowed significantly, raising the possibility of a hormonal influence
Other environmental risks are largely related to occupational exposures to carcinogenic compounds (i.e. aromatic amines).
Lifestyle factors and chemoprevention may be able to reduce bladder cancer risk but currently available literature is inconclusive
Smoking cessation substantially lowers lifetime risk, though not reaching the same level as a never smoker.

Published Date: April 16th, 2019

Written by: Justin T. Matulay, MD, and Ashish Kamat, MD, MBBS

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Rota M, Bosetti C, Boccia S, Boffetta P, La Vecchia C. Occupational exposures to polycyclic aromatic hydrocarbons and respiratory and urinary tract cancers: an updated systematic review and a meta-analysis to 2014. Arch Toxicol. 2014;88(8):1479-1490.
Zeegers MP, Tan FE, Dorant E, van Den Brandt PA. The impact of characteristics of cigarette smoking on urinary tract cancer risk: a meta-analysis of epidemiologic studies. Cancer. 2000;89(3):630-639.
Meliker JR, Nriagu JO. Arsenic in drinking water and bladder cancer: review of epidemiological evidence. Trace Metals Other. 2007;9:551-584.
Saint-Jacques N, Parker L, Brown P, Dummer TJ. Arsenic in drinking water and urinary tract cancers: a systematic review of 30 years of epidemiological evidence. Environ Health. 2014;13:44.
Al-Zalabani AH, Stewart KF, Wesselius A, Schols AM, Zeegers MP. Modifiable risk factors for the prevention of bladder cancer: a systematic review of meta-analyses. Eur J Epidemiol. 2016;31(9):811-851.
Crippa A, Larsson SC, Discacciati A, Wolk A, Orsini N. Red and processed meat consumption and risk of bladder cancer: a dose-response meta-analysis of epidemiological studies. Eur J Nutr. 2018;57(2):689-701.
Li F, An S, Hou L, Chen P, Lei C, Tan W. Red and processed meat intake and risk of bladder cancer: a meta-analysis. Int J Clin Exp Med. 2014;7(8):2100-2110.
Andreatta MM, Munoz SE, Lantieri MJ, Eynard AR, Navarro A. Artificial sweetener consumption and urinary tract tumors in Cordoba, Argentina. Prev Med. 2008;47(1):136-139.
Moller-Jensen O, Knudsen JB, Sorensen BL, Clemmesen J. Artificial sweeteners and absence of bladder cancer risk in Copenhagen. Int J Cancer. 1983;32(5):577-582.
Morrison AS, Buring JE. Artificial sweeteners and cancer of the lower urinary tract. N Engl J Med. 1980;302(10):537-541.
Garcia-Closas M, Malats N, Silverman D, et al. NAT2 slow acetylation, GSTM1 null genotype, and risk of bladder cancer: results from the Spanish Bladder Cancer Study and meta-analyses. Lancet. 2005;366(9486):649-659.
Moore LE, Baris DR, Figueroa JD, et al. GSTM1 null and NAT2 slow acetylation genotypes, smoking intensity and bladder cancer risk: results from the New England bladder cancer study and NAT2 meta-analysis. Carcinogenesis. 2011;32(2):182-189.
Gu J, Wu X. Genetic susceptibility to bladder cancer risk and outcome. Per Med. 2011;8(3):365-374.
Rothman N, Garcia-Closas M, Chatterjee N, et al. A multi-stage genome-wide association study of bladder cancer identifies multiple susceptibility loci. Nat Genet. 2010;42(11):978-984.
Michaud DS. Chronic inflammation and bladder cancer. Urol Oncol. 2007;25(3):260-268.
Vermeulen SH, Hanum N, Grotenhuis AJ, et al. Recurrent urinary tract infection and risk of bladder cancer in the Nijmegen bladder cancer study. Br J Cancer. 2015;112(3):594-600.
Clouston D, Lawrentschuk N. Metaplastic conditions of the bladder. BJU Int. 2013;112 Suppl 2:27-31.
Mostafa MH, Sheweita SA, O'Connor PJ. Relationship between schistosomiasis and bladder cancer. Clin Microbiol Rev. 1999;12(1):97-111.
Lewis JD, Habel LA, Quesenberry CP, et al. Pioglitazone Use and Risk of Bladder Cancer and Other Common Cancers in Persons With Diabetes. JAMA. 2015;314(3):265-277.
Tuccori M, Filion KB, Yin H, Yu OH, Platt RW, Azoulay L. Pioglitazone use and risk of bladder cancer: population based cohort study. BMJ. 2016;352:i1541.
Tang H, Shi W, Fu S, et al. Pioglitazone and bladder cancer risk: a systematic review and meta-analysis. Cancer Med. 2018;7(4):1070-1080.
Dormandy JA, Charbonnel B, Eckland DJ, et al. Secondary prevention of macrovascular events in patients with type 2 diabetes in the PROactive Study (PROspective pioglitAzone Clinical Trial In macroVascular Events): a randomised controlled trial. Lancet. 2005;366(9493):1279-1289.
Erdmann E, Harding S, Lam H, Perez A. Ten-year observational follow-up of PROactive: a randomized cardiovascular outcomes trial evaluating pioglitazone in type 2 diabetes. Diabetes Obes Metab. 2016;18(3):266-273.
Talar-Williams C, Hijazi YM, Walther MM, et al. Cyclophosphamide-induced cystitis and bladder cancer in patients with Wegener granulomatosis. Ann Intern Med. 1996;124(5):477-484.
Travis LB, Curtis RE, Glimelius B, et al. Bladder and kidney cancer following cyclophosphamide therapy for non-Hodgkin's lymphoma. J Natl Cancer Inst. 1995;87(7):524-530.
Wallis CJ, Mahar AL, Choo R, et al. Second malignancies after radiotherapy for prostate cancer: systematic review and meta-analysis. BMJ. 2016;352:i851.
Elwood PC, Gallagher AM, Duthie GG, Mur LA, Morgan G. Aspirin, salicylates, and cancer. Lancet. 2009;373(9671):1301-1309.
Nicastro HL, Grubbs CJ, Margaret Juliana M, et al. Preventive effects of NSAIDs, NO-NSAIDs, and NSAIDs plus difluoromethylornithine in a chemically induced urinary bladder cancer model. Cancer Prev Res (Phila). 2014;7(2):246-254.
Sabichi AL, Lee JJ, Grossman HB, et al. A randomized controlled trial of celecoxib to prevent recurrence of nonmuscle-invasive bladder cancer. Cancer Prev Res (Phila). 2011;4(10):1580-1589.
Cholesterol Treatment Trialists C, Emberson JR, Kearney PM, et al. Lack of effect of lowering LDL cholesterol on cancer: meta-analysis of individual data from 175,000 people in 27 randomised trials of statin therapy. PLoS One. 2012;7(1):e29849.
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Baris D, Karagas MR, Verrill C, et al. A case-control study of smoking and bladder cancer risk: emergent patterns over time. J Natl Cancer Inst. 2009;101(22):1553-1561.
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Orellana-Serradell O, Poblete CE, Sanchez C, et al. Proapoptotic effect of endocannabinoids in prostate cancer cells. Oncol Rep. 2015;33(4):1599-1608.
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Liu H, Wang XC, Hu GH, et al. Fruit and vegetable consumption and risk of bladder cancer: an updated meta-analysis of observational studies. Eur J Cancer Prev. 2015;24(6):508-516.
78. Xu C, Zeng XT, Liu TZ, et al. Fruits and vegetables intake and risk of bladder cancer: a PRISMA-compliant systematic review and dose-response meta-analysis of prospective cohort studies. Medicine (Baltimore). 2015;94(17):e759.

The Current Status of Cytoreductive Nephrectomy

Kidney cancer is the 6th most common malignancy among men and 10th most among women.¹ Renal cell carcinoma (RCC) accounts for the vast majority of these tumors. Further details regarding the epidemiology of kidney cancer have been discussed in, "Epidemiology and Etiology of Kidney Cancer." While 20-30% of patients undergoing nephrectomy will develop metastases during follow-up,² a significant proportion (historically up to 25-30%) of patients with renal cell carcinoma present with metastases at the time of diagnosis.³ More recent estimates suggest that, with stage migration due to an increasing incidental diagnosis of kidney cancer, approximately 15% of patients newly diagnosed with kidney cancer have metastases at the time of diagnosis.¹ Historically, patients treated with cytokine-based systemic therapy had a median overall survival of 10 months.³ Therefore, options to improve outcomes for these patients were sought.

The History of Cytoreductive Nephrectomy

The notion of cytoreductive nephrectomy (CN), removal of the kidney and primary tumor in the face of metastatic disease, was based on a series of observations. First, patients treated with the primary tumor in-situ who underwent treatment with interferon fared particularly poorly.^2,4 Second, case reports demonstrated that a small number of patients treated with CN experienced regression of their metastatic disease.^5,6

As a result, two randomized controlled trials were undertaken to assess the value of CN in the era of cytokine-based therapy. In these two methodologically similar randomized controlled trials, Flanigan et al. and Mickish et al. randomized patients to CN plus interferon vs interferon alone.⁷ Reported in 2001, among 241 American patients, Flanigan et al. demonstrated a 3-month survival benefit⁸ whereas, among 83 European participants, Mickish et al. demonstrated a 10-month survival benefit.⁹ Subsequent pooled analyses showed a strongly statistically significant benefit with overall survival of 13.6 months among patients receiving CN plus interferon and 7.8 months among those receiving interferon alone (difference = 5.8 months, p=0.002).⁷ On the basis of these data, CN became part of the treatment paradigm for metastatic RCC.

It bears mention that despite the proven survival benefits, the mechanism of CN is unclear. Notably, the response to systemic therapy did not differ in the two pivotal RCTs.⁷ thus, CN does not potentiate the response to (cytokine-based) systemic therapy. Postulated mechanisms include removal of the “immunologic sink”,^4,10 decreased production of cytokines and growth factors by the primary tumor,^11-13 delayed metastatic progression,¹⁴ and survival benefit from nephrectomy induced azotemia.¹⁵

However, shortly after the publication of the randomized data demonstrating the survival benefit to adding cytoreductive nephrectomy to cytokine-based systemic therapy, the introduction of targeted therapies revolutionized the systemic therapy of metastatic RCC. From the aforementioned 10-month median overall survival in the cytokine-era,³ median overall survival for patients receiving a sequential regime of targeted therapies may exceed 40 months.¹⁶ Much more detail regarding systemic therapy in advanced RCC is available in the article, "Systemic Therapy for Advanced Renal Cell Carcinoma."

Cytoreductive Nephrectomy in the Targeted Therapy Era

A number of retrospective studies have examined the role of cytoreductive nephrectomy in the context of targeted therapy. Summarized by Bhindi et al. in a recent systematic review,¹⁷ these 10 retrospective studies consistently demonstrated a significant survival benefit to cytoreduction. However, the potential for selection bias is significant among these studies, particularly among studies in which it was not possible to quantify the burden of metastatic disease.

The CARMENA trial (Cancer du Rein Metastatique Nephrectomie et Antiangiogéniques or, alternatively, Clinical Trial to Assess the Importance of Nephrectomy) provides the only available randomized data on the role of cytoreductive nephrectomy in the targeted therapy era.¹⁸ This study has been extensively reported on by UroToday authors including “ASCO 2018: Sunitinib Alone Shows Non-inferiority Versus Standard of Care in mRCC - The CARMENA Study," “ASCO 2018: CARMENA: Cytoreductive Nephrectomy Followed by Sunitinib vs. Sunitinib Alone in Metastatic Renal Cell Carcinoma - Results of a Phase III Noninferiority Trial," and “Nephrectomy in the Era of Targeted Therapy: Takeaways from the CARMENA Trial."

To briefly summarize, CARMENA randomized 450 patients with intermediate or poor-risk confirmed clear cell renal cell carcinoma in a 1:1 fashion to nephrectomy followed by sunitinib or sunitinib alone.¹⁸ To be eligible for enrollment in CARMENA, patients had to be naïve to systemic therapy, eligible for treatment with sunitinib and deemed amenable for cytoreductive nephrectomy by their treating surgeon. Using the Memorial Sloan Kettering Cancer Center (MSKCC) risk stratification, these patients had intermediate- or poor-risk disease. Additionally, patients had to have an ECOG performance score of 0 or 1 and no evidence of brain metastasis or have undergone prior local therapy for brain metastasis without evidence of progression for at least 6 weeks. After a median follow-up of 51 months, the median overall survival for patients receiving systemic therapy alone was 18.4 months and was 13.9 months for those patients undergoing cytoreductive nephrectomy followed by sunitinib. The resulting Cox models demonstrated non-inferiority with a hazard ratio of 0.89 (95% CH 0.71 to 1.10) based on an intention to treat analysis. In a per-protocol analysis, the resultant analysis showed comparable results (HR 0.98, 95% CI 0.77 to 1.25). However, in this case, the upper limit of the 95% confidence interval crossed the investigator's pre-specified non-inferiority threshold of 1.20.

A number of nuances regarding CARMENA bear consideration. First, the investigators required eight years at 79 sites to accrue 450 of an initially planned 576 patients. Thus, each institution enrolled fewer than a single patient each year – suggesting either that many potentially eligible patients may not have been enrolled due to either their clinician’s lack of equipoise (and thus unwillingness to leave treatment allocation to chance) or the patients’ own unwillingness to be randomized. The resulting cohort, while having a good performance status (ECOG 0 or 1) and deemed fit for cytoreductive nephrectomy, the enrolled patients had a significantly higher burden of disease that may be expected from population-based American cohorts.¹⁹ Second, there was significant cross-over within the study, with a large proportion of patients assigned to sunitinib alone eventually undergoing palliative nephrectomy for symptomatic control. Potentially more concerning, given the proven survival benefit of targeted therapy, are the patients who were not able to receive sunitinib following cytoreductive nephrectomy.

To further address the question of the timing of cytoreductive nephrectomy, the SURTIME trial (Immediate Surgery or Surgery after Sunitinib Malate In Treating Patients with Kidney Cancer (NCT01099423) randomized 99 patients to immediate CN followed by sunitinib, beginning 4 weeks after surgery and continuing for four courses, or three 6-week courses of sunitinib (in the absence of disease progression or unacceptable toxicity) followed by CN followed by 2 courses of adjuvant sunitinib. While significantly underpowered due to poor accrual, the trial reported a 28-week progression-free rate of 42% in the immediate CN arm and 43% in the deferred CN arm (p=0.6).²⁰ Interestingly, intention-to-treat analysis of the secondary outcome of overall survival demonstrated significantly longer survival among patients in the delayed CN arm (median 32.4 months) compared to the immediate CN arm (median 15.1 months) (HR 0.57, 95% CI 0.34 to 0.95).

Since these trials were designed and accrued, a number of additional systemic therapy agents have been approved for first-line therapy in metastatic RCC. Many of these agents have demonstrated superiority to sunitinib.²¹ While improved overall survival increases the time for patients to develop local symptoms which may warrant surgery, improved systemic therapy is likely to reduce the value of local treatments. Notably, the efficacy of nivolumab and ipilimumab did not differ on the basis of whether the patient had previously undergoing nephrectomy.²²

Taken together, CARMENA and SURTIME suggest that systemic therapy should be prioritized over cytoreductive nephrectomy for patients with metastatic RCC. However, the EAU guidelines, while emphasizing the CN is no longer the standard of care, highlight that CN may be considered for select patients including those with an intermediate-risk disease who have a long-term sustained benefit from systemic therapy and those with a good-risk disease who do not require systemic therapy.²³Published Date: April 16th, 2019

Written by: Christopher J.D. Wallis, MD, PhD and Zachary Klaassen, MD, MSc

References:

Siegel RL, Miller KD, Jemal A. Cancer statistics, 2018. CA: a cancer journal for clinicians. 2018;68(1):7-30.
Ljungberg B, Campbell SC, Choi HY, et al. The epidemiology of renal cell carcinoma. European Urology. 2011;60(4):615-621.
Motzer RJ, Mazumdar M, Bacik J, Berg W, Amsterdam A, Ferrara J. Survival and prognostic stratification of 670 patients with advanced renal cell carcinoma. Journal of clinical oncology : official journal of the American Society of Clinical Oncology. 1999;17(8):2530-2540.
Robertson CN, Linehan WM, Pass HI, et al. Preparative cytoreductive surgery in patients with metastatic renal cell carcinoma treated with adoptive immunotherapy with interleukin-2 or interleukin-2 plus lymphokine activated killer cells. The Journal of urology. 1990;144(3):614-617; discussion 617-618.
Marcus SG, Choyke PL, Reiter R, et al. Regression of metastatic renal cell carcinoma after cytoreductive nephrectomy. The Journal of urology. 1993;150(2 Pt 1):463-466.
Snow RM, Schellhammer PF. Spontaneous regression of metastatic renal cell carcinoma. Urology. 1982;20(2):177-181.
Flanigan RC, Mickisch G, Sylvester R, Tangen C, Van Poppel H, Crawford ED. Cytoreductive nephrectomy in patients with metastatic renal cancer: a combined analysis. The Journal of urology. 2004;171(3):1071-1076.
Flanigan RC, Salmon SE, Blumenstein BA, et al. Nephrectomy followed by interferon alfa-2b compared with interferon alfa-2b alone for metastatic renal-cell cancer. The New England journal of medicine. 2001;345(23):1655-1659.
Mickisch GH, Garin A, van Poppel H, et al. Radical nephrectomy plus interferon-alfa-based immunotherapy compared with interferon alfa alone in metastatic renal-cell carcinoma: a randomised trial. Lancet. 2001;358(9286):966-970.
Spencer WF, Linehan WM, Walther MM, et al. Immunotherapy with interleukin-2 and alpha-interferon in patients with metastatic renal cell cancer with in situ primary cancers: a pilot study. The Journal of urology. 1992;147(1):24-30.
Lahn M, Fisch P, Kohler G, et al. Pro-inflammatory and T cell inhibitory cytokines are secreted at high levels in tumor cell cultures of human renal cell carcinoma. European urology. 1999;35(1):70-80.
Kawata N, Yagasaki H, Yuge H, et al. Histopathologic analysis of angiogenic factors in localized renal cell carcinoma: the influence of neoadjuvant treatment. Int J Urol. 2001;8(6):275-281.
Slaton JW, Inoue K, Perrotte P, et al. Expression levels of genes that regulate metastasis and angiogenesis correlate with advanced pathological stage of renal cell carcinoma. Am J Pathol. 2001;158(2):735-743.
Lara PN, Jr., Tangen CM, Conlon SJ, Flanigan RC, Crawford ED, Southwest Oncology Group Trial S. Predictors of survival of advanced renal cell carcinoma: long-term results from Southwest Oncology Group Trial S8949. The Journal of urology. 2009;181(2):512-516; discussion 516-517.
Gatenby RA, Gawlinski ET, Tangen CM, Flanigan RC, Crawford ED. The possible role of postoperative azotemia in enhanced survival of patients with metastatic renal cancer after cytoreductive nephrectomy. Cancer research. 2002;62(18):5218-5222.
Escudier B, Goupil MG, Massard C, Fizazi K. Sequential therapy in renal cell carcinoma. Cancer. 2009;115(10 Suppl):2321-2326.
Bhindi B, Abel EJ, Albiges L, et al. Systematic Review of the Role of Cytoreductive Nephrectomy in the Targeted Therapy Era and Beyond: An Individualized Approach to Metastatic Renal Cell Carcinoma. European Urology. 2019;75(1):111-128.
Mejean A, Ravaud A, Thezenas S, et al. Sunitinib Alone or after Nephrectomy in Metastatic Renal-Cell Carcinoma. The New England journal of medicine. 2018.
Arora S, Sood A, Dalela D, et al. Cytoreductive Nephrectomy: Assessing the Generalizability of the CARMENA Trial to Real-world National Cancer Data Base Cases. European urology. 2019;75(2):352-353.
Bex A, Mulders P, Jewett M, et al. Comparison of Immediate vs Deferred Cytoreductive Nephrectomy in Patients with Synchronous Metastatic Renal Cell Carcinoma Receiving Sunitinib: The SURTIME Randomized Clinical Trial. JAMA Oncol. 2018.
Wallis CJD, Klaassen Z, Bhindi B, et al. First-line Systemic Therapy for Metastatic Renal Cell Carcinoma: A Systematic Review and Network Meta-analysis. European urology. 2018;74(3):309-321.
Motzer RJ, Tannir NM, McDermott DF, et al. Nivolumab plus Ipilimumab versus Sunitinib in Advanced Renal-Cell Carcinoma. The New England journal of medicine. 2018;378(14):1277-1290.
Bex A, Albiges L, Ljungberg B, et al. Updated European Association of Urology Guidelines for Cytoreductive Nephrectomy in Patients with Synchronous Metastatic Clear-cell Renal Cell Carcinoma. European Urology. 2018;74(6):805-809.

Evidence-Based Therapeutic Approaches for mCRPC

Prostate cancer exhibits a wide spectrum of disease behavior. Despite the majority of cases presenting with relatively indolent biologic behavior, prostate cancer remains the second leading cause of cancer-related death in the United States, behind only lung cancer.¹ With current treatment paradigms, nearly all patients who die of prostate cancer first receive androgen-deprivation therapy and then progress to castrate-resistant prostate cancer.

There is a large spectrum of prostate cancer progression. For patients who are initially diagnosed with a clinically-localized disease, such a pathway is highlighted in the following diagram. For patients who present with de novo metastatic disease, they join this algorithm at “development of metastatic hormone-sensitive prostate cancer (mHSPC)”.

diagram-evidence-based-theraputic-approaches-mCRPC@2x (1).jpg

The clinical approach to patients with metastatic castrate-resistant prostate cancer (mCRPC) depends, in general terms, on three factors: whether the patient is symptomatic from their disease, the patient’s performance status, and previous therapies which the patient may have received. These factors have been used to guide treatment recommendations in the guidelines from many medical/urologic societies. The definition of “symptomatic” prostate cancer is somewhat imprecise. However, most consider that patients who require only acetaminophen or non-steroidal anti-inflammatory drugs (NSAIDs) to be minimally symptomatic while those who require regular narcotic medications for pain that is attributable to documented metastasis are deemed symptomatic.

Advanced androgen axis targeting agents (such as abiraterone and enzalutamide) and chemotherapeutics (such as docetaxel) are increasingly used earlier in the disease process, including in de novo metastatic castrate-sensitive prostate cancer and in non-metastatic castrate resistant prostate. While there is some evidence that re-challenge with docetaxel may provide benefit in patients who previously demonstrate docetaxel response, ^{2, 3} the use of advanced androgen axis targeting agents and docetaxel earlier in the disease trajectory may preclude their use at the development of mCRPC. Acknowledging the changes this utilization has on the treatment of mCRPC, this article will focus on guideline-recommended treatment options.

As the androgen axis continues to be important in patients who have developed castration resistance, ongoing continuous treatment with androgen-deprivation therapy is recommended.⁴ Historically, a number of secondary hormonal maneuver have been employed. However, routine use of these preceded the availability of therapies with proven survival benefits. As no secondary hormonal maneuver has been shown to prolong survival, they are not widely recommended. However, there is evidence that, for patients who are currently receiving LHRH agonist or antagonist monotherapy, the addition of androgen receptor antagonists and resulting total androgen blockade is associated with short-term PSA-responses. Conversely, for patients who are currently receiving total androgen blockage, anti-androgen withdrawal is recommended as some patients may experience an antiandrogen withdrawal response.

For patients who are asymptomatic or minimally-symptomatic, have good performance status, and have not yet received docetaxel chemotherapy, there are numerous treatment options. These include docetaxel, abiraterone plus prednisone, enzalutamide, and sipuleucel-T5. Docetaxel was the first agent shown to have a survival benefit in patients with mCRPC in 2004⁶ and it quickly became standard of care for these patients as there were no alternatives with a demonstrated survival benefit. In 2012, COU-AA-302 was the first study to demonstrate a survival benefit for a non-cytotoxic agent in the treatment of mCRPC: patients treated with abiraterone plus prednisone demonstrated approximated 4 months longer overall survival (OS) than those receiving prednisone alone.⁷ Subsequently, in 2014, the PREVAIL study demonstrated similar benefits for enzalutamide in this patient population.⁸ Both abiraterone and enzalutamide target the androgen axis. In contrast, sipuleucel-T is an autologous active cellular immunotherapy. Published in 2010, the IMPACT study demonstrated that this approach was associated with approximately 20% improved overall survival.⁹ For patients who opt against these standard treatments, observation alone, first-generation anti-androgens, or ketoconazole accompanied by steroids may be offered.⁵ While not included in these guidelines, the FIRSTANA trial compared docetaxel and two doses of cabazitaxel in chemotherapy naïve patients with mCRPC. Overall, no large differences between the regimes were seen with respect to oncologic efficacy or tolerability.¹⁰

For patients who have good performance status and have not yet received docetaxel but who are symptomatic (again, based on a definition requiring regular use of narcotic analgesics for the pain that is attributable to documented metastasis), there are again a number of treatment options. Abiraterone plus prednisone, enzalutamide, and docetaxel form the standard of care for these patients. In addition, the alpha-emitter radium-223 may be offered to patients who have symptoms attributable to bony metastatic disease in the absence of visceral disease on the basis of the results of the ALSYMPCA trial. This phase 3 trial demonstrated that treatment with radium-223 significantly improved overall survival as well as skeletal-related events.¹¹ As with asymptomatic or minimally-symptomatic patients who have good performance status and are chemotherapy-naïve, symptomatic patients who decline standard treatments may be offered alternative therapies though these do not have proven survival benefit. In this patient population, these treatments include ketoconazole with steroids, mitoxantrone, or radionuclide therapy.⁵

For symptomatic patients with poor performance status who have not previously received docetaxel, there is a relative paucity of direct evidence to inform treatment choices as most patients with poor performance status are excluded from clinical trials. However, guidelines typically extrapolate from studies in patients with better performance status to guide therapy in these patients.⁵ Aggressive prostate cancer treatment may especially be warranted where the functional impairments resulting in poor performance status are directly attributable to prostate cancer. In contrast, patients with poor performance status as a result of other medical conditions have less to gain from aggressive prostate cancer therapy. Considering these factors, individual, tailored therapy is warranted with a thorough discussion of potential risks and benefits of therapy. The AUA guidelines currently recommend either abiraterone plus prednisone or enzalutamide for these patients.⁵ For patients with poor performance status that is attributable to their disease burden, docetaxel or mitoxantrone may be offered whereas, when the poor performance status is related to bony metastatic disease, radium-223 is a recommended option. For patients unable or unwilling to receive standard therapies, ketoconazole with steroids or radionuclide therapy remain options though these have not demonstrated survival benefit⁵. In contrast, the CUA guidelines do not stratify by performance status and recommend docetaxel with abiraterone plus prednisone or enzalutamide as alternatives for patients who cannot receive or refuse docetaxel and radium-223 as an alternative for patients who have bony pain related to their metastases and no visceral disease.⁴

Among patients with mCRPC who have previously received docetaxel-based chemotherapy, treatment options may again be stratified by performance status. There are 4 agents with a proven survival benefit in this population: abiraterone plus prednisone; enzalutamide; cabazitaxel; and radium-223. Given that this is a relatively advanced disease state and these treatments remain non-curative and yet have a significant potential burden of toxicity, care should be taken to provide prostate cancer treatments which preserve these patients’ excellent quality of life. It is also at this time that sequencing of agents becomes particularly relevant as many patients will have received an advanced androgen axis targeting agent (abiraterone or enzalutamide) prior to receiving docetaxel and will now be on their third line of mCRPC treatment.

In 2011, the COU-AA-301 trial demonstrated that abiraterone plus prednisone could improve overall survival approximately 4 months for patients with advanced mCRPC following docetaxel chemotherapy.¹² Subsequently, in 2012, the AFFIRM trial demonstrated similar results for enzalutamide in this patient population.¹³ TROPIC tested cabazitaxel versus mitoxantrone, each with prednisone, in patients who had progressed following docetaxel for mCRPC and demonstrated an improvement of approximately 2.5 months overall survival for patients receiving cabazitaxel.¹⁴ As discussed previously among patients who had not yet received docetaxel, ALSYMPCA demonstrated an improvement in both survival and skeletal-related events for patients receiving radium-223.¹¹ In addition to these agents, docetaxel re-challenge is suggested for patients who discontinued therapy due to reversible toxicity. The AUA guidelines again offer ketoconazole plus steroids for patients who are unable or unwilling to take other agents.

In patients with advanced mCRPC who are symptomatic and have poor performance status following previous docetaxel chemotherapy, symptom management is strongly advocated in keeping with the American Society for Clinical Oncology’s guidance regarding the treatment of patients with advanced solid tumors. Aggressive treatment at this time may lead to unnecessary cost and toxicity, may delay access to the end of life care, and is unlikely to provide meaningful benefit. Therefore, palliative care is prioritized. Abiraterone plus prednisone, enzalutamide, ketoconazole plus steroid or radionuclide therapy are offered within the AUA guidelines⁵ but there is no strong data to support the use of these agents in this patient population.

Apart from specific mCRPC medication, bone health remains important in all patients with advanced prostate cancer due to a confluence of risk factors: age-related declines in bone mineral density, the deleterious effects of androgen-deprivation therapy on bones¹⁵ (even among patients with localized prostate cancer¹⁶), and the involvement of bony metastatic disease. Therefore, calcium and vitamin D are recommended for all patients with mCRPC. In addition, a bone-targeting agent, either denosumab or zoledronic acid, is recommended. These agents have been shown to decrease disease-related skeletal events though, unlike radium-223, they have not been found to improve survival. The timing of initiation of bone-targeted agents is somewhat unclear as there is evidence that the risk of significant toxicity (particularly, osteonecrosis of the jaw) increases substantially after 2 years of therapy¹⁷ and may patients with mCRPC will be expected to live longer than this.

Additionally, the symptomatic benefit of palliative radiotherapy should not be underestimated, and this should be offered where it is deemed clinically appropriate.

Special considerations should be undertaken for some patients as these may guide treatment choices. In heavily pre-treated patients with mCRPC, Mateo et al. found that mutations or deletions in DNA-repair genes could be found in 33% of patients.¹⁸ These patients demonstrated a notably strong response to treatment with the PARP inhibitor olaparib. A biomarker suite including BRCA 1 and 2, ATM, Fanconi’s anemia genes, and CHECK2 had a specificity of 94% for identifying treatment response. Thus, identification of these defects in DNA-repair may guide treatment choice. More recently, a phase 2 trial demonstrated that olaparib added to abiraterone plus prednisone improved overall survival compared to abiraterone plus prednisone alone in a population of patients who had previously received docetaxel but were not enriched for DNA-repair defects.¹⁹

Recently, the phase 3 trial of PROSTVAC, viral vector-based immunotherapy, in chemotherapy naïve patients with asymptomatic or minimally symptomatic mCRPC were reported. Despite promising results in a phase 2 trial where median OS was improved by 8.5 months, this phase 3 trial was unfortunately negative with a non-significant median difference in overall survival of approximately 1 month.²⁰

Despite the survival benefits of many agents in metastatic castrate-resistant prostate cancer, these treatments remain non-curative. Therefore, consideration for enrollment in ongoing clinical trials should be considered for all eligible patients.

Published Date: April 16th, 2019

Written by: Zachary Klaassen, MD, MSc

References:

Siegel RL, Miller KD, Jemal A. Cancer statistics, 2018. CA Cancer J Clin 2018; 68(1):7-30.
Thomas C, Brandt MP, Baldauf S, et al. Docetaxel-rechallenge in castration-resistant prostate cancer: defining clinical factors for successful treatment response and improvement in overall survival. Int Urol Nephrol 2018; 50(10):1821-1827.
Oudard S, Kramer G, Caffo O, et al. Docetaxel rechallenge after an initial good response in patients with metastatic castration-resistant prostate cancer. BJU Int 2015; 115(5):744-52.
Saad F, Chi KN, Finelli A, et al. The 2015 CUA-CUOG Guidelines for the management of castration-resistant prostate cancer (CRPC). Can Urol Assoc J 2015; 9(3-4):90-6.
Lowrance WT, Murad MH, Oh WK, et al. Castration-Resistant Prostate Cancer: AUA Guideline Amendment 2018. J Urol 2018; 200(6):1264-1272.
Tannock IF, de Wit R, Berry WR, et al. Docetaxel plus prednisone or mitoxantrone plus prednisone for advanced prostate cancer. N Engl J Med 2004; 351(15):1502-12.
Ryan CJ, Smith MR, de Bono JS, et al. Abiraterone in metastatic prostate cancer without previous chemotherapy. N Engl J Med 2013; 368(2):138-48.
Beer TM, Armstrong AJ, Rathkopf DE, et al. Enzalutamide in metastatic prostate cancer before chemotherapy. N Engl J Med 2014; 371(5):424-33.
Kantoff PW, Higano CS, Shore ND, et al. Sipuleucel-T immunotherapy for castration-resistant prostate cancer. N Engl J Med 2010; 363(5):411-22.
Oudard S, Fizazi K, Sengelov L, et al. Cabazitaxel Versus Docetaxel As First-Line Therapy for Patients With Metastatic Castration-Resistant Prostate Cancer: A Randomized Phase III Trial-FIRSTANA. J Clin Oncol 2017:JCO2016721068.
Parker C, Nilsson S, Heinrich D, et al. Alpha emitter radium-223 and survival in metastatic prostate cancer. N Engl J Med 2013; 369(3):213-23.
de Bono JS, Logothetis CJ, Molina A, et al. Abiraterone and increased survival in metastatic prostate cancer. N Engl J Med 2011; 364(21):1995-2005.
Scher HI, Fizazi K, Saad F, et al. Increased survival with enzalutamide in prostate cancer after chemotherapy. N Engl J Med 2012; 367(13):1187-97.
de Bono JS, Oudard S, Ozguroglu M, et al. Prednisone plus cabazitaxel or mitoxantrone for metastatic castration-resistant prostate cancer progressing after docetaxel treatment: a randomised open-label trial. Lancet 2010; 376(9747):1147-54.
Shahinian VB, Kuo YF, Freeman JL, et al. Risk of fracture after androgen deprivation for prostate cancer. N Engl J Med 2005; 352(2):154-64.
Wallis CJ, Mahar AL, Satkunasivam R, et al. Cardiovascular and Skeletal-Related Events Following Localised Prostate Cancer Treatment: Role of Surgery, Radiotherapy and Androgen-Deprivation. Urology 2016; 97:145-152.
Barasch A, Cunha-Cruz J, Curro FA, et al. Risk factors for osteonecrosis of the jaws: a case-control study from the CONDOR dental PBRN. J Dent Res 2011; 90(4):439-44.
Mateo J, Carreira S, Sandhu S, et al. DNA-Repair Defects and Olaparib in Metastatic Prostate Cancer. N Engl J Med 2015; 373(18):1697-708.
Clarke N, Wiechno P, Alekseev B, et al. Olaparib combined with abiraterone in patients with metastatic castration-resistant prostate cancer: a randomised, double-blind, placebo-controlled, phase 2 trial. Lancet Oncol 2018; 19(7):975-986.
Gulley JL, Borre M, Vogelzang NJ, et al. Phase III Trial of PROSTVAC in Asymptomatic or Minimally Symptomatic Metastatic Castration-Resistant Prostate Cancer. J Clin Oncol 2019:JCO1802031.

Prostate Cancer and Utilization of Multi-Parametric MRI

Over the last decade, imaging for prostate cancer has improved immensely. Specifically, prostate multiparametric MRI (mpMRI) has improved primarily as a result of an increase in magnet strength from 1 to 3-tesla. mpMRI consists of anatomic and functional imaging techniques: anatomic imaging includes T1- and T2-weighted images, and functional imaging includes diffusion-weighted imaging (DWI) and dynamic contrast-enhanced (DCE) sequences. Currently, the recommendation is for a 1.5 tesla MRI with an endorectal coil or a 3-tesla MRI with no endorectal coil.¹

Initial T1-weighted images are performed first to determine if hemorrhage is present in the prostate. As such, most experts recommend waiting 3-8 weeks after a prostate biopsy to decrease artifact associated with hemorrhage from the biopsy.² Subsequently, T2-weighted images provide anatomic configuration of the prostate gland: the normal peripheral zone appears as areas of high signal intensity, whereas areas of low signal intensity may represent prostate cancer, prostatitis, BPH, etc. T2-weighted images also provide information regarding extraprostatic extension (EPE) or seminal vesical invasion (SVI), which are represented by areas of low signal intensity. DWI assess the diffusion of water within the magnetic field—the closer the cells are together (ie. for a prostate cancer nodule), the lower the motion of water, which leads to a high signal intensity in this phase. The DCE phase is a T1-weighed image with gadolinium-based contrast, which assesses vascular permeability of the prostate over a period of typically 5-10 minutes. Importantly, the combination of T2, DCE, and DWI phases yields both a NPV and PPV of >90%.³

table-1-prostate-cancer-utilization@2x.jpg

The objective of this article is to focus on indications for mpMRI use in the localized prostate cancer setting, specifically exploring its use before prostate biopsy, after a negative biopsy, on active surveillance, and prior to radical prostatectomy for surgical planning purposes.

Before Prostate Biopsy

Until recently, the utilization of mpMRI as a “triage test” prior to transrectal ultrasound (TRUS)-guided prostate biopsy was a contentious topic, relying on single centers suggesting that such an approach may decrease unnecessary biopsies.^5,6 However, in 2017, the PROMIS trial provided level 1b evidence for utilizing mpMRI prior to TRUS-guided biopsy among men with elevated PSA.⁷ PROMIS was a multi-center, paired-cohort study to assess the diagnostic accuracy of mpMRI and TRUS biopsy against a gold-standard reference template mapping biopsy. Men were included (n=576) if they had a PSA <15 ng/ml and no history of the previous biopsy. On mapping biopsy, 71% of men had cancer, including 40% with clinically significant prostate cancer (Gleason score ≥4+3 or maximum cancer length ≥6 mm). For clinically significant disease, mpMRI was more sensitive (93%) than TRUS-biopsy (48%), albeit less specific (41% for mpMRI; 96% for TRUS-biopsy). Based on these data, a triage mpMRI would allow 25% of men to safely avoid a prostate biopsy, while at the same time reducing detection of clinically insignificant prostate cancer. Importantly, secondary to the poor specificity and positive predictive value, this study does not suggest that mpMRI should replace prostate biopsy and that men with suspicious lesions should still have histologic confirmation of prostate cancer.

Shortly after PROMIS was published, PRECISION reported results of their trial which assigned 500 men with a clinical suspicion of prostate cancer who had not previously undergone a prostate biopsy to undergo MRI with or without a targeted biopsy vs standard TRUS-guided biopsy.⁸ Men in the MRI group underwent a targeted biopsy if there was a suspicion of prostate cancer on imaging and did not undergo a biopsy if the MRI was negative. The primary outcome for this randomized clinical trial was a diagnosis of clinically significant prostate cancer. In the MRI-targeted biopsy group, 28% had a negative MRI and thus no biopsy. Among men undergoing targeted biopsy, 38% had clinically significant cancer, compared to 26% in the TRUS-guided biopsy group (p=0.005). Furthermore, fewer men in the MRI-targeted biopsy group had clinically insignificant prostate cancer compared to the TRUS-guided biopsy group.

Since the publication of these two trials, debate regarding the implementation of mpMRI prior to biopsy has ensued. Detractors have mentioned that the negative predictive value of mpMRI in PROMIS for detecting Gleason grade group ≥2 was only 76%, albeit no grade group ≥3 were missed on mpMRI.⁷ mpMRI prior to prostate biopsy has already been widely accepted in the UK and Australia where mpMRI is reimbursed in this setting.⁹ There is evidence to suggest that men with a negative mpMRI should not be biopsied unless caveats such as a strong family history, abnormal digital rectal exam, or BRCA mutation are present. At present, experts have pressed for a new paradigm for prostate cancer detection in which an abnormal mpMRI should have a targeted biopsy performed; if the mpMRI is negative then a routine follow-up protocol should be employed.⁹ It is noteworthy to mention that widespread dissemination will undoubtedly rely on (i) affordability/reimbursement of mpMRI, (ii) quality of the mpMRI, and (iii) skill of the radiologist.

After Negative Prostate Biopsy

It is generally accepted that men with a history of negative TRUS-guided biopsy and persistently elevated or increasing PSA should undergo a mpMRI prior to consideration of a second (or in some cases third or fourth) prostate biopsy. In a study of 265 patients with a PSA >4.0 ng/ml and one negative TRUS-biopsy mpMRI detected prostate cancer in 41% of men, including 87% with clinically significant prostate cancer.¹⁰

mpMRI has been shown in the previous negative biopsy setting to detect tumors in up to 40% of cases, often in the anterior region of the prostate.^11-14 An advantage of mpMRI fusion biopsy in patients with prior negative biopsy is the ability of MRI to identify suspicious lesions in areas not normally sampled by standard TRUS-guided biopsy, specifically the anterior and apical parts of the prostate. Thus, the benefit of fusion biopsy is particularly accentuated in the prior negative biopsy cohort. Furthermore, a study by Kongnyuy et al.¹⁵ suggested that there may be racial differences with regards to anterior tumors. In a cohort of 195 African-American men matched 1:1 to white men undergoing mpMRI, 47.7% of African-American men had anterior prostate lesions. Amongst these men, a history of prior negative biopsy was significantly associated with an anterior prostate lesion (OR 1.81, 95%CI 1.03-3.20). Despite an overall higher cancer detection rate among African American than white men, the presence of anterior prostate lesions and lesions harboring clinically significant cancer were not different between races.

On Active Surveillance

Over the last decade, adoption of active surveillance as a management strategy for men with clinically low-risk prostate cancer has appropriately continued to increase. However, until recently, the utilization of mpMRI in active surveillance management has been somewhat discretionary and clinician dependent.¹⁶

Earlier this year the European Association of Urology (EAU) released a position statement for active surveillance, which included 10 recommendation statements;¹⁷ the 3rd statement assessed “use and timing of MRI in active surveillance.” mpMRI can be used to increase clinically significant cancer detection, thus ensuring men are appropriately included in surveillance regimens and those with potentially threatening disease can have appropriate and timely intervention. The statement recommends that mpMRI can be performed at several time points during active surveillance:

At the time of initial diagnosis – the EAU statement recommends that men diagnosed with a low-risk disease without a prior mpMRI should under a mpMRI prior to enrolment to ensure no significant disease was missed on initial biopsy. In cases of initial targeted mpMRI biopsy, both targeted and systematic biopsies should be performed.¹⁷ In addition to the excitement generated by PROMIS ⁷ and PRECISION,⁸ a recent systematic review assessed the role of mpMRI among active surveillance patients, noting that a lesion suspicious for prostate cancer was found in nearly two-thirds of men otherwise suitable for surveillance.¹⁸
Before confirmatory biopsy – the EAU statement recommends that a mpMRI be performed before the confirmatory biopsy, within 12 months from initial diagnosis, and to include targeted and systematic biopsies.¹⁷ The rate of reclassification after targeted biopsies among men on active surveillance without a prior mpMRI may be as high as 22%.^18-20 A recent publication assessed the value of serial mpMRI imaging among 111 men on active surveillance with > 1-year of follow-up, noting that among 33 reclassifications after one year, 55% were reclassified on only TRUS-guided biopsy.²¹ As such, the value of serial mpMRI in active surveillance algorithms remains unclear.
During follow-up – the EAU statement does not support the use of solely using mpMRI instead of repeat biopsy in active surveillance follow-up.¹⁷ As mentioned, the use of serial mpMRIs over long-term follow-up is not currently recommended, however it may be used in situations where a targeted lesion is being followed. This is an area of great research interest considering that institutional studies with vast experience with mpMRI suggest that mpMRI supplanting follow-up biopsies is safe and feasible.²²

Last month, the ASIST trial published results of the randomized, multicenter, prospective trial assessing if mpMRI with targeted biopsy could identify a greater proportion of men with grade group ≥2 cancer on confirmatory biopsy compared with systematic biopsies.²³ Among 273 men included in the study, 64% in the MRI group had a suspicious region of interest. Unfortunately, no difference was observed in the rate of grade group ≥2 upgrading in the intention to treat or per protocol cohort, grade group ≥2 upgrading within each stratum separately, or grade group ≥3. This trial confirms that there is still a role for TRUS-guided biopsy among active surveillance patients, in addition to tempering the current role for targeted biopsies in this setting.

Before Radical Prostatectomy

With improved mpMRI technology has come an interest in more precise clinical staging of localized prostate cancer, particularly before performing radical prostatectomy. Ultimately, the patient and urologist are concerned about the risk of EPE preoperatively, which dictates the degree of nerve-sparing performed at the time of radical prostatectomy. Somford et al.²⁴ assessed mpMRI images among 183 men to determine the positive and negative predictive values of mpMRI for EPE at radical prostatectomy for different prostate cancer risk groups. The overall prevalence of EPE at radical prostatectomy was 49.7% (24.7% low-risk; 77.1% high-risk) – the overall staging sensitivity was 58.2%, specificity was 89.1%, positive predictive value was 84.1% and a negative predictive value was 68.3%. The positive predictive value was best in the high-risk cohort (88.8%) and a negative predictive value was best in the low-risk cohort (87.7%).

Data regarding whether preoperative imaging influences surgical planning is limited. However, Schiavina et al.²⁵ assessed the impact of mpMRI on preoperative decision making among 137 patients planned for radical prostatectomy who underwent mpMRI. They found that mpMRI changes robotic surgeon’s initial surgical plan with regards to the degree of nerve-sparing in nearly half of patients. Interestingly, there was an equal alteration in surgical planning when considering a more aggressive (to less aggressive) and less aggressive (to more aggressive) preliminary plan. Although the above results for EPE prediction and tailored surgical planning are encouraging, this degree of advanced mpMRI interpretation should be reserved for expert radiologists where sensitivities and specificities for predicting EPE are typically both >80%.²⁶

Conclusions

The improvement of MRI technology and development of mpMRI for prostate imaging is one of the most important technologic advancements in urologic oncology over the past decade. The PROMIS and PRECISION trials have delineated the utility of mpMRI among men considering a prostate biopsy. Likely the most accepted and concrete indication for utilization of mpMRI is in men with a negative prostate biopsy and persistent/increasingly elevated PSA, specifically to enhance the ability to detect previously unsampled (often anterior) tumors. The recent EAU statement on active surveillance has provided much-needed guidance as to when to include mpMRI in the surveillance algorithm; work is still necessary to delineate who benefits from serial mpMRI, particularly after 1 year on active surveillance. Finally, there is increased utilization of mpMRI among patients planned for radical prostatectomy to assess the degree of acceptable nerve sparing without compromising oncologic efficacy, however the high-level of mpMRI interpretation to accurately assess EPE in these instances requires expert radiologic experience.

Published Date: April 16th, 2019

Written by: Zachary Klaassen, MD, MSc

References: 1. Muller BG, Futterer JJ, Gupta RT, Katz A, Kirkham A, Kurhanewicz J, et al. The role of magnetic resonance imaging (MRI) in focal therapy for prostate cancer: recommendations from a consensus panel. BJU Int. 2014;113:218-27.
2. Rosenkrantz AB, Kopec M, Kong X, Melamed J, Dakwar G, Babb JS, et al. Prostate cancer vs. post-biopsy hemorrhage: diagnosis with T2- and diffusion-weighted imaging. J Magn Reson Imaging. 2010;31:1387-94.
3. Abd-Alazeez M, Kirkham A, Ahmed HU, Arya M, Anastasiadis E, Charman SC, et al. Performance of multiparametric MRI in men at risk of prostate cancer before the first biopsy: a paired validating cohort study using template prostate mapping biopsies as the reference standard. Prostate Cancer Prostatic Dis. 2014;17:40-6.
4. Barentsz JO, Weinreb JC, Verma S, Thoeny HC, Tempany CM, Shtern F, et al. Synopsis of the PI-RADS v2 Guidelines for Multiparametric Prostate Magnetic Resonance Imaging and Recommendations for Use. Eur Urol. 2016;69:41-9.
5. Thompson JE, Moses D, Shnier R, Brenner P, Delprado W, Ponsky L, et al. Multiparametric magnetic resonance imaging guided diagnostic biopsy detects significant prostate cancer and could reduce unnecessary biopsies and over detection: a prospective study. J Urol. 2014;192:67-74.
6. Thompson JE, van Leeuwen PJ, Moses D, Shnier R, Brenner P, Delprado W, et al. The Diagnostic Performance of Multiparametric Magnetic Resonance Imaging to Detect Significant Prostate Cancer. J Urol. 2016;195:1428-35.
7. Ahmed HU, El-Shater Bosaily A, Brown LC, Gabe R, Kaplan R, Parmar MK, et al. Diagnostic accuracy of multi-parametric MRI and TRUS biopsy in prostate cancer (PROMIS): a paired validating confirmatory study. Lancet. 2017;389:815-22.
8. Kasivisvanathan V, Rannikko AS, Borghi M, Panebianco V, Mynderse LA, Vaarala MH, et al. MRI-Targeted or Standard Biopsy for Prostate-Cancer Diagnosis. N Engl J Med. 2018;378:1767-77.
9. Nzenza T, Murphy DG. PRECISION delivers on the PROMIS of mpMRI in early detection. Nat Rev Urol. 2018.
10. Hoeks CM, Schouten MG, Bomers JG, Hoogendoorn SP, Hulsbergen-van de Kaa CA, Hambrock T, et al. Three-Tesla magnetic resonance-guided prostate biopsy in men with increased prostate-specific antigen and repeated, negative, random, systematic, transrectal ultrasound biopsies: detection of clinically significant prostate cancers. Eur Urol. 2012;62:902-9.
11. Kirkham AP, Haslam P, Keanie JY, McCafferty I, Padhani AR, Punwani S, et al. Prostate MRI: who, when, and how? Report from a UK consensus meeting. Clin Radiol. 2013;68:1016-23.
12. Lawrentschuk N, Fleshner N. The role of magnetic resonance imaging in targeting prostate cancer in patients with previous negative biopsies and elevated prostate-specific antigen levels. BJU Int. 2009;103:730-3.
13. Hambrock T, Somford DM, Hoeks C, Bouwense SA, Huisman H, Yakar D, et al. Magnetic resonance imaging guided prostate biopsy in men with repeat negative biopsies and increased prostate specific antigen. J Urol. 2010;183:520-7.
14. Zugor V, Kuhn R, Engelhard K, Poth S, Bernat MM, Porres D, et al. The Value of Endorectal Magnetic Resonance Imaging of the Prostate in Improving the Detection of Anterior Prostate Cancer. Anticancer Res. 2016;36:4279-83.
15. Kongnyuy M, Sidana A, George AK, Muthigi A, Iyer A, Fascelli M, et al. The significance of anterior prostate lesions on multiparametric magnetic resonance imaging in African-American men. Urol Oncol. 2016;34:254 e15-21.
16. Scarpato KR, Barocas DA. Use of mpMRI in active surveillance for localized prostate cancer. Urol Oncol. 2016;34:320-5.
17. Briganti A, Fossati N, Catto JWF, Cornford P, Montorsi F, Mottet N, et al. Active Surveillance for Low-risk Prostate Cancer: The European Association of Urology Position in 2018. Eur Urol. 2018;74:357-68.
18. Schoots IG, Petrides N, Giganti F, Bokhorst LP, Rannikko A, Klotz L, et al. Magnetic resonance imaging in active surveillance of prostate cancer: a systematic review. Eur Urol. 2015;67:627-36.
19. Recabal P, Assel M, Sjoberg DD, Lee D, Laudone VP, Touijer K, et al. The Efficacy of Multiparametric Magnetic Resonance Imaging and Magnetic Resonance Imaging Targeted Biopsy in Risk Classification for Patients with Prostate Cancer on Active Surveillance. J Urol. 2016;196:374-81.
20. Pessoa RR, Viana PC, Mattedi RL, Guglielmetti GB, Cordeiro MD, Coelho RF, et al. Value of 3-Tesla multiparametric magnetic resonance imaging and targeted biopsy for improved risk stratification in patients considered for active surveillance. BJU Int. 2017;119:535-42.
21. Hamoen EHJ, Hoeks CMA, Somford DM, van Oort IM, Vergunst H, Oddens JR, et al. Value of Serial Multiparametric Magnetic Resonance Imaging and Magnetic Resonance Imaging-guided Biopsies in Men with Low-risk Prostate Cancer on Active Surveillance After 1 Yr Follow-up. Eur Urol Focus. 2018.
22. Walton Diaz A, Shakir NA, George AK, Rais-Bahrami S, Turkbey B, Rothwax JT, et al. Use of serial multiparametric magnetic resonance imaging in the management of patients with prostate cancer on active surveillance. Urol Oncol. 2015;33:202 e1- e7.
23. Klotz L, Loblaw A, Sugar L, Moussa M, Berman DM, Van der Kwast T, et al. Active Surveillance Magnetic Resonance Imaging Study (ASIST): Results of a Randomized Multicenter Prospective Trial. Eur Urol. 2018.
24. Somford DM, Hamoen EH, Futterer JJ, van Basten JP, Hulsbergen-van de Kaa CA, Vreuls W, et al. The predictive value of endorectal 3 Tesla multiparametric magnetic resonance imaging for extraprostatic extension in patients with low, intermediate and high risk prostate cancer. J Urol. 2013;190:1728-34.
25. Schiavina R, Bianchi L, Borghesi M, Dababneh H, Chessa F, Pultrone CV, et al. MRI Displays the Prostatic Cancer Anatomy and Improves the Bundles Management Before Robot-Assisted Radical Prostatectomy. J Endourol. 2018;32:315-21.
26. Tay KJ, Gupta RT, Brown AF, Silverman RK, Polascik TJ. Defining the Incremental Utility of Prostate Multiparametric Magnetic Resonance Imaging at Standard and Specialized Read in Predicting Extracapsular Extension of Prostate Cancer. Eur Urol. 2016;70:211-3.

Treatment Advances in Non Metastatic Castration-Resistant Prostate Cancer

Background

Since the seminal work of Huggins and Hodges¹ seventy years ago, androgen deprivation therapy (ADT) has formed the cornerstone of management for advanced prostate cancer with indications including concurrent therapy with primary curative-intent radiotherapy, salvage therapy after recurrence following local therapy, and in the treatment of metastatic disease. While efficacious, nearly all patients will eventually develop castration resistance with disease progression despite castrate levels of testosterone. Among patients who receive ADT for biochemical recurrence following radical prostatectomy or radiotherapy, the development of castration resistance typically occurs prior to the identification of metastasis on conventional imaging, nonmetastatic castration-resistant prostate cancer (nmCRPC). NmCRPC is typically identified on the basis of the PCWG3 consensus definition for prostate-specific antigen (PSA) progression on ADT, namely a 25% PSA increase from nadir (starting PSA ≥1.0 ng/mL), with a minimum rise of 2 ng/mL in the setting of castrate testosterone (< 50 ng/dL).² In these patients, treatment is aimed at delaying the development of metastasis, preserving quality of life, and increasing overall survival.

Nocturia: A Nighttime Condition with Daytime Consequences

Michael, a 61-one-year old executive accountant, presents for annual PSA monitoring and digital rectal examination. He reports that alpha-blocker therapy using tamsulosin has improved his benign prostatic hypertrophy, but that he still wakes frequently at night to void. He is otherwise healthy except for a history of type 2 diabetes mellitus that is well controlled with metformin. He views his nighttime trips to the bathroom as a normal part of aging (“all my friends have the same problem”). Michael’s wife, who has attended the appointment with him, interjects that Michael’s trips to the bathroom wake her and so she is tired during the day. On further questioning, Michael reports that he has trouble concentrating during his many meetings, and that he feels tired and sleepy during his drive home from work. How might we best manage his care?

Michael’s case mirrors those seen frequently in many urology practices. Nocturia, the most common lower urinary tract symptom affecting men and women of all ages, has numerous negative effects on physical and mental health, productivity, and quality of life.⁴ At the same time, prevailing misconceptions and a historic lack of safe, effective therapies for nocturia have created a striking treatment gap.^4,34,35,48 In this article, we review the definition, prevalence, and etiologies of nocturia and behavioral and medical treatment options. We then focus on the clinical profile and development of NOCTIVA^TM(desmopressin acetate), a proprietary and novel nasal spray of vasopressin analog that is the first medication approved in the United States for adults with nocturia due to overproduction of urine at night.^5,32 We conclude by discussing practical strategies for the safe, effective initiation and continuation of NOCTIVA^TMtherapy in clinical practice.

Definition and Epidemiology

The International Continence Society (ICS) defines nocturia as waking at least once at night to void, with each void preceded and followed by sleep.³ This definition excludes first morning void (the first void after waking with the intention to rise).³ Left untreated, nocturia significantly reduces daytime functioning, mood, and quality of life, and increases the risk of falls, injuries, and mortality.^4,6,8,42,28 Multiple studies indicate that waking just twice at night to void is bothersome and has clinically significant effects.^76,2,16,13 Thus, when considering nocturia as a condition of the lower urinary tract, voiding two or more times a night is viewed as clinically meaningful.

Despite these serious consequences, nocturia has been chronically understudied, underdetected, and underreported.⁴ Patients often do not disclose their nocturia to healthcare providers because they are reluctant to discuss toileting or do not connect their nocturia with other signs and symptoms they may be experiencing.^41,51 Additionally, many patients, and some clinicians, misperceive nocturia as a benign and natural part of aging or as merely a symptom of benign prostatic hypertrophy in males or overactive bladder in males and females.²⁵

In reality, nocturia frequently arises independently of overactive bladder and benign prostatic hypertrophy and is the most common lower urinary tract symptom affecting adults of both sexes and all ages.^{4,6,8,26,49,50,51,52,18}

In a systematic review and meta-analysis of 43 studies published between 1990 and 2009, between 2% and 18% of adults in their 20s to 40s reported waking at least twice nightly to void, as did 29% to 59% of men and 28% to 61.5% of women aged 70 and older.²⁶ In another study of more than 5,200 men participating in the National Health and Nutrition Examination Survey (NHANES), the prevalence of nocturia ranged from 8.2% among those aged 20 to 34 years to 55.8% among those aged 75 years or more.¹⁸

Nocturia also is highly prevalent among adults from diverse ethnic groups. In a population-based study of rural community health centers in Korea, 87% of men and 86% of women aged 65 years and older reported waking at least once nightly to void.⁴⁹ In another population-based study of more than 4,100 adults aged 40 years and older in China, approximately 75% of individuals reported waking at least once per night to void and more than 33% did so at least twice nightly.⁵¹ In a population-level study of reproductive-aged women in Turkey, approximately one-third of those in their 20s and 30s reported waking at least once per night to void, as did approximately 46% of women in their 40s.⁵⁶ Finally, in a population-based study of female primary care patients aged 18 to 85 years in Brazil, approximately 58% reported waking at least once nightly to void.⁵²

Consequences of Nocturia

The many negative effects of nocturia hinge on its impact on sleep. Sleep consists of two main states: rapid eye movement (REM) sleep, which comprises approximately 25% of total sleep time and is implicated in mental functioning, and non-REM (NREM) sleep, which makes up approximately 75% of total sleep time and is concerned with homeostatic processes.^14,60

Importantly, NREM sleep includes four stages: the transition from wakefulness to sleep (stage 1), light sleep (stage 2), and deep, restorative, slow-wave sleep (stages 3 and 4).¹⁴Because stages 3 and 4 occur during the first 4 hours of sleep, waking during this time decreases restorative slow-wave sleep even if there are no major changes in REM and NREM time.^14,60Persons who wake at least twice per night in order to void usually sleep only 2 to 3 hours before their first trip to the bathroom.^6,15 This curtails their first uninterrupted sleep period, which reduces slow-wave sleep and leads to greater daytime fatigue and sleepiness, a lower pain threshold, longer reaction times, and reductions in psychomotor performance, attention span, and memory.^19,78,7

Nocturia is usually a chronic condition. The repetitive nature of the sleep disruption is likely why nocturia also significantly increases the risk of somatic diseases, emotional symptoms, motor vehicle accidents, falls, fractures, and mortality.^{19,62,59,65,66,67,20,22,68} In a large cross-sectional study of adults in the United States, nocturia correlated strongly with cardiovascular disease, hypertension, and stroke, even after controlling for known confounders such as comorbid diabetes and respiratory sleep disorders.⁶² In another large study of adults in Minnesota, nocturia was independently associated with coronary heart disease among men younger than 60 years.²³ Other studies have linked poor sleep due to nocturia with immune and inflammatory dysregulation and aberrant glucose metabolism, which in turn are associated with diabetes mellitus, the metabolic syndrome, cardiovascular disease, and numerous other chronic diseases.^63,64,59

Researchers also have linked nocturia with an increased risk for anxiety and mood disorders. A recent review of 12 population-based studies identified a bidirectional association between nocturia and depression and anxiety.⁵⁷ In another study of more than 5,500 adults who responded to the Boston Area Community Health survey, the severity of nocturia correlated with depression among both men and women, even after controlling for covariates such as age, ethnicity, smoking, and socioeconomic status.¹⁷ Although the association was strongest among younger individuals, nocturia increased the odds of depression more than three-fold among women reporting sleep disturbances due to urologic symptoms (adjusted odds ratio [OR], 3.37; 95% confidence interval [CI], 1.63-6.94).¹⁷ Finally, in a population-based study of rural Koreans, individuals with nocturia reported adverse emotional effects, lower energy levels, and reduced daytime functioning.⁴⁹

Falls during nighttime toileting increase the risk of fracture and mortality, and these risks increase with increasing numbers of nocturic episodes per night.²⁰ In a recent longitudinal study of approximately 1,800 middle-aged and older men who were followed for an average of 6.2 years, rates of hip fracture were 2.7% among men who rose at least twice nightly to void but only 1.0% among men who rose once nightly and 0.9% among men without nocturia. Rising at least twice per night to void significantly increased the risk of hip fracture regardless of age (adjusted OR, 1.36; 95% CI, 1.03-1.80; P=.03).⁶⁸ In another 5-year observational study of elderly adults in Japan, those with two or more nocturic episodes per night were at significantly increased risk of falls leading to fracture (hazard ratio [HR], 2.20; 95% CI, 1.04-4.68; P=.04) and death (HR, 1.91, 95% CI, 1.07-3.43; P=.03).²² Nocturia remained a significant risk factor for mortality even after controlling for smoking, comorbidities, and medications that increase the likelihood of falls, such as tranquilizers and hypnotics (HR, 1.98, 95% CI, 1.09-3.59; P=.03).²²

Several other studies also have linked nocturia with an increased risk for mortality.^23,21 In a multivariate analysis of NHANES data from adults aged 20 years and older, awakening at least twice nightly to void correlated significantly with mortality, particularly among individuals younger than 65 years.²¹ The study authors hypothesized that the health effects of chronic sleep disruption from nocturia ultimately increased the risk of death.

Finally, clinically significant nocturia can erode nearly all aspects of health-related quality of life. In a study of more than 3,500 adults in Finland aged 18 to 79 years, those with at least two nocturic episodes per night scored significantly lower on 14 of 15 dimensions of health-related quality of life as measured by the generic 15D instrument.¹³ The negative effects of nocturia were similar in both genders.¹³ In another recent qualitative study of 20 adults in the United States who averaged three nocturic episodes per night, nocturia was associated with high levels of daytime fatigue, poor emotional well-being, and reduced social and cognitive functioning that limited respondents’ ability to work and perform daily activities.⁴³

The adverse effects of the chronic nature of nocturia are costly. In a recent study, researchers analyzed data from the Boston Area Community Health Study, the U.S. Bureau of Labor Statistics, and the Work Productivity and Impairment questionnaire.⁴² They concluded that at least 28 million U.S. adults rise at least twice nightly to void, incurring 127 lost hours of productivity per person every year, $61 billion in economic losses, and at least $1.5 billion in health care costs related to falls.⁴²

Etiologies and Assessment of Nocturia

The assessment of patients with nocturia should begin with a thoughtful consideration of its etiology or etiologies. It is helpful to keep in mind that awakening (or not) because of the need to void is a product of the relationship between the amount of urine produced at night and the ability of the bladder to store it.⁹ Normal nocturnal bladder capacity depends on many factors, including near-complete bladder emptying, low nighttime intracystic pressure, normal bladder sensation during filling, adequate sphincter function (no stress incontinence), a lack of involuntary contractions (no bladder overactivity), and a lack of excess urine production at night.^{9,10,78, 4,11,12}Derangements in any of these variables can lead to clinically significant nocturia.

Thus, nocturia can result from nocturnal or global polyuria, bladder storage problems, psychologic factors and sleep disturbances, fluid intake behaviors, medications, or mixed syndromes.^{27,24,29,3,30,31} Among these etiologies, by far the most prevalent is nocturnal polyuria, which the International Continence Society defines as the nighttime production of more than 33% of total 24-hour urine volume by adults aged 65 years and older, and the nighttime production more than 20% of total 24-hour urine volume by younger adults.^3,30 Nocturnal polyuria becomes more common with age, but it is the most common cause of nocturia in all age groups has been implicated in up to 80% of cases of nocturia.^27,25,3

It is important to distinguish nocturnal polyuria from global polyuria, defined as total 24-hour urine output greater than 40 mL per kg of body weight.^3,30 A frequency-volume assessment helps differentiate these two syndromes: Patients record the time and volume of each void, typically for 3 days.²⁵ The sum of each nighttime void volume and the first morning void volume is then divided by the total 24-hour urine volume.

When evaluating a nocturic adult, physicians also should consider the possible role of fluid intake behaviors, congestive heart failure, type 2 diabetes, peripheral edema due to venous disease, overactive bladder (increased urinary urgency and frequency that may or may not involve nocturia) in men and women, and benign prostatic hypertrophy in men.⁴⁵Mood and anxiety disorders are common comorbidities; it is helpful to ask if patients are waking because they need to void or are deciding to use the bathroom once awake (nocturnal convenience void).⁵³ Short, self-administered screening tools such as the Hospital Anxiety and Depression Scale (HADS) and the Geriatric Depression Scale (GDS) are not commonly used in urology practice but are feasible to deploy and can help identify patients whose nocturia and overall well-being might benefit from mental health care.^57,58

Physicians should also ask nocturic patients about respiratory sleep disorders, which are another common comorbidity.⁴⁵ In particular, obstructive sleep apnea causes pulmonary vasoconstriction and hypoxia, leading to increased atrial natriuretic peptide levels, renal sodium and water excretion, and nocturia.⁵³ In recent prospective and retrospective studies of adults with obstructive sleep apnea, severity correlated with nocturic episodes per night, and patients who were treated with continuous positive airway pressure (CPAP) showed a subsequent improvement in nocturia.^46,47

In summary, when assessing patients with nocturia, it is important to keep in mind that nocturnal polyuria is very often the cause, but also to look for global polyuria, overactive bladder, benign prostatic hypertrophy, and somatic, psychiatric, and respiratory sleep disorders. Nocturia is complex and multifactorial; a tailored approach to management maximizes the likelihood of treatment response and should involve multidisciplinary approaches, when appropriate.

Treatment Considerations

Conventionally, the management of nocturia begins with lifestyle changes and behavioral therapy. Patients should be encouraged to restrict fluid intake after early evening, restrict caffeine and alcohol, take diuretics in the mid-afternoon, elevate their legs in the evening to help mobilize fluids, and void immediately before bed. However, behavior modification alone tends to be ineffective and not durable.^25,33 Patients usually cannot maintain such extensive lifestyle changes, and fluid restriction is ineffective if patients have subnormal levels of circulating vasopressin.^34,35,10

Unfortunately, there also has been a historic lack of safe, effective medications for nocturia. Approved treatments for overactive bladder and benign prostatic hypotrophy have been prescribed off-label for nocturia but are usually ineffective. This is because nocturia is primarily a “kidney” condition; most cases are due to nocturnal polyuria, or the excessive production of urine at night by the kidneys due to alterations in circulating vasopressin.^29,25Medications for overactive bladder and benign prostatic hypertrophy target “downstream” organs: the bladder (anticholinergics/antimuscarinics and β3-adrenergic agonists) and the prostate gland (⍺-blockers).^{39,40,41,33,24,25}

A more effective approach to treating nocturia is to administer a synthetic analog of vasopressin. Vasopressin or antidiuretic hormone acts on V receptors 1, 2, and 3) to induce vasoconstriction, osmoregulation, and corticotropin secretion.⁶⁹ In the renal collecting tubule, vasopressin activates the V2 receptor, which increases production of the aquaporin-2 water channel and its migration to the apical plasma membrane.⁵⁴The result is greater osmotic water permeability, increased water reabsorption in the distal tubule and collecting ducts, and decreased urine production.^55,53

Desmopressin is a synthetic analog of arginine vasopressin that selectively targets the V2 receptor, thereby retaining the antidiuretic properties of vasopressin without exhibiting its unwanted pressor activity.²⁵ Desmopressin was first approved in the United States in oral form.³⁶ In a systematic review and meta-analysis of 10 randomized trials comparing oral desmopressin or placebo in 2,191 healthy adults with nocturia, desmopressin (100 micrograms [mcg]) extended the first uninterrupted sleep period by more than 1 hour in most patients and decreased nocturic episodes by a mean of 0.72 events per night.³⁸Compared with placebo, however, desmopressin was associated with a five-fold increase in the risk of hyponatremia at doses of 10 mcg or more (relative risk, 5.1; 95% CI, 3.0-8.8).³⁸ In two other randomized trials of oral desmopressin in nocturic women and men, 34% and 46% of treated patients had fewer than half the number of voids compared with baseline, compared with 3% of 7% of patients in the placebo groups.^35,37

These efficacy data for desmopressin are important because improving or resolving clinically significant nocturia can significantly improve sleep architecture, leading to more restorative sleep. In a recent post-hoc analysis of data from three clinical trials of 841 nocturic adults (90% of whom had nocturnal polyuria), treatment with desmopressin was associated with significant increases in first uninterrupted sleep period, even after accounting for numerous demographic and clinical covariates.⁶¹ In another post-hoc analysis of clinical trial data, treatment with desmopressin lengthened first uninterrupted sleep period, leading to improvements on nearly all subscales of the Pittsburgh Sleep Quality Index.⁷⁵Finally, in a study of 105 men treated for nocturia, those who responded to treatment (waking at least once less during the night to void) experienced a 1.8-hour mean increase in first uninterrupted sleep period, while non-responders averaged a 0.6-hour decrease in first uninterrupted sleep period during follow-up.

However, oral desmopressin tablets are not FDA-approved for the treatment of nocturia due to nocturnal polyuria and are seldom used in urology practice.^81,Barkin,⁴⁸ In a recent retrospective study of 403 adults seen in tertiary urology practice for the primary complaint of nocturia, 76% of patients had nocturnal polyuria but only 5% used oral desmopressin.⁴⁸ Notably, the completion of bladder diaries did not improve nocturia, underscoring the limitations of behavioral therapy.⁴⁸ A sublingual melt formulation of desmopressin has recently been approved by the FDA for the treatment of nocturia in adults but is not yet commercially available.⁸⁰ Likewise, an older intranasal spray formulation of desmopressin been found to improve nocturnal polyuria in men with benign prostatic hypertrophy.^53,70 but is not approved for the treatment of nocturia.³¹

NOCTIVA

In March 2017, the U.S. Food and Drug Administration approved NOCTIVA for the treatment of nocturia due to nocturnal polyuria in adults who awaken at least twice nightly to void.⁷⁹ NOCTIVA is a preservative-free proprietary emulsification of desmopressin acetate and cyclopentadecanolide, a permeation enhancer that facilitates rapid absorption of desmopressin across the nasal mucosa and allows for use of a lower dose.^{79,5, 1} The bottle is also designed to deliver a unique spray pattern that maximizes the distribution of the emulsification throughout the nasal cavity. These unique characteristics of NOCTIVA facilitate microdosing, rapid absorption, and pharmacokinetic consistency from dose to dose. Two FDA-approved dosing bottles are available: NOCTIVA 1.66 mcg and NOCTIVA 0.83 mcg.

The NOCTIVA development program included 10 studies: two phase 1 trials, one phase 2 trial, four phase 3, double-blind, placebo-controlled trials, one phase 3 open-label study in elderly patients, and two open-label, long-term safety extension trials.⁷⁴ In this article, we focus on the results of the most recent double-blind phase 3 trials and the long-term extension trials.

Pivotal Trials: Design and Patients

The safety and efficacy of NOCTIVA 1.66 mcg and NOCTIVA 0.83 mcg were evaluated in two multicenter, randomized, double-blind, placebo-controlled phase 3 trials (DB3 and DB4).¹ The intention-to-treat population consisted of 1,333 adults aged 50 years and older who averaged 3.3 nocturic voids per night during screening.

Co-primary endpoints in both trials were change from baseline in mean number of nocturic episodes per night and percentage of patients achieving at least a 50% reduction in nocturic episodes per night.

Secondary efficacy endpoints included nocturnal urine volume, first uninterrupted sleep period (time from bedtime to the first nocturic void), percentage of nights in which patients had one or no nocturic voids.

The DB4 study also assessed the change from baseline in scores on the Impact of Nighttime Urination (INTU) questionnaire, a validated 10-item tool that assesses the clinical meaningfulness (based on patient perceptions) of reducing nocturic episodes per night.^71,72The daytime impact domain of the INTU tool assesses concentration, tiredness, ability to complete activities, irritability, restfulness, and daytime drowsiness, while the nighttime domain assesses bother, premature waking, insufficient sleep, and level of emotional concern about needing to get out of bed to urinate. The overall score ranges from 0 to 100, with 100 representing the greatest detrimental impact of nocturia. Patients in the DB4 study completed three INTU questionnaires that corresponded with three voiding diaries.

During the 2-week lead-in periods, patients received intranasal placebo spray every night and completed two 3-day nightly voiding diaries. At[DR1] the end of the lead-in periods, all patients were randomly assigned to receive NOCTIVA 1.66 mcg (containing 0.75 mcg desmopressin), NOCTIVA 0.83 mcg (containing 1.5 mcg desmopressin), or placebo. Study drug and placebo were administered intranasally every night, and efficacy and safety assessments were performed every 2 weeks.¹ No fluid restrictions or other behavioral changes were imposed on study participants. The second trial (DB4) also evaluated an intermediate dose of NOCTIVA containing 1.0 mcg desmopressin .

Most (57%) trial participants were male, and mean age was 66 years (range, 50-90 years).¹ Investigator-assessed etiologies of nocturia included nocturnal polyuria, overactive bladder, benign prostatic hypertrophy, global polyuria, and unknown causes. The trial arms were well-matched for these etiologies and for demographic and clinical characteristics. Key exclusion criteria included nocturnal enuresis, diabetes insipidus, unstable diabetes mellitus, obstructive sleep apnea, New York Heart Association class 2 to 4 congestive heart failure, a documented history of polydipsia, uncontrolled hypertension (systolic pressure >165 mm Hg and diastolic pressure >100 mm Hg), unstable angina, syndrome of inappropriate antidiuretic hormone secretion (SIADH), severe daytime lower urinary tract symptoms with more than 8 daytime voids per day, prior treatment with desmopressin for nocturia, and illness requiring systemic corticosteroid therapy. Concomitant medications for benign prostatic hypertrophy and overactive bladder were permitted if patients had been on stable doses for the past 6 months and did not change these doses during the study.

NOCTIVA Met Endpoints in Phase 3 Trials

Both doses of NOCTIVA achieved statistical significance for the two co-primary endpoints in a pooled analysis of data from both trials.¹ On average, nocturic voids decreased by 1.5 episodes with NOCTIVIA 1.66 mcg and by 1.4 episodes with NOCTIVA 0.83 mcg, versus a reduction of 1.2 episodes with placebo (each P<0.0001). Results were similar in each individual trial. In the pooled analysis, the percentage of patients who experienced at least a 50% reduction in mean nocturic episodes per night was 48.7% in the 1.66-mcg group and 37.9% in the 0.83-mcg group versus 30.3% in the placebo group (P<.0001 and P=.0055, respectively). NOCTIVA 1.66 mcg showed a statistically significant effect for this co-primary endpoint in each individual trial, whereas NOCTIVA 0.83 mcg showed a statistically significant effect only in the pooled analysis.

Both doses of NOCTIVA also significantly reduced nocturnal urine production compared with placebo. In the pooled analysis, nocturnal urine volume at baseline was approximately 805 mL in all three pooled treatment groups. At week 12, mean reductions in nocturnal urine volume were 259.7 mL in the pooled 1.66-mcg group and 195.2 mL in the 0.83-mcg group versus 132.7 mL in the placebo group (P<.0001 and P=.0025, respectively). Results were similar in the individual trials.

As we have discussed, waking during the first 3 to 4 hours of sleep interrupts restorative sleep, leading to next-day fatigue, discomfort, and a decreased pain threshold.¹⁴ NOCTIVA significantly increased first uninterrupted sleep periods in the pooled analysis of data from both trials. Mean increases were 108 minutes in the 1.66-mcg group and 96 minutes in the 0.83-mcg group versus 72 minutes in the placebo group (each P<.0001).¹ By the end of treatment week 12, first uninterrupted sleep periods averaged 252 minutes (i.e., 4.2 hours) in the 1.66-mcg group and 240 minutes (4.0 hours) in the 0.83-mcg group, versus 210 minutes (3.5 hours) in the placebo group (each P<.0001).¹⁰

Compared with placebo, NOCTIVA also significantly increased the percentage of nights in which patients had either no nocturia or a single nocturic episode.¹These percentages were 46.6% in the 1.66-mcg group and 39.9% in the 0.83-mcg group versus 33.8% in the placebo group in the pooled analysis (P<.0001 and P=.012, respectively). NOCTIVA 1.66 mcg produced a statistically significant effect for this secondary endpoint in each trial, whereas NOCTIVA 0.83 mcg reached statistical significance in the pooled analysis but not in the individual trials. In the pooled analysis, the percentages of nights with no nocturic episodes were 10.9% with NOCTIVA 1.66 mcg and 8.2% with NOCTIVA 0.83 mcg versus 5.3% with placebo (P<.0001 and P=.020, respectively).

In summary, NOCTIVA 1.66 mcg and NOCTIVA 0.83 mcg met co-primary and secondary endpoints in the pooled analysis of data from both trials. NOCTIVA 1.66 mcg also met these endpoints in each of the two individual trials, despite a considerable placebo response. The reason for this placebo response remains unclear. Education regarding lifestyle modifications might have played a role, although patients were instructed not to alter their usual fluid intake .

NOCTIVA also shows durable efficacy. In addition to the double-blind trials, two phase 3, open-label studies evaluated NOCTIVA 0.83 mcg for up to 43 weeks and NOCTIVA 1.66 mcg for up to 126 weeks. In both studies, NOCTIVA reduced nocturic episodes by approximately two episodes per night from baseline, and this improvement persisted throughout follow-up.

Impact on Daily Life

The higher 1.66-mcg dose of NOCTIVA was associated with significant improvements in patient-reported quality of life.¹ In the DB4 trial, NOCTIVA 1.66 mcg produced significant improvements from baseline in the overall INTU impact score (P=.0255) and in the nighttime domain score (P=.0118). Overall impact scores decreased by a mean of 14.1 points in the 1.66-mcg group, 12.4 points in the 0.83-mcg group, and 11.5 points in the placebo group.¹ Nighttime domain impact scores decreased by a mean of 18.0 points in the 1.66-mcg group, 16.0 points in the 0.83-mcg group, and 14.5 points in the placebo group. Differences in overall and nighttime impact scores between the 0.83-mcg group and the placebo group did not reach statistical significance.

Safety

NOCTIVA demonstrated an acceptable safety profile. Nasal discomfort and nasopharyngitis were the most common treatment-related adverse events in the two double-blind trials. These usually were mild to moderate in severity and affected similar proportions (2.6% to 5.6%) of individuals in the treatment and placebo arms.¹ The incidence of serious adverse events also was similar among arms (2% in the NOCTIVA 1.66 and 0.83 mcg groups and 3% in the placebo group). In the 1.66-mch arm, there was one case each of serious treatment-emergent hyponatremia and worsening hypertension that were considered probably related to treatment.

A total of 5.9% of patients in the pooled analysis discontinued treatment due to adverse effects, most commonly nasal symptoms such as congestion, rhinorrhea, sinus discomfort, and throat irritation.¹ Hyponatremia developed 6 days to 12 weeks after treatment initiation and affected similar proportions of men and women. The proportion of patients who developed serum sodium levels between 130 and 134 mmol/L was 11.2% in the 1.66-mcg group, 8.4% in the 0.83-mcg group, and 4.4% in the placebo group. The proportion of patients who developed serum sodium levels in the 126 to 129 mmol/L range was 2.0% in the 0.83-mcg and 1.66-mcg groups and 0% in the placebo group.

The incidence of moderate to severe hyponatremia (serum sodium 125 mmol/L or less regardless of symptoms or less than 130 mmol/L with symptoms) was 1.1% in the 1.66-mcg group, 0% in the 0.83-mcg group, and 0.2% in the placebo group.¹ All five patients in the 1.66-mcg group who developed serum sodium levels of 125 mmol/L or less were older than 65 years, and four were receiving contraindicated medications (inhaled or systemic corticosteroids).¹ The only placebo patient who developed a serum sodium level less than 125 mmol/L also was older than 65 years. Nausea and vomiting consistent with hyponatremia affected one patient each in the 1.66-mcg and placebo groups.

NOCTIVA has not been compared with other formulations of desmopressin in head-to-head trials.¹⁰ However, it is noteworthy that even though the DB3 and DB4 trials did not impose fluid restrictions and 54.5% of participants were 65 years or older,¹ the incidence of hyponatremia was generally less than that in studies of oral and orally disintegrating desmopressin formulations (3% to 16%).⁷³ However, because NOCTIVA contains desmopressin, its prescribing label includes a boxed warning for hyponatremia.⁷⁹ Clinicians should avoid prescribing NOCTIVA for patients at increased risk for severe hyponatremia and should ensure that serum sodium concentration is normal before starting or resuming NOCTIVA. The use of NOCTIVA during pregnancy is not recommended and NOCTIVA also should not be used for the treatment of primary nocturnal enuresis in children, as the clinical trials excluded these populations.

Case Study and Clinical Takeaways

As discussed previously, 61-year-old Michael typifies the experience of nocturnal polyuria in many older men. However, women and younger patients also commonly experience bothersome, clinically significant nocturia. The mental and physical impact of nocturia can especially difficult for younger patients, who often juggle demanding work schedules and parenting or caregiving responsibilities.^43,26

For example, Lisa is a 46-year-old flight attendant with a 5-year history of overactive bladder. She reports that antimuscarinic treatment with solifenacin (started at 5 mg and subsequently increased to 10 mg) has greatly improved her daytime urgency but not her nocturia. She continues to wake every 2 to 2.5 hours at night to void despite drinking only 32 ounces of water per day, avoiding all fluids after 6 PM, limiting caffeine to a single cup of coffee in the morning, and abstaining from alcohol. Lisa also states that her nocturia is causing significant daytime fatigue and difficulty functioning at work. She asks about intranasal desmopressin treatment with NOCTIVA.

Lisa appears to be a good candidate for NOCTIVA therapy. Her fluid intake and voiding patterns indicate that her nocturia is due to nocturnal polyuria, and she has no contraindications for receiving NOCTIVA such as current hyponatremia, a history of hyponatremia, or pregnancy, urinary retention, estimated glomerular filtration rate [GFR] below 50 mL/min/1.73 m², polydipsia, primary nocturnal enuresis, syndrome of inappropriate antidiuretic hormone secretion [SIADH], New York Heart Association (NYHA) Class II-IV congestive heart failure, uncontrolled hypertension, or concomitant use of loop diuretics or systemic or inhaled glucocorticoids.⁷⁹

NOCTIVA is available in two microdose formulations: 1.66 mcg for patients younger than 65 years who are not at increased risk for hyponatremia, and NOCTIVA 0.83 mcg for patients who are 65 years of age or older or for younger patients at increased risk for hyponatremia.⁷⁹ After at least 7 days of treatment, the 0.83-mcg dose can be increased to 1.66 mcg if needed, provided that the serum sodium concentration stays within normal range during treatment with the 0.83-mcg dose.

Based Lisa’s age, history, and nocturia, she and her urologist decide to start NOCTIVA 1.66 mcg. Her serum sodium level is confirmed to be within normal range (141 meq/L) at baseline and she makes an appointment to have it re-measured 7 days and again 1 month after starting NOCTIVA.⁷⁹ If her serum sodium remains within normal limits, she can continue NOCTIVA 1.66 mcg as long as she agrees to periodic serum sodium monitoring.

Periodic serum sodium monitoring should be performed more frequently in patients who are 65 years of age and older or at increased risk for hyponatremia. These include patients who are on medications that can increase the risk for hyponatremia, including selective serotonin reuptake inhibitors (SSRIs), serotonin and norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants, chlorpromazine, opiate analgesics, anti-inflammatory medications, lamotrigine, and carbamapezine. ^76,77,79

Since Lisa is receiving the SSRI sertraline, her urologist advises repeat serum sodium monitoring every 6 months. She also is instructed to have her serum sodium level measured 7 days and 1 month after any increase in her antidepressant dose or if she adds or switches to other medications that can cause hyponatremia. She is given a list of these medications to take home along with a print-out summarizing her treatment instructions.

Lisa’s urologist informs her that her bottle of NOCTIVA contain 30 days of medication when used once per night, can be stored at room temperature for up to 60 days after opening, and does not need to be re-primed unless she goes more than 3 nights without using it.⁷⁹ She is instructed to spray NOCTIVA once in each nostril 30 minutes before bedtime and not to double-dose, even if it seems that not much liquid is dispensed when the applicator is pumped.⁷⁹

Finally, Lisa is educated to stop using NOCTIVA if she develops a condition that could increase its intranasal absorption, such as respiratory infections or hay fever, or if she develops any condition that might lead to fluid or electrolyte imbalances, such as illnesses that cause vomiting. She should only re-start NOCTIVA after such conditions fully resolve. Lisa returns after 1 month of treatment. Her serum sodium remains within normal limits (137 mEq/L) and she reports that she is now able to sleep 4 hours before waking to void. She reports significant improvements in her mood, energy levels, and productivity.

Summary

Nocturia, the most prevalent lower urinary tract symptom among adults of all ages, significantly reduces energy levels, productivity, and quality of life, increases the risk of serious somatic and mental illnesses, and is an independent risk factor for falls, fractures, and mortality. Although nocturnal polyuria is the most common cause of nocturia, the condition is complex and multifactorial and all possible etiologies must be considered to maximize the chances of treatment efficacy. Management should include lifestyle and behavioral modifications, although these can be difficult to sustain and usually are not effective by themselves.

Medications for overactive bladder and benign prostatic hypertrophy are not approved for the treatment of nocturnal polyuria and are usually ineffective in this context. NOCTIVA, a novel formulation of intranasal desmopressin, is the first FDA-approved treatment for adults with nocturnal polyuria who wake at least twice per night to void. In two randomized, double-blind, placebo-controlled trials, NOCTIVA significantly reduced mean nocturic episodes, increased the likelihood of achieving at least a 50% reduction from baseline in mean nocturic episode, significantly reduced nocturnal urine production, increased the percentage of nights in which patients had one or fewer nocturic episodes, and significantly increased the mean first uninterrupted sleep period. NOCTIVA 1.66 mcg also was associated with significant positive patient-reported improvements of quality of life based on a validated survey tool.

NOCTIVA showed a tolerable safety profile, with only 1.1% of treated patients in the safety analysis developing serum sodium levels of 125 mmoL per L or less. All these patients were older than 65 years, and two were receiving contraindicated medications in the form of inhaled or systemic corticosteroids. The safe, effective use of NOCTIVA requires appropriate patient selection, education, and monitoring of treatment response. NOCTIVA is available in two desmopressin microdoses (1.66 mcg and 0.83 mcg), enabling physicians to tailor therapy accordingly.

Published Date: April 16th, 2019

Written by: Roger R. Dmochowski, MD, MMHC, FACS and Benjamin M. Brucker, MD

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Diagnosing and Staging of Prostate Cancer

Secondary to the introduction of prostate specific antigen (PSA) screening in the 1980’s/1990’s, symptomatic presentation of prostate cancer has become less frequent. Symptoms of locally advanced prostate cancer may include obstructive urinary symptoms, gross hematuria, and/or upper tract urinary obstruction leading to renal failure. Once the diagnosis of prostate cancer is made, staging is important, which may include imaging studies in cases of high-risk disease. This article will focus on contemporary diagnosis/screening modalities in addition to the staging of localized prostate cancer.

Diagnosis

Screening

The goal of screening for any malignancy is early detection with the hopes of intervening with treatment at an earlier time period in order to reduce cancer-specific mortality. Screening for prostate cancer involves a digital rectal examination (DRE) and a serum PSA blood test. Screening in certain instances may lead to over treatment of clinically insignificant disease, for which urologists have been criticized with regards to prostate cancer over treatment.^{1, 2} Notwithstanding, during the PSA screening era for prostate cancer, disease mortality has declined by ~40% with a substantial decrease in men presenting with advanced malignancy.³

Two randomized control trials (RCTs) were initiated in 1993 to compare prostate cancer-specific mortality between prostate cancer screened and unscreened men.^{4, 5} The European Randomized Study of Screening for Prostate Cancer (ERSPC) trial identified 182,000 men (ages 50-74 years) who were randomly assigned to a group that was offered PSA screening once every four years or to a control group that did not receive screening⁴. During a median follow-up of 9 years, the cumulative incidence of prostate cancer was 8.2% in the screening group and 4.8% in the control group. The rate ratio (RR) for death from prostate cancer in the screening vs control group, was 0.80 (95%CI 0.65-0.98). This correlated to 1410 men needing to be screened and 48 additional cases of prostate cancer treated to prevent one death from prostate cancer. The Prostate, Lung, Colorectal, and Ovarian (PLCO) cancer screening trial randomly assigned men in the US to receive either annual screening (n=38,343) or usual care (n=38,350).⁵ Importantly, in this trial “usual care” occasionally included screening; rates of screening in the control group increased from 40% in the first year to 52% in the sixth year for PSA testing. After seven years of follow-up, the incidence of prostate cancer per 10,000 person-years was 116 in the screening group and 95 in the control group (RR 1.22; 95CI 1.16-1.29). The incidence of death per 10,000 person-years was 2.0 in the screening group and 1.7 in the control group (RR 1.13; 95%CI 0.75-1.70), thus the results of the study suggested that prostate cancer screening did not reduce cancer-specific mortality.

Since the initial reporting of these two RCTs nearly a decade ago, several follow-up iterations have been published for the ERSPC^{6, 7} and PLCO^{8, 9} trials, confirming initial results: a screening benefit in the ERSPC trial and no benefit in the PLCO trial. These trials have been thoroughly analyzed as to potential reasons for differing results. The PLCO trial had (i) a shorter screening interval, (ii) higher threshold for prostate biopsy, (iii) halted regular screening after six rounds, and had (iv) “contamination” in the control group, considering that these men often received screening. As such, the PLCO has been described as organized screening vs opportunistic screening, rather than screening vs no screening.^{8, 9}

Recommendations for Screening

The United States Preventative Services Task Force (USPSTF) has been highly critical of PSA screening and relied heavily on results of the PLCO trial for their recommendations against routine screening for prostate cancer.^{2, 10} The American Urological Association (AUA) guidelines for prostate cancer screening were most recently released in 2013 and revalidated in 2018,¹¹ suggesting shared decision making for men 55-69 years of age who are considering PSA-based screening. These recommendations were based on the benefits outweighing the harms of screening in this age group. Other organizations, such as the European Association of Urology (EAU), recommend a baseline PSA test at age 40-45, which is then used to guide a subsequent screening interval.¹² Most recently, the USPSTF changed their recommendation against PSA screening for men aged 55-69 (Grade D) to a Grade C recommendation for prostate cancer screening: clinicians should not screen men who do not express a preference for screening.¹³

Triggers for Biopsy

Various “triggers” for prostate biopsy have been proposed with no consensus agreement. Generally, urologists agree that a positive DRE finding should be followed by a prostate biopsy. When the DRE is unremarkable, PSA thresholds are primarily used to guide recommendations for consideration of a prostate biopsy. The upper limit of a normal PSA has historically been set at 4 ng/mL, however the ERSPC has suggested this level should be lowered to 2.5-3.0 ng/mL. A recent study suggested that men <50 years of age with a PSA >1.5 ng/mL should consider a prostate biopsy, as more than half of these patients diagnosed with prostate cancer exceed the Epstein criteria for active surveillance.¹⁴ Furthermore, in an ad hoc analysis of the placebo arm of the Prostate Cancer Prevention Trial (PCPT), Thompson et al.¹⁵ showed a continuum of prostate cancer risk at all PSA values: PSA cutoff values of 1.1, 2.1, 3.1, and 4.1 ng/mL yielded sensitivities of 83.4%, 52.6%, 32.2%, and 20.5%, and specificities of 38.9%, 72.5%, 86.7%, and 93.8%, respectively, for detecting any prostate cancer. Undoubtedly, there is no perfect trigger for deciding whether to perform a prostate biopsy, as all factors must be taken into account, including age, race, family history, PSA trend, etc.

Staging

The clinical staging of prostate cancer relies on factors prior to treatment, such as PSA, DRE, prostate biopsy results, and imaging findings. Pathologic staging of prostate cancer relies on the stage of disease after surgical extirpation of the prostate. The following discussion will primarily focus on clinical staging.

Prostate Biopsy and Gleason Classification

At the time of prostate biopsy, a “systematic sampling” of the prostate is undertaken, typically consisting of 10-12 biopsy cores of tissue. Positive samples are then scored a primary and secondary Gleason score: 3+3, 3+4, 4+3, 4+4, 4+5, 5+4, or 5+5. Over the last 20 years, the D’Amico risk stratification has been commonly used to guide treatment¹⁶ Low-risk disease (cT1-2a, PSA ≤10 ng/mL, and Gleason ≤6), intermediate-risk disease (T2b or PSA >10 ng/ml but <20 ng/ML, or Gleason score 7), and high-risk disease (T2c, or PSA >20 ng/mL or Gleason 8-10), conferred freedom of disease 10-years after radical prostatectomy rates of 83%, 46%, and 29%, respectively.¹⁶

Several years ago, the Gleason Grade Group (GGG) was proposed to better reflect the true cancer biologic aggressiveness and better guide treatment: GGG 1 is Gleason 6, GGG 2 is 3+4=7, GGG 3 is Gleason 4+3=7, GGG 4 is Gleason 8, GGG 5 is Gleason 9-10.¹⁷ In a Swedish population-level database of 5,880 men diagnosed with prostate cancer, using the GGG schema demonstrated four-year biochemical recurrence-free survival rates of 89% (GGG 1), 82% (GGG 2), 74% (GGG 3), 77% (GGG 4), and 49% (GGG 5) on biopsy, and 92% (GGG 1), 85% (GGG 2), 73% (GGG 3), 63% (GGG 4), and 51% (GGG 5) based on prostatectomy data¹⁸ Generally, the GGG classification offers a simplified nomenclature with predictive accuracy comparable to previously used classification schemes.

Classification

table 1 diagnosing staging prostate cancer2x

table 2 diagnosing staging prostate cancer2x

Imaging

Several imaging modalities have been used to radiographically stage prostate patients. Generally, staging studies have included a radionuclide bone scan (to assess for skeletal metastases) and a computed tomography (CT) scan of the abdomen and pelvis (to assess for lymphadenopathy). Selecting appropriate patients for imaging is a point of much debate. The general consensus is that there is no role for imaging patients with low-risk disease, whereas imaging is appropriate for patients with either PSA >20 ng/mL, GGG 4-5, cT3-T4 or clinical symptoms of bone metastases.¹¹

The improvement in multi-parametric MRI (mpMRI) technology has allowed, not only the ability to perform targeted prostate biopsies but also to stage patients for locoregional extent of disease. mpMRI comprises anatomic sequences (T1/T2) supplemented by functional imaging techniques such as diffusion-weighted and dynamic contrast-enhanced (DCE) imaging. When performed at high resolution, DCE facilitates detection of disease, as well as an assessment of extracapsular extension, urethral sphincter, and seminal vesicles involvement.²⁰ Furthermore, mpMRI may provide accurate information for planning robotic prostatectomy. In a study assessing the ability of mpMRI to assist with planning neurovascular bundle preservation, mpMRI results changed preoperatively planning in 26% of cases based on the extent of disease.²¹

Conclusions

Prostate cancer screening has been crucial to decreasing the burden of disease and improving mortality rates. However, early practices of over-screening and over-treatment have led to strong recommendations from non-urologic governing bodies recommending against prostate cancer screening, which has just recently changed to provide screening options for certain men (55-69 years of age). Prostate cancer screening should be based on a shared decision-making model, allowing patients to make educated decisions that best fit their healthcare needs. As prognostic tools continue to be refined and imaging technology improves, diagnosis and staging of prostate cancer will hopefully lead to an improved selection of men that need screening and ultimately those who may benefit from treatment.

Published Date: April 16th, 2019

Written by: Zachary Klaassen, MD, MSc

References:

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Prostate Cancer and Tumor Markers

The discovery of prostate-specific antigen (PSA) in the late 1970s and its widespread application and adoption in the 1980s and 1990s ushered in the prostate cancer screening and disease monitoring era. As the first tumor marker for prostate cancer, it is organ specific but not cancer specific.¹ thus providing the opportunity for further tumor marker investigation. A potential biomarker must go through a rigorous vetting process from discovery → differentiation of case from control → ability to detect preclinical disease (defining a positive test) → indications for application and validation → cancer control studies.² Secondary to the cost and time involved, biomarkers are rarely tested in large randomized controlled trials (RCTs). However, the development of the Prospective Randomized Open, Blinded Endpoint (PROBE) initiative for biomarker studies was designed to overcome spectrum and ascertainment bias and give guidance for validation studies.³ Biomarkers are typically evaluated based on their positive predictive value (probability that a positive test indicates the presence of disease) and negative predictive value (probability that a negative test indicates the absence of disease), entities that rely on the test’s specificity, sensitivity, and prevalence of the disease. This article will focus on briefly reviewing the clinical utility of several commonly used tumor markers associated with prostate cancer detection.

Blood

PSA
PSA is part of the kallikrein gene family located on chromosome 19 and functions as a serine protease, predominantly produced by prostate luminal cells. PSA in the serum is typically bound to proteins (~80% of PSA; complexed) or unbound (free PSA). The production of PSA is androgen dependent⁴ and in the absence of cancer varies with age,⁵ race,^{6, 7} and prostate volume.⁸ African-American men without prostate cancer have a higher PSA level compared to similar Caucasian men when assessed on a volume-to-volume ratio.⁹ Additionally, many studies have suggested that PSA in men with higher body mass index (BMI) have lower PSAs, a concept referred to as “hemodilution”:¹⁰ a greater plasma volume leading to lower hematocrit and PSA. Recent studies have provided further support for the hemodilution theory, in that only a fraction of lower PSA values in obese men are attributed to testosterone and dihydrotestosterone levels, with the remaining lower PSA explained presumably by hemodilution.¹¹ The greatest contributor to elevated PSA is prostatic diseases, namely prostatitis, BPH and prostate cancer. Without question, the decrease in specificity associated with PSA and prostate cancer is an elevated PSA in men with prostatitis and/or BPH.

Free PSA (fPSA)
fPSA is PSA that is enzymatically inactive and non-complexed, making up 4-45% of total PSA;¹² men with PSA from prostate cancer cells have a lower percentage of total PSA that is free, compared to those without prostate cancer.¹³ fPSA has FDA approval for men with a negative digital rectal examination (DRE) and total PSA level of 4-10 ng/mL, largely on the basis of a prospective study of men demonstrating a %fPSA (fPSA/total PSA) cutoff of 25% detecting 95% of prostate cancers, while avoiding 20% of biopsies.¹⁴ A generally acceptable cut-point ranges from 15-25%. Twenty years later, %fPSA is still used for clinically appropriate men, most commonly used in those with an elevated PSA and a negative prostate biopsy. In these men, studies have reported a 5% cancer under-detection rate and 21% cutoff for repeating prostate biopsy.¹⁵

Kallikreins
PSA, also known as human kallikrein 3 (hK3), is the most famous of the kallikreins, however, there are other kallikreins that have recently been explored as prostate cancer tumor markers. hK2 shares 80% amino acid homology with PSA, however, is weakly expressed in benign tissue and intensely expressed in prostate cancer tissue.¹⁶ Low-grade disease generally has low expression of hK2, whereas aggressive disease has high levels of expression.¹⁶ Recently, the hK2 kallikrein has been incorporated into a panel of kallikrein markers (total PSA, free PSA, intact PSA, and hK2, along with clinical information), commercially available as the 4KScore Test, used for calculating a patient’s percent risk for aggressive prostate cancer. First described in 2008, Vickers et al.¹⁷ tested the utility of the kallikrein panel in 740 men in the Swedish arm of the ERSPC screening trial. They found that adding free and intact PSA with hK2 to total PSA improved the clinical area under the curve (AUC) from 0.72 to 0.84. When the authors applied a 20% risk of prostate cancer as the threshold for biopsy, 424 (57%) of biopsies would have been avoided, missing 31 of 152 low-grade and 3 of 40 high-grade cancers.¹⁷ Since this study a decade ago, many studies have validated these findings, including among 6,129 men participating in the ProtecT study:¹⁸ the AUC for the four kallikreins was 0.719 (95%CI 0.704-0.734) vs 0.634 (95%CI 0.617-0.651, p<0.001) for PSA and age alone for any-grade cancer, and 0.820 (95%CI 0.802-0.838) vs 0.738 (95%CI 0.716-0.761) for high-grade prostate cancer.

Prostate Health Index (phi)
The phi test combines total, free and [-2]proPSA into a single score for improving the accuracy of prostate cancer detection. In the seminal study leading to FDA approval, Catalona et al.¹⁹ assessed phi scores among 892 patients without prostate cancer and a PSA between 2-10 ng/mL. They found that an increasing phi score was associated with a 4.7-fold increased risk of prostate cancer and a 1.6-fold increased risk of Gleason score ≥ 4+3 disease at prostate biopsy. Furthermore, the phi score AUC exceeded that of %fPSA (0.72 vs 0.67) to discriminate high vs low-grade disease or negative biopsy. In a subsequent study, Loeb et al.²⁰ confirmed the phi score’s ability to outperform total, free and [-2]proPSA for identifying clinically significant prostate cancer.

Urine

Prostate Cancer Antigen 3 (PCA3)
PCA3 is a long noncoding RNA shed into the urine that is not expressed outside the prostate and is associated with much higher expression in malignant than benign prostate tissue.²¹ Prior to collecting urine for a PCA3 test, a “rigorous” DRE is performed in order to enhance the sensitivity of the test. The commercial PCA3 score is reported as a ratio of urine PCA3 mRNA to urine PSA mRNA x 1000. The optimal cutoff is still debated, however in a contemporary comparative effectiveness review, Bradley et al.²² showed that a PCA3 threshold of 25 resulted in a sensitivity of 74% and specificity of 57% for a positive biopsy. This threshold led to FDA approval of the PCA3 test in 2012 among men with a prior negative prostate biopsy.

Since then, several groups have reported results of PCA3 in biopsy naïve men. In a retrospective review of 3,073 men undergoing initial biopsy, Chevli et al.²³ found that the mean PCA3 was 27.2 for those without, and 52.5 for patients with prostate cancer. Prostate cancer was identified in 1,341 (43.6%) men; on multivariable analysis, PCA3 was associated with any (OR 3.0, 95%CI 2.5-3.6) and high-grade (OR 2.4, 95%CI 1.9-3.1) prostate cancer after adjusting for clinicopathologic variables. Furthermore, PCA3 outperformed PSA in the prediction of prostate cancer (AUC 0.697 vs 0.599, p<0.01) but did not for high-grade disease (AUC 0.682 vs 0.679, p=0.702).²³

microRNAs (miRNAs)
miRNAs are small, noncoding single-stranded RNAs involved in the regulation of mRNA. Due to their short sequence (typically 19-22 nucleotides), miRNAs are highly stable in most body fluids (including urine) as they are resistant to RNase degradation.²⁴ Several miRNAs have been implicated as potential biomarkers in prostate cancer diagnosis and management, including miRNA-141, miRNA-375, miRNA-221, miRNA-21, miRNA-182 and miRNA-187.^{25, 26} miR-187 detected in urine has been suggested as a candidate for improving the predictive value for a positive biopsy; a prediction model including serum PSA, urine PCA3, and miR-187 provided 88.6% sensitivity and 50% specificity (AUC 0.711, p = 0.001) for a positive biopsy.²⁶ Ultimately, these miRNAs need to be further validated in terms of their ability to regulate various pathways important for prostate cancer management and their potential role as tumor markers.

Combining Tumor Markers

In an effort to improve the predictive accuracy of a positive biopsy, the last several years have seen a plethora of studies combining biomarkers to not only improve predictive accuracy above that offered by PSA, but also individual, newer biomarkers. As previously mentioned, the decrease in specificity associated with PSA and prostate cancer is secondary to an elevated PSA in men with prostatitis and/or BPH. The “perfect” biomarker (or combination) would delineate prostate cancer (and ultimately high-grade prostate cancer) from other benign entities.

Vedder et al.²⁷ assessed the added value of %fPSA, PCA3, and 4KScore Test to the ERSPC prediction models among men in the Dutch arm of the ERSPC screening trial. Prostate cancer was detected in 119 of 708 men – adding %fPSA did not improve the predictive value of the risk calculators, however, the 4KScore discriminated better than PCA3 in univariate models (AUC 0.78 vs. 0.62; p=0.01). In the overall population, there was no statistically significant difference between the multivariable model with PCA3 (AUC 0.73) versus the model with the 4KScore (AUC 0.71; p=0.18). Among 127 men with a previous negative biopsy, Auprich et al.²⁸ compared the performance of total PSA, %fPSA, PSA velocity (PSAV), and PCA3 at first, second and ≥ third repeat biopsy. At first repeat biopsy, PCA3 predicted prostate cancer best (AUC 0.80) compared with total PSA. A second repeat biopsy, %fPSA demonstrated the highest accuracy (AUC 0.82), and again at ≥ third repeat biopsy %fPSA demonstrated the highest accuracy (AUC 0.70).²⁸

This sampling of studies demonstrates that many combinations of biomarkers are being studied in an effort to improve detection of high-grade cancer and decrease the number of unnecessary biopsies. The next generation of biomarker combinations has and will continue to incorporate multi-parametric prostate MRI into predictive algorithms for clinically significant prostate cancer.^29-31

Conclusions

For over four decades, research efforts have been directed towards improving the detection of prostate cancer and attempting to build on the predictive accuracy of the first prostate cancer tumor marker, PSA. With the United States Preventative Services Task Force’s 2012 recommendation for the urgent need to identify new screening efforts to better identify indolent versus aggressive disease, the last several years have seen a dramatic increase in prostate cancer biomarker options. As briefly highlighted, biomarker combinations studies have demonstrated improved predictive accuracy of positive biopsies; however, these combinations are far from perfect, are expensive and much work remains to be done. Furthermore, the specific indication (pre-biopsy, post-negative biopsy, active surveillance, etc) and a combination of tumor markers remain to be fully elucidated.

Published Date: April 16th, 2019

Written by: Zachary Klaassen, MD, MSc

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2. Srivastava S. The early detection research network: 10-year outlook. Clin Chem. 2013;59:60-7.
3. Pepe MS, Feng Z, Janes H, Bossuyt PM, Potter JD. Pivotal evaluation of the accuracy of a biomarker used for classification or prediction: standards for study design. J Natl Cancer Inst. 2008;100:1432-8.
4. Henttu P, Liao SS, Vihko P. Androgens up-regulate the human prostate-specific antigen messenger ribonucleic acid (mRNA), but down-regulate the prostatic acid phosphatase mRNA in the LNCaP cell line. Endocrinology. 1992;130:766-72.
5. Partin AW, Criley SR, Subong EN, Zincke H, Walsh PC, Oesterling JE. Standard versus age-specific prostate specific antigen reference ranges among men with clinically localized prostate cancer: A pathological analysis. J Urol. 1996;155:1336-9.
6. Smith DS, Carvalhal GF, Mager DE, Bullock AD, Catalona WJ. Use of lower prostate specific antigen cutoffs for prostate cancer screening in black and white men. J Urol. 1998;160:1734-8.
7. Espaldon R, Kirby KA, Fung KZ, Hoffman RM, Powell AA, Freedland SJ, et al. Probability of an abnormal screening prostate-specific antigen result based on age, race, and prostate-specific antigen threshold. Urology. 2014;83:599-605.
8. Naya Y, Stamey TA, Cheli CD, Partin AW, Sokoll LJ, Chan DW, et al. Can volume measurement of the prostate enhance the performance of complexed prostate-specific antigen? Urology. 2002;60:36-41.
9. Fowler JE, Jr., Bigler SA, Kilambi NK, Land SA. Relationships between prostate-specific antigen and prostate volume in black and white men with benign prostate biopsies. Urology. 1999;53:1175-8.
10. Ohwaki K, Endo F, Muraishi O, Hiramatsu S, Yano E. Relationship between prostate-specific antigen and hematocrit: does hemodilution lead to lower PSA concentrations in men with a higher body mass index? Urology. 2010;75:648-52.
11. Klaassen Z, Howard LE, Moreira DM, Andriole GL, Jr., Terris MK, Freedland SJ. Association of Obesity-Related Hemodilution of Prostate-Specific Antigen, Dihydrotestosterone, and Testosterone. Prostate. 2017;77:466-70.
12. McCormack RT, Rittenhouse HG, Finlay JA, Sokoloff RL, Wang TJ, Wolfert RL, et al. Molecular forms of prostate-specific antigen and the human kallikrein gene family: a new era. Urology. 1995;45:729-44.
13. Catalona WJ, Beiser JA, Smith DS. Serum free prostate specific antigen and prostate specific antigen density measurements for predicting cancer in men with prior negative prostatic biopsies. J Urol. 1997;158:2162-7.
14. Catalona WJ, Partin AW, Slawin KM, Brawer MK, Flanigan RC, Patel A, et al. Use of the percentage of free prostate-specific antigen to enhance differentiation of prostate cancer from benign prostatic disease: a prospective multicenter clinical trial. JAMA. 1998;279:1542-7.
15. Stephan C, Lein M, Jung K, Schnorr D, Loening SA. Re: Editorial: can prostate specific antigen derivatives reduce the frequency of unnecessary prostate biopsies? J Urol. 1997;157:1371.
16. Darson MF, Pacelli A, Roche P, Rittenhouse HG, Wolfert RL, Saeid MS, et al. Human glandular kallikrein 2 expression in prostate adenocarcinoma and lymph node metastases. Urology. 1999;53:939-44.
17. Vickers AJ, Cronin AM, Aus G, Pihl CG, Becker C, Pettersson K, et al. A panel of kallikrein markers can reduce unnecessary biopsy for prostate cancer: data from the European Randomized Study of Prostate Cancer Screening in Goteborg, Sweden. BMC Med. 2008;6:19.
18. Bryant RJ, Sjoberg DD, Vickers AJ, Robinson MC, Kumar R, Marsden L, et al. Predicting high-grade cancer at ten-core prostate biopsy using four kallikrein markers measured in blood in the ProtecT study. J Natl Cancer Inst. 2015;107.
19. Catalona WJ, Partin AW, Sanda MG, Wei JT, Klee GG, Bangma CH, et al. A multicenter study of [-2]pro-prostate specific antigen combined with prostate specific antigen and free prostate specific antigen for prostate cancer detection in the 2.0 to 10.0 ng/ml prostate specific antigen range. J Urol. 2011;185:1650-5.
20. Loeb S, Sanda MG, Broyles DL, Shin SS, Bangma CH, Wei JT, et al. The prostate health index selectively identifies clinically significant prostate cancer. J Urol. 2015;193:1163-9.
21. de Kok JB, Verhaegh GW, Roelofs RW, Hessels D, Kiemeney LA, Aalders TW, et al. DD3(PCA3), a very sensitive and specific marker to detect prostate tumors. Cancer Res. 2002;62:2695-8.
22. Bradley LA, Palomaki GE, Gutman S, Samson D, Aronson N. Comparative effectiveness review: prostate cancer antigen 3 testing for the diagnosis and management of prostate cancer. J Urol. 2013;190:389-98.
23. Chevli KK, Duff M, Walter P, Yu C, Capuder B, Elshafei A, et al. Urinary PCA3 as a predictor of prostate cancer in a cohort of 3,073 men undergoing initial prostate biopsy. J Urol. 2014;191:1743-8.
24. Schwarzenbach H, Nishida N, Calin GA, Pantel K. Clinical relevance of circulating cell-free microRNAs in cancer. Nat Rev Clin Oncol. 2014;11:145-56.
25. Sharma N, Baruah MM. The microRNA signatures: aberrantly expressed miRNAs in prostate cancer. Clin Transl Oncol. 2018.
26. Casanova-Salas I, Rubio-Briones J, Calatrava A, Mancarella C, Masia E, Casanova J, et al. Identification of miR-187 and miR-182 as biomarkers of early diagnosis and prognosis in patients with prostate cancer treated with radical prostatectomy. J Urol. 2014;192:252-9.
27. Vedder MM, de Bekker-Grob EW, Lilja HG, Vickers AJ, van Leenders GJ, Steyerberg EW, et al. The added value of percentage of free to total prostate-specific antigen, PCA3, and a kallikrein panel to the ERSPC risk calculator for prostate cancer in prescreened men. Eur Urol. 2014;66:1109-15.
28. Auprich M, Augustin H, Budaus L, Kluth L, Mannweiler S, Shariat SF, et al. A comparative performance analysis of total prostate-specific antigen, percentage free prostate-specific antigen, prostate-specific antigen velocity and urinary prostate cancer gene 3 in the first, second and third repeat prostate biopsy. BJU Int. 2012;109:1627-35.
29. Johnston E, Pye H, Bonet-Carne E, Panagiotaki E, Patel D, Galazi M, et al. INNOVATE: A prospective cohort study combining serum and urinary biomarkers with novel diffusion-weighted magnetic resonance imaging for the prediction and characterization of prostate cancer. BMC Cancer. 2016;16:816.
30. Sciarra A, Panebianco V, Cattarino S, Busetto GM, De Berardinis E, Ciccariello M, et al. Multiparametric magnetic resonance imaging of the prostate can improve the predictive value of the urinary prostate cancer antigen 3 test in patients with elevated prostate-specific antigen levels and a previous negative biopsy. BJU Int. 2012;110:1661-5.
31. Perlis N, Al-Kasab T, Ahmad A, Goldberg E, Fadak K, Sayid R, et al. Defining a Cohort that May Not Require Repeat Prostate Biopsy Based on PCA3 Score and Magnetic Resonance Imaging: The Dual Negative Effect. J Urol. 2018;199:1182-7.

Epidemiology and Etiology of Prostate Cancer

Epidemiology

Incidence
For the last 30+ years, prostate cancer has been the most common noncutaneous malignancy among men in the United States, with 1 in 7 men being diagnosed with the disease.⁴ Similar to the United States, prostate cancer is the second most commonly diagnosed malignancy among men worldwide, with 1.1 million new cases diagnosed per year.⁵ In developed countries, the age-standardized rate (ASR) of prostate cancer incidence is 69.5 per 100,000 compared to 14.5 per 100,000 in developing countries.⁵ Crude differences in incidence between developed and developing countries are likely secondary to poor use of screening⁶ and lower life expectancies in developing countries.

Mortality
Among all men in the United States, 1 in 38 men will die from prostate cancer.⁴ Prostate cancer ranks as the leading cause of cancer death globally, with the highest mortality rates noted in the Caribbean and Southern/Middle Africa.5 Furthermore, the ASR for mortality in developed countries is 10.0 per 100,000 compared to 6.6 per 100,000 in developing countries.⁵ Many hypotheses have been considered as to the decline in mortality seen in the United States after 1991, with the most commonly accepted (in addition to utilization of screening) being an increase in aggressive curative treatment of prostate cancer diagnosed in the 1980s.^7,8

A Global Perspective
The incidence and epidemiology from a global perspective is much different than what may typically be seen in the United States and Europe. For example, in India the incidence of prostate cancer is a fraction (1.7-5.3 per 100,000) of other first world countries (North America: 83.2-173.7 per 100,000),⁶ but secondary to the sheer size of the population (1.2 billion) the crude prevalence of prostate cancer is on par with countries such as the United States, UK, France, and Italy. Despite greater awareness of prostate cancer screening, data from India suggest that 4% of patients <50 years of age present with metastatic disease. Among worldwide prostate cancer incidence, 14% of cases are diagnosed within the Asia-Pacific region, with a wide variation of incidence rates across the Asian-Pacific countries. In Latin American countries, prostate cancer represents 28% of all incidence cancers (highest) and 13% of all cancer mortalities (second after lung cancer). Specifically, in Trinidad and Tobago, Guyana and Barbados, the incidence is 3-4x that of the United States. Particularly in Cuba, the mortality rates continue to increase, despite greater adoption of screening. The incidence of prostate cancer in the Middle East is higher than the Asian countries, specifically in Lebanon (37.2 per 100,000), Jordan (15.3 per 100,000), and Palestine (15.2 per 100,000). A closer look at the demographics at presentation among Middle Eastern men shows that 25% present with metastatic disease, with rates as high as 58% among men from Iraq. There are several hypotheses for the shift in incidence and prevalence of prostate cancer among non-North America/European countries, including (1) an increased awareness of prostate cancer leading to greater utilization of PSA testing, and (2) adoption of a more “Western” diet/lifestyle and less the traditional Indian/Asian/Mediterranean diet, particularly in the urban centers.

Unfortunately, a greater burden of disease among non-North American/European regions has presented several problems:

A wide variation in incidence/prevalence across countries in these regions, particularly in Asia-Pacific and Latin America
Huge discrepancies in quality and access to care between the private and public sector
Poor access to newer standards of care, leading to high rates of surgical castration and limited access to radiation therapy (ie. for treatment of bone metastases)
Limited organized cancer registries, thus grossly underestimating the true incidence and prevalence of prostate cancer

Age and Family History
Age is an established risk factor for prostate cancer, as men <40 years of age are highly unlikely to be diagnosed with prostate cancer, whereas men >70 years of age have a 1 in 8 chance of prostate cancer diagnosis.¹ In a population-based analysis of more than 200,000 patients, increasing age was associated with higher 15-year cancer-specific mortality (CSM) rates: 2.3% for men diagnosed ≤50 years of age, 3.4% for men 51-60 years of age, 4.6% for men 61-70 years of age, and 6.3% for men ≥71 years of age.⁹

A family history of prostate cancer is also strongly predictive of a prostate cancer diagnosis. To be considered hereditary prostate cancer, a family must have three affected generations, three first-degree relatives affected, or two relatives diagnosed prior to age 55.¹⁰ Men with one first-degree relative previously diagnosed with prostate cancer have a risk of a prostate cancer diagnosis that is 2-3x that of individuals with no family history.¹¹ Data on 65,179 white men from the PLCO cancer screening trial showed that men with a family history of prostate cancer had a significantly higher incidence of prostate cancer (16.9% vs 10.8%, p<0.01) and higher cancer-specific mortality (0.56% vs 0.37%, p<0.01).¹²

Race
Both prostate cancer incidence and mortality have been shown to be significantly related to race. African-Americans and Jamaicans of African descent have the highest incidence of prostate cancer in the world.¹ Despite decreases in mortality since the 1990s among all races, death rates of African Americans are still 2.4x higher than Caucasian patients.¹³ Several studies have assessed possible reasons for this discrepancy. In an ad hoc analysis of the REDUCE trial, African American men had greater non-compliance with study-mandated² and 4-year prostate biopsies, despite having greater prostate cancer risk (at 2-year biopsy),¹⁴ suggesting that population-level estimates of the excess prostate cancer burden in African American men may underestimate the degree of prostate cancer disparity. Gene expression assessment of prostate cancer specimens has noted numerous differentially expressed genes between African American and white patients, suggesting that there may be racial differences in androgen biosynthesis and metabolism.¹⁵ However, studies in mCRPC patients assessing clinical response to the potent anti-androgen abiraterone have not demonstrated racial differences when prospectively evaluated.¹⁶

The incidence of prostate cancer among races other than African-American and Caucasians is lower, including men of Asian descent living in the United States, although their incidence of prostate cancer is higher than those living within continental Asia.¹⁷ Interestingly, men moving from developing countries to high prostate cancer incidence countries demonstrate a shift in prostate cancer risk similar to that of their new country of residence.¹⁸ Ultimately, the relative components of genetics, socioeconomic factors, cultural, and environmental factors associated with racial differences observed are poorly understood.

Trends
There has been a significant drop in prostate cancer incidence in the last decade (~10% annually per year from 2010-2014), likely secondary to a decrease in PSA testing after the US Preventative Services Task Force (USPSTF) Grade D recommendation for screening of men older than 75 years of age (2008) and subsequently all men (2012) due to concern for overdiagnosis and overtreatment.^13,19 Following the USPSTF recommendations, an analysis of the National Cancer Database suggested that in the month after the recommendation, incident prostate cancer diagnoses decreased by 1,363 cases, followed by a drop of 164 cases per month thereafter for the first year (28% decrease in incident cases).²⁰ There has been considerable debate as to whether patients present with the more advanced disease since the USPSTF recommendations with no general consensus.²¹ Recently, the USPSTF changed their recommendation for PSA screening among men aged 55-69 years of age to a Grade C, suggesting that men in this age bracket should undergo periodic PSA-based screening for prostate cancer based on a decision after discussion regarding the potential benefits and harms of screening with their clinician.²²

Etiology and Risk Factors

Diet and Obesity
Initial evidence that diet and lifestyle may have a role in prostate cancer epidemiological outcomes was provided by ecological studies which demonstrated that men in Western countries had higher rates of prostate cancer than developing/non-Western countries.⁶ To strengthen this possible association, subsequent studies demonstrated that men from non-Western countries migrating to Western countries adopted similar lifestyle and prostate cancer risk as those in Western countries.²³ Nonetheless, several prospective studies since these ecologic descriptions assessing self-reported dietary patterns of healthy foods and the risk of prostate cancer have failed to show an association with diet and risk of prostate cancer.^24,25 Epidemiological evidence suggesting that statins reduce the risk of advanced stage prostate cancer suggests a possible role of cholesterol and prostate cancer risk.²⁶ Regardless, the complexity of the Western diet and the association/interaction with healthier lifestyles are limitations to understanding how diet influences prostate cancer risk.

Obesity has become an epidemic in the United States, and observational studies have suggested a modest increase in the risk of prostate cancer among obese individuals.^27,28 The pathophysiology between obesity and prostate cancer is likely secondary to higher levels of estradiol, insulin, and free IGF-1 levels, as well as lower free testosterone and adiponectin levels.²⁹ However, a clear pathophysiological explanation between obesity and prostate cancer is still uncertain and may be associated with lower serum PSA and larger prostates leading to fewer prostate biopsies.³⁰

Inflammation
Chronic inflammation has been implicated in the development of several cancers and may also be associated with prostate cancer. Possible etiologic factors suggested include: infectious agents, dietary carcinogens, hormonal imbalances, as well as physical and chronic trauma.³¹ As a result, intra-prostatic inflammation may lead to DNA damage, epithelial proliferation, cellular turnover, and angiogenesis.³¹ In men part of the placebo arm of the Prostate Cancer Prevention Trial (PCPT), those with at least one biopsy core of inflammation had an odds ratio (OR) of 1.78 (95%CI 1.04-3.06) for prostate cancer compared to men with no cores of inflammation.³² Furthermore, this association was even higher when considering a high-grade prostate cancer diagnosis (OR 2.24, 95%CI 1.06-4.71).³²

Medications
As mentioned, there has been emerging evidence that HMG-CoA reductase inhibitors (statins) may be associated with a lower risk of prostate cancer mortality following diagnosis.³³ Although there have been disparate results for the beneficial nature of statins and prostate cancer, a recent meta-analysis from observational studies of nearly 1 million patients noted that both post- and pre-diagnosis use of statins are beneficial for both overall survival (HR 0.81, 95%CI 0.72-0.91) and cancer-specific survival (HR 0.77, 95%CI 0.66-0.85).³⁴ Nonetheless, the exact role statins play in prostate carcinogenesis/protection is still widely debated.

Similar optimism with statins has been associated with metformin use and prostate cancer outcomes. Among patients with diabetes, metformin has been associated with a significant dose-dependent benefit for both prostate cancer-specific (HR 0.76, 95%CI 0.64-0.89 for each additional six months of metformin use) and all-cause mortality.³⁵ In a systematic review and meta-analysis of observational studies assessing clinical outcomes of patients with prostate cancer and metformin, medication use was marginally associated with a reduction in risk of biochemical recurrence (HR 0.82, 95%CI 0.67-1.01), but not associated with metastasis, prostate-cancer mortality or all-cause mortality.³⁶

Genetics
Prostate cancer is known to have an extraordinarily complex genetic makeup, including somatic copy number alterations, point mutations, structural rearrangements, and changes in chromosomal number.37 It is estimated that 5-10% of all prostate cancers may be caused by dominantly inherited genetic factors.¹¹ These include, but are not limited to HPC1, HPC2, HPC20, HPCX, PCAP, and CAPB.³⁸ More famously are the mutations associated with BRCA1 and BRCA2 and the associated increase in the risk of clinically significant prostate cancer, and prostate cancer-specific mortality among men with screen-detected prostate cancer.^39-41 Recent research has evaluated epigenetic markers for prostate cancer such as miRNA. The first report of miRNA and prostate cancer was reported in 2007,⁴² and since then many reports have implicated over 30 unique miRNAs and prostate carcinogenesis.

Conclusions

The epidemiology and etiology of prostate cancer are complex and multi-factorial. Prostate cancer remains a malignancy spanning the spectrum of localized/indolent disease to de novo advanced disease that is ultimately fatal. Although there are accepted differences in race and geography, the ultimate interplay between sociodemographic factors, environmental/lifestyle factors, and genetic differences remains to be fully elucidated.

Published Date: April 16th, 2019

Written by: Zachary Klaassen, MD, MSc

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Barocas DA, Mallin K, Graves AJ, et al. Effect of the USPSTF Grade D Recommendation against Screening for Prostate Cancer on Incident Prostate Cancer Diagnoses in the United States. J Urol. 2015;194(6):1587-1593.
Barry MJ, Nelson JB. Patients Present with More Advanced Prostate Cancer since the USPSTF Screening Recommendations. J Urol. 2015;194(6):1534-1536.
Force USPST, Grossman DC, Curry SJ, et al. Screening for Prostate Cancer: US Preventive Services Task Force Recommendation Statement. JAMA. 2018;319(18):1901-1913.
Yatani R, Shiraishi T, Nakakuki K, et al. Trends in frequency of latent prostate carcinoma in Japan from 1965-1979 to 1982-1986. J Natl Cancer Inst. 1988;80(9):683-687.
Wu K, Hu FB, Willett WC, Giovannucci E. Dietary patterns and risk of prostate cancer in U.S. men. Cancer Epidemiol Biomarkers Prev. 2006;15(1):167-171.
Key TJ, Allen N, Appleby P, et al. Fruits and vegetables and prostate cancer: no association among 1104 cases in a prospective study of 130544 men in the European Prospective Investigation into Cancer and Nutrition (EPIC). Int J Cancer. 2004;109(1):119-124.
Jespersen CG, Norgaard M, Friis S, Skriver C, Borre M. Statin use and risk of prostate cancer: a Danish population-based case-control study, 1997-2010. Cancer Epidemiol. 2014;38(1):42-47.
MacInnis RJ, English DR. Body size and composition and prostate cancer risk: systematic review and meta-regression analysis. Cancer Causes Control. 2006;17(8):989-1003.
Renehan AG, Tyson M, Egger M, Heller RF, Zwahlen M. Body-mass index and incidence of cancer: a systematic review and meta-analysis of prospective observational studies. Lancet. 2008;371(9612):569-578.
Buschemeyer WC, 3rd, Freedland SJ. Obesity and prostate cancer: epidemiology and clinical implications. Eur Urol. 2007;52(2):331-343.
Freedland SJ, Platz EA, Presti JC, Jr., et al. Obesity, serum prostate specific antigen and prostate size: implications for prostate cancer detection. J Urol. 2006;175(2):500-504; discussion 504.
De Marzo AM, Platz EA, Sutcliffe S, et al. Inflammation in prostate carcinogenesis. Nat Rev Cancer. 2007;7(4):256-269.
Gurel B, Lucia MS, Thompson IM, Jr., et al. Chronic inflammation in benign prostate tissue is associated with high-grade prostate cancer in the placebo arm of the prostate cancer prevention trial. Cancer Epidemiol Biomarkers Prev. 2014;23(5):847-856.
Stopsack KH, Greenberg AJ, Mucci LA. Common medications and prostate cancer mortality: a review. World J Urol. 2017;35(6):875-882.
Zhong S, Zhang X, Chen L, Ma T, Tang J, Zhao J. Statin use and mortality in cancer patients: Systematic review and meta-analysis of observational studies. Cancer Treat Rev. 2015;41(6):554-567.
Margel D, Urbach DR, Lipscombe LL, et al. Metformin use and all-cause and prostate cancer-specific mortality among men with diabetes. J Clin Oncol. 2013;31(25):3069-3075.
Raval AD, Thakker D, Vyas A, Salkini M, Madhavan S, Sambamoorthi U. Impact of metformin on clinical outcomes among men with prostate cancer: a systematic review and meta-analysis. Prostate Cancer Prostatic Dis. 2015;18(2):110-121.
Schoenborn JR, Nelson P, Fang M. Genomic profiling defines subtypes of prostate cancer with the potential for therapeutic stratification. Clin Cancer Res. 2013;19(15):4058-4066.
Gronberg H, Isaacs SD, Smith JR, et al. Characteristics of prostate cancer in families potentially linked to the hereditary prostate cancer 1 (HPC1) locus. JAMA. 1997;278(15):1251-1255.
Mitra AV, Bancroft EK, Barbachano Y, et al. Targeted prostate cancer screening in men with mutations in BRCA1 and BRCA2 detects aggressive prostate cancer: preliminary analysis of the results of the IMPACT study. BJU Int. 2011;107(1):28-39.
Akbari MR, Wallis CJ, Toi A, et al. The impact of a BRCA2 mutation on mortality from screen-detected prostate cancer. Br J Cancer. 2014;111(6):1238-1240.
Castro E, Goh C, Olmos D, et al. Germline BRCA mutations are associated with higher risk of nodal involvement, distant metastasis, and poor survival outcomes in prostate cancer. J Clin Oncol. 2013;31(14):1748-1757.
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Erdafitinib PI

HIGHLIGHTS OF PRESCRIBING INFORMATION

These highlights do not include all the information needed to use BALVERSA^TMsafely and effectively. See full prescribing information for BALVERSA.

BALVERSA (erdafitinib) tablets, for oral use Initial U.S. Approval: 2019

---------------------------------INDICATIONS AND USAGE--------------------------------

BALVERSA is a kinase inhibitor indicated for the treatment of adult patients with locally advanced or metastatic urothelial carcinoma that has

susceptible FGFR3 or FGFR2 genetic alterations and
progressed during or following at least one line of prior platinum-containing chemotherapy including within 12 months of neoadjuvant or adjuvant platinum-containing chemotherapy.

Select patients for therapy based on an FDA-approved companion diagnostic for BALVERSA. (1, 2.1)

This indication is approved under accelerated approval based on tumor response rate. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials. (1, 14)

-----------------------------DOSAGE AND ADMINISTRATION-----------------------------

Confirm the presence of FGFR genetic alterations in tumor specimens prior to initiation of treatment with BALVERSA. (2.1)
Recommended initial dosage: 8 mg orally once daily with a dose increase to 9 mg daily if criteria are met. (2.2)
Swallow whole with or without food. (2.2)

----------------------------DOSAGE FORMS AND STRENGTHS---------------------------

Tablets: 3 mg, 4 mg, and 5 mg. (3)

-----------------------------------CONTRAINDICATIONS------------------------------------

None. (4)

-----------------------------WARNINGS AND PRECAUTIONS-----------------------------

Ocular disorders: BALVERSA can cause central serous retinopathy/retinal pigment epithelial detachment (CSR/RPED). Perform monthly ophthalmological examinations during the first four months of treatment, every 3 months afterwards, and at any time for visual symptoms. Withhold BALVERSA when CSR/RPED occurs and permanently discontinue if it does not resolve within 4 weeks or if Grade 4 in severity. (2.3, 5.1)
Hyperphosphatemia: Increases in phosphate levels are a pharmacodynamic effect of BALVERSA. Monitor for hyperphosphatemia and manage with dose modifications when required. (2.3, 5.2)
Embryo-fetal toxicity: Can cause fetal harm. Advise patients of the potential risk to the fetus and to use effective contraception (5.3, 8.1, 8.3).

BALVERSATM (erdafitinib) tablets

-----------------------------------ADVERSE REACTIONS------------------------------------

The most common adverse reactions including laboratory abnormalities (≥20%) were phosphate increased, stomatitis, fatigue, creatinine increased, diarrhea, dry mouth, onycholysis, alanine aminotransferase increased, alkaline phosphatase increased, sodium decreased, decreased appetite, albumin decreased, dysgeusia, hemoglobin decreased, dry skin, aspartate aminotransferase increased, magnesium decreased, dry eye, alopecia, palmar-plantar erythrodysesthesia syndrome, constipation, phosphate decreased, abdominal pain, calcium increased, nausea, and musculoskeletal pain. (6.1)

To report SUSPECTED ADVERSE REACTIONS, contact Janssen Products, LP. at 1-800-526-7736 (1-800-JANSSEN and www.BALVERSA.com) or FDA at

1-800-FDA-1088 or www.fda.gov/medwatch.

------------------------------------DRUG INTERACTIONS-----------------------------------

Strong CYP2C9 or CYP3A4 inhibitors: Consider alternative agents or monitor closely for adverse reactions. (7.1)
Strong CYP2C9 or CYP3A4 inducers: Avoid concomitant use with BALVERSA. (7.1)
Moderate CYP2C9 or CYP3A4 inducers: Increase BALVERSA dose up to 9 mg. (7.1)
Serum phosphate level-altering agents: Avoid concomitant use with agents that can alter serum phosphate levels before the initial dose modification period. (2.3, 7.1)
CYP3A4 substrates: Avoid concomitant use with sensitive CYP3A4 substrates with narrow therapeutic indices. (7.2)
OCT2 substrates: Consider alternative agents or consider reducing the dose of OCT2 substrates based on tolerability. (7.2)
P-gp substrates: Separate BALVERSA administration by at least 6 hours before or after administration of P-gp substrates with narrow therapeutic indices. (7.2)

------------------------------USE IN SPECIFIC POPULATIONS-----------------------------

Lactation: Advise not to breastfeed. (8.2)

See 17 for PATIENT COUNSELING INFORMATION and FDA-approved patient labeling.

Revised: 04/2019

FULL PRESCRIBING INFORMATION: CONTENTS*

INDICATIONS AND USAGE
DOSAGE AND ADMINISTRATION
1. Patient Selection
2. Recommended Dosage and Schedule
3. Dose Modifications for Adverse Reactions
DOSAGE FORMS AND STRENGTHS
CONTRAINDICATIONS
WARNINGS AND PRECAUTIONS
1. Ocular Disorders
2. Hyperphosphatemia
3. Embryo-Fetal Toxicity
ADVERSE REACTIONS
1. Clinical Trials Experience
DRUG INTERACTIONS
1. Effect of Other Drugs on BALVERSA
2. Effect of BALVERSA on Other Drugs
USE IN SPECIFIC POPULATIONS
1. Pregnancy
2. Lactation
3. Females and Males of Reproductive Potential
4. Pediatric Use
5. Geriatric Use
6. CYP2C9 Poor Metabolizers
DESCRIPTION
CLINICAL PHARMACOLOGY
1. 12.1.Mechanism of Action
2. 12.2.Pharmacodynamics
3. 12.3.Pharmacokinetics
4. 12.5 Pharmacogenomics
NONCLINICAL TOXICOLOGY
1. 13.1.Carcinogenesis, Mutagenesis, and Impairment of Fertility
CLINICAL STUDIES
1. 14.1.Urothelial Carcinoma with Susceptible FGFR Genetic Alterations
HOW SUPPLIED/STORAGE AND HANDLING
PATIENT COUNSELING INFORMATION

*Sections or subsections omitted from the full prescribing information are not listed.

FULL PRESCRIBING INFORMATION

INDICATIONS AND USAGE

BALVERSATM is indicated for the treatment of adult patients with locally advanced or metastatic urothelial carcinoma (mUC), that has:

susceptible FGFR3 or FGFR2 genetic alterations, and
progressed during or following at least one line of prior platinum-containing chemotherapy, including within 12 months of neoadjuvant or adjuvant platinum- containing chemotherapy.

Select patients for therapy based on an FDA-approved companion diagnostic for BALVERSA [see Dosage and Administration (2.1) and Clinical Studies (14)].

This indication is approved under accelerated approval based on tumor response rate. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials [see Clinical Studies (14)].

DOSAGE AND ADMINISTRATION
1. 2.1.Patient Selection

Select patients for the treatment of locally advanced or metastatic urothelial carcinoma with BALVERSA based on the presence of susceptible FGFR genetic alterations in tumor specimens as detected by an FDA-approved companion diagnostic [see Clinical Studies (14.1)].

Information on FDA-approved tests for the detection of FGFR genetic alterations in urothelial cancer is available at: http://www.fda.gov/CompanionDiagnostics.

2.2.Recommended Dosage and Schedule

The recommended starting dose of BALVERSA is 8 mg (two 4 mg tablets) orally once daily, with a dose increase to 9 mg (three 3 mg tablets) once daily based on serum phosphate (PO4) levels and tolerability at 14 to 21 days [see Dosage and Administration (2.3)].

Swallow tablets whole with or without food. If vomiting occurs any time after taking BALVERSA, the next dose should be taken the next day. Treatment should continue until disease progression or unacceptable toxicity occurs.

If a dose of BALVERSA is missed, it can be taken as soon as possible on the same day. Resume the regular daily dose schedule for BALVERSA the next day. Extra tablets should not be taken to make up for the missed dose.

Dose Increase based on Serum Phosphate Levels

Assess serum phosphate levels 14 to 21 days after initiating treatment. Increase the dose of BALVERSA to 9 mg once daily if serum phosphate level is < 5.5 mg/dL and there are no ocular disorders or Grade 2 or greater adverse reactions. Monitor phosphate levels monthly for hyperphosphatemia [see Pharmacodynamics (12.2)].

2.3.Dose Modifications for Adverse Reactions

The recommended dose modifications for adverse reactions are listed in Table 1.

Table 1: BALVERSA Dose Reduction Schedule

Dose	1st dose reduction	2nd dose reduction	3rd dose reduction	4th dose reduction	5th dose reduction
9 mg ➝ (three 3 mg tablets)	8 mg (two 4 mg tablets)	6 mg (two 3 mg tablets)	5 mg (one 5 mg tablet)	4 mg (one 4 mg tablet)	Stop

8 mg ➝ (two 4 mg tablets)	6 mg (two 3 mg tablets)	5 mg (one 5 mg tablet)	4 mg (one 4 mg tablet)	Stop

Table 2 summarizes recommendations for dose interruption, reduction, or discontinuation of BALVERSA in the management of specific adverse reactions.

Table 2: Dose Modifications for Adverse Reactions

Adverse Reaction	BALVERSA Dose Modification
Hyperphosphatemia
In all patients, restrict phosphate intake to 600-800 mg daily. If serum phosphate is above 7.0 mg/dL, consider adding an oral phosphate binder until serum phosphate level returns to < 5.5 mg/dL.
5.6-6.9 mg/dL (1.8-2.3 mmol/L)	Continue BALVERSA at current dose.
7.0-9.0 mg/dL (2.3-2.9 mmol/L)	Withhold BALVERSA with weekly reassessments until level returns to < 5.5 mg/dL (or baseline). Then restart BALVERSA at the same dose level. A dose reduction may be implemented for hyperphosphatemia lasting > 1 week.
> 9.0 mg/dL (> 2.9 mmol/L)	Withhold BALVERSA with weekly reassessments until level returns to < 5.5 mg/dL (or baseline). Then may restart BALVERSA at 1 dose level lower.
> 10.0 mg/dL (> 3.2 mmol/L) or significant alteration in baseline renal function or Grade 3 hypercalcemia	Withhold BALVERSA with weekly reassessments until level returns to < 5.5 mg/dL (or baseline). Then may restart BALVERSA at 2 dose levels lower.
Central Serous Retinopathy/Retinal Pigment Epithelial Detachment (CSR/RPED)
Grade 1: Asymptomatic; clinical or diagnostic observations only	Withhold until resolution. If resolves within 4 weeks, resume at the next lower dose level. Then, if no recurrence for a month, consider re-escalation. If stable for 2 consecutive eye exams but not resolved, resume at the next lower dose level.
Grade 2: Visual acuity 20/40 or better or ≤ 3 lines of decreased vision from baseline	Withhold until resolution. If resolves within 4 weeks, may resume at the next lower dose level.
Grade 3: Visual acuity worse than 20/40 or > 3 lines of decreased vision from baseline	Withhold until resolution. If resolves within 4 weeks, may resume two dose levels lower. If recurs, consider permanent discontinuation.
Grade 4: Visual acuity 20/200 or worse in affected eye	Permanently discontinue.
Other Adverse Reactionsa
Grade 3	Withhold BALVERSA until resolves to Grade 1 or baseline, then may resume dose level lower.
Grade 4	Permanently discontinue.

a Dose adjustment graded using the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAEv4.03).

DOSAGE FORMS AND STRENGTHS

Tablets:

3 mg: Yellow, round biconvex, film-coated, debossed with “3” on one side; and “EF” on the other side.
4 mg: Orange, round biconvex, film-coated, debossed with “4” on one side; and “EF” on the other side.
5 mg: Brown, round biconvex, film-coated, debossed with “5” on one side; and “EF” on the other side.

CONTRAINDICATIONS

None.

WARNINGS AND PRECAUTIONS
1. 5.1.Ocular Disorders

BALVERSA can cause ocular disorders, including central serous retinopathy/ retinal pigment epithelial detachment (CSR/RPED) resulting in visual field defect.

CSR/RPED was reported in 25% of patients treated with BALVERSA, with a median time to first onset of 50 days. Grade 3 CSR/RPED, involving central field of vision, was reported in 3% of patients. CSR/RPED resolved in 13% of patients and was ongoing in 13% of patients at the study cutoff. CSR/RPED led to dose interruptions and reductions in 9% and 14% of patients, respectively and 3% of patients discontinued BALVERSA.

Dry eye symptoms occurred in 28% of patients during treatment with BALVERSA and were Grade 3 in 6% of patients. All patients should receive dry eye prophylaxis with ocular demulcents as needed.

Perform monthly ophthalmological examinations during the first 4 months of treatment and every 3 months afterwards, and urgently at any time for visual symptoms. Ophthalmological examination should include assessment of visual acuity, slit lamp examination, fundoscopy, and optical coherence tomography.

Withhold BALVERSA when CSR occurs and permanently discontinue if it does not resolve within 4 weeks or if Grade 4 in severity. For ocular adverse reactions, follow the dose modification guidelines [see Dosage and Administration (2.3)].

5.2.Hyperphosphatemia

Increases in phosphate levels are a pharmacodynamic effect of BALVERSA [see Pharmacodynamics (12.2)]. Hyperphosphatemia was reported as adverse reaction in 76% of patients treated with BALVERSA. The median onset time for any grade event of hyperphosphatemia was 20 days (range: 8 –116) after initiating BALVERSA. Thirty-two percent of patients received phosphate binders during treatment with BALVERSA.

Monitor for hyperphosphatemia and follow the dose modification guidelines when required [see Dosage and Administration 2.2, 2.3].

5.3.Embryo-Fetal Toxicity

Based on the mechanism of action and findings in animal reproduction studies, BALVERSA can cause fetal harm when administered to a pregnant woman. In an embryo-fetal toxicity study, oral administration of erdafitinib to pregnant rats during the period of organogenesis caused malformations and embryo-fetal death at maternal exposures that were less than the human exposures at the maximum human recommended dose based on area under the curve (AUC). Advise pregnant women of the potential risk to the fetus. Advise female patients of reproductive potential to use effective contraception during treatment with BALVERSA and for one month after the last dose. Advise male patients with female partners of reproductive potential to use effective contraception during treatment with BALVERSA and for one month after the last dose [see Use in Specific Populations (8.1, 8.3) and Clinical Pharmacology (12.1)].

ADVERSE REACTIONS

The following serious adverse reactions are also described elsewhere in the labeling:

Ocular Disorders [see Warning and Precautions (5.1)].
Hyperphosphatemia [see Warning and Precautions (5.2)].

6.1.Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

The safety of BALVERSA was evaluated in the BLC2001 study that included 87 patients with locally advanced or metastatic urothelial carcinoma which had susceptible FGFR3 or FGFR2 genetic alterations, and which progressed during or following at least one line of prior chemotherapy including within 12 months of neoadjuvant or adjuvant chemotherapy [see Clinical Studies (14.1)]. Patients were treated with BALVERSA at 8 mg orally once daily; with a dose increase to 9 mg in patients with phosphate levels <5.5 mg/dL on Day 14 of Cycle 1. Median duration of treatment was 5.3 months (range: 0 to 17 months).

The most common adverse reactions (ARs) including laboratory abnormalities (≥20%) were phosphate increased, stomatitis, fatigue, creatinine increased, diarrhea, dry mouth, onycholysis, alanine aminotransferase increased, alkaline phosphatase increased, sodium decreased, decreased appetite, albumin decreased, dysgeusia, hemoglobin decreased, dry skin, aspartate aminotransferase increased, magnesium decreased, dry eye, alopecia, palmar- plantar erythrodysesthesia syndrome, constipation, phosphate decreased, abdominal pain, calcium increased, nausea, and musculoskeletal pain. The most common Grade 3 or greater ARs (>1%) were stomatitis, nail dystrophy, palmar-plantar erythrodysesthesia syndrome, paronychia, nail disorder, keratitis, onycholysis, and hyperphosphatemia.

An adverse reaction with a fatal outcome in 1% of patients was acute myocardial infarction.

Serious adverse reactions occurred in 41% of patients including eye disorders (10%).

Permanent discontinuation due to an adverse reaction occurred in 13% of patients. The most frequent reasons for permanent discontinuation included eye disorders (6%).

Dosage interruptions occurred in 68% of patients. The most frequent adverse reactions requiring dosage interruption included hyperphosphatemia (24%), stomatitis (17%), eye disorders (17%), and palmar-plantar erythro-dysaesthesia syndrome (8%).

Dose reductions occurred in 53% of patients. The most frequent adverse reactions for dose reductions included eye disorders (23%), stomatitis (15%), hyperphosphatemia (7%), palmar-plantar erythro-dysaesthesia syndrome (7%),

paronychia (7%), and nail dystrophy (6%).

Table 3 presents ARs reported in ≥10% of patients treated with BALVERSA at 8 mg once daily.

Table 3: Adverse Reactions Reported in ≥ 10% (Any Grade) or ≥5% (Grade 3-4) of Patients

Adverse Reaction	BALVERSA 8 mg daily (N=87)
Adverse Reaction	All Grades (%)	Grade 3-4 (%)
Any	100	67
Gastrointestinal disorders	92	24
Stomatitis	56	9
Diarrhea	47	2
Dry mouth	45	0
Constipation	28	1
Abdominal paina	23	2
Nausea	21	1
Vomiting	13	2
Metabolism and nutrition disorders	90	16
Decreased appetite	38	0
General disorders and admin. site conditions	69	13
Fatigueb	54	10
Pyrexia	14	1
Skin and subcutaneous disorders	75	16
Onycholysisc	41	10
Dry skind	34	0
Palmar-plantar erythrodysaesthesia	26	6
Alopecia	26	0
Nail discoloration	11	0
Eye disorders	62	11
Dry eyee	28	6
Vision blurred	17	0
Lacrimation increased	10	0
Nervous system disorders	57	5
Dysgeusia	37	1
Infections and infestations	56	20
Paronychia	17	3
Urinary tract infection	17	6
Conjunctivitis	11	0
Respiratory, thoracic and mediastinal disorders	40	7
Oropharyngeal pain	11	1
Dyspneaf	10	2
Renal and urinary tract disorders	38	10
Hematuria	11	2
Musculoskeletal and connective tissue disorders	31	0
Musculoskeletal paing	20	0
Arthralgia	11	0
Investigations	44	5
Weight decreasedh	16	0

a Includes abdominal pain, abdominal discomfort, abdominal pain upper, and abdominal pain lower

b Includes asthenia, fatigue, lethargy, and malaise

c Includes onycholysis, onychoclasis, nail disorder, nail dystrophy, and nail ridging

d Includes dry skin and xerostomia

e Includes dry eye, xerophthalmia, keratitis, foreign body sensation, and corneal erosion

f Includes dyspnea and dyspnea exertional

g Includes back pain, musculoskeletal discomfort, musculoskeletal pain, musculoskeletal chest pain, neck pain, pain in extremity

h Includes weight decreased and cachexia

Table 4: Laboratory Abnormalities Reported in ≥ 10% (All Grade) or ≥ 5% (Grade 3-4) of Patients

Laboratory Abnormality	BALVERSA 8 mg daily (N=86a)
Laboratory Abnormality	All Grades (%)	Grade 3-4 (%)
Hematology
Hemoglobin decreased	35	3
Platelets decreased	19	1
Leukocytes decreased	17	0
Neutrophils decreased	10	2
Chemistry
Phosphate increased	76	1
Creatinine increased	52	5
Sodium decreased	40	16
Alanine aminotransferase increased	41	1
Alkaline phosphatase increased	41	1
Albumin decreased	37	0
Aspartate aminotransferase increased	30	0
Magnesium decreased	30	1
Phosphate decreased	24	9
Calcium increased	22	3
Potassium increased	16	0
Fasting glucose increased	10	0

a One of the 87 patients had no laboratory tests.

DRUG INTERACTIONS
1. 7.1.Effect of Other Drugs on BALVERSA

Table 5 summarizes drug interactions that affect the exposure of BALVERSA or serum phosphate level and their clinical management.

Strong CYP2C9 or CYP3A4 Inhibitors
Clinical Impact	Co-administration of BALVERSA with strong inhibitors of CYP2C9 or CYP3A4 increased erdafitinib plasma concentrations [see Clinical Pharmacology (12.3)]. Increased erdafitinib plasma concentrations may lead to increased drug-related toxicity [see Warnings and Precautions (5)].
Clinical Management	Consider alternative therapies that are not strong inhibitors of CYP2C9 or CYP3A4 during treatment with BALVERSA. If co-administration of a strong inhibitor of CYP2C9 or CYP3A4 is unavoidable, monitor closely for adverse reactions and consider dose modifications accordingly [see Dosage and Administration (2.3)]. If the strong inhibitor is discontinued, the BALVERSA dose may be increased in the absence of drug-related toxicity.
Strong CYP2C9 or CYP3A4 Inducers
Clinical Impact	Co-administration of BALVERSA with strong inducers of CYP2C9 or CYP3A4 may decrease erdafitinib plasma concentrations significantly [see Clinical Pharmacology (12.3)]. Decreased erdafitinib plasma concentrations may lead to decreased activity.
Clinical Management	Avoid co-administration of strong inducers of CYP2C9 or CYP3A4 with BALVERSA.
Moderate CYP2C9 or CYP3A4 Inducers
Clinical Impact	Co-administration of BALVERSA with moderate inducers of CYP2C9 or CYP3A4 may decrease erdafitinib plasma concentrations [see Clinical Pharmacology (12.3)]. Decreased erdafitinib plasma concentrations may lead to decreased activity.
Clinical Management	If a moderate CYP2C9 or CYP3A4 inducer must be co-administered at the start of BALVERSA treatment, administer BALVERSA dose as recommended (8 mg once daily with potential to increase to 9 mg once daily based on serum phosphate levels on Days 14 to 21 and tolerability). If a moderate CYP2C9 or CYP3A4 inducer must be co-administered after the initial dose increase period based on serum phosphate levels and tolerability, increase BALVERSA dose up to 9 mg. When a moderate inducer of CYP2C9 or CYP3A4 is discontinued, continue BALVERSA at the same dose, in the absence of drug-related toxicity.

Table 5: Drug Interactions that Affect BALVERSA

Table 5: Drug Interactions that Affect BALVERSA (continued)

Serum Phosphate Level-Altering Agents
Clinical Impact	Co-administration of BALVERSA with other serum phosphate level-altering agents may increase or decrease serum phosphate levels [see Pharmacodynamics (12.2)]. Changes in serum phosphate levels due to serum phosphate level-altering agents (other than erdafitinib) may interfere with serum phosphate levels needed for the determination of initial dose increased based on serum phosphate levels [see Dosage and Administration (2.3)].
Clinical Management	Avoid co-administration of serum phosphate level-altering agents with BALVERSA before initial dose increase period based on serum phosphate levels (Days 14 to 21) [see Dosage and Administration (2.3)].

7.2 Effect of BALVERSA on Other Drugs

Table 6 summarizes the effect of BALVERSA on other drugs and their clinical management.

Table 6: BALVERSA Drug Interactions that Affect Other Drugs

CYP3A4 Substrates
Clinical Impact	Co-administration of BALVERSA with CYP3A4 substrates may alter the plasma concentrations of CYP3A4 substrates [see Clinical Pharmacology (12.3)]. Altered plasma concentrations of CYP3A4 substrates may lead to loss of activity or increased toxicity of the CYP3A4 substrates.
Clinical Management	Avoid co-administration of BALVERSA with sensitive substrates of CYP3A4 with narrow therapeutic indices.
OCT2 Substrates
Clinical Impact	Co-administration of BALVERSA with OCT2 substrates may increase the plasma concentrations of OCT2 substrates [see Clinical Pharmacology (12.3)]. Increased plasma concentrations of OCT2 substrates may lead to increased toxicity of the OCT2 substrates.
Clinical Management	Consider alternative therapies that are not OCT2 substrates or consider reducing the dose of OCT2 substrates (e.g., metformin) based on tolerability.
P-glycoprotein (P-gp) Substrates
Clinical Impact	Co-administration of BALVERSA with P-gp substrates may increase the plasma concentrations of P-gp substrates [see Clinical Pharmacology (12.3)]. Increased plasma concentrations of P-gp substrates may lead to increased toxicity of the P-gp substrates.
Clinical Management	If co-administration of BALVERSA with P-gp substrates is unavoidable, separate BALVERSA administration by at least 6 hours before or after administration of P-gp substrates with narrow therapeutic index.

USE IN SPECIFIC POPULATIONS
1. 8.1.Pregnancy

Risk Summary

Based on the mechanism of action and findings in animal reproduction studies, BALVERSA can cause fetal harm when administered to a pregnant woman [see Clinical Pharmacology (12.1)]. There are no available data on BALVERSA use in pregnant women to inform a drug-associated risk. Oral administration of erdafitinib to pregnant rats during organogenesis caused malformations and embryo-fetal death at maternal exposures that were less than the human exposures at the maximum recommended human dose based on AUC (see Data). Advise pregnant women and females of reproductive potential of the potential risk to the fetus.

The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively.

Data

Animal Data

In an embryo-fetal toxicity study, erdafitinib was orally administered to pregnant rats during the period of organogenesis. Doses ≥4mg/kg/day (at total maternal exposures <0.1% of total human exposures at the maximum recommended human dose based on AUC) produced embryo-fetal death, major blood vessel malformations and other vascular anomalies, limb malformations (ectrodactyly, absent or misshapen long bones), an increased incidence of skeletal anomalies in multiple bones (vertebrae, sternebrae, ribs), and decreased fetal weight.

8.2.Lactation

Risk Summary

There are no data on the presence of erdafitinib in human milk, or the effects of erdafitinib on the breastfed child, or on milk production. Because of the potential for serious adverse reactions from erdafitinib in a breastfed child, advise lactating women not to breastfeed during treatment with BALVERSA and for one month following the last dose.

8.3.Females and Males of Reproductive Potential

Pregnancy Testing

Pregnancy testing is recommended for females of reproductive potential prior to initiating treatment with BALVERSA.

Contraception

Females

BALVERSA can cause fetal harm when administered to a pregnant woman. Advise females of reproductive potential to use effective contraception during treatment with BALVERSA and for one month after the last dose [see Use in Specific Population (8.1)].

Males

Advise male patients with female partners of reproductive potential to use effective contraception during treatment with BALVERSA and for one month after the last dose [see Use in Specific Populations (8.1)].

Infertility

Females

Based on findings from animal studies, BALVERSA may impair fertility in females of reproductive potential [see Nonclinical Toxicology (13.1)].

8.4.Pediatric Use

Safety and effectiveness of BALVERSA in pediatric patients have not been established.

In 4 and 13-week repeat-dose toxicology studies in rats and dogs, toxicities in bone and teeth were observed at an exposure less than the human exposure (AUC) at the maximum recommended human dose. Chondroid dysplasia/metaplasia were reported in multiple bones in both species, and tooth abnormalities included abnormal/irregular denting in rats and dogs and discoloration and degeneration of odontoblasts in rats.

8.5.Geriatric Use

Of the 416 patients treated with BALVERSA in clinical studies, 45% were 65 years of age or older, and 12% were 75 years of age or older. No overall differences in safety or effectiveness were observed between these patients and younger patients [see Clinical Studies (14)].

8.6.CYP2C9 Poor Metabolizers

CYP2C9*3/*3 Genotype: Erdafitinib plasma concentrations were predicted to be higher in patients with the CYP2C9*3/*3 genotype. Monitor for increased adverse reactions in patients who are known or suspected to have CYP2C9*3/*3 genotype [see Pharmacogenomics (12.5)].

DESCRIPTION

Erdafitinib, the active ingredient in BALVERSA, is a kinase inhibitor. The chemical name is N-(3,5-dimethoxyphenyl)-N’-(1-methylethyl)-N-[3-(1-methyl-1H-pyrazol- 4-yl)quinoxalin-6-yl]ethane-1,2-diamine. Erdafitinib is a yellow powder. It is practically insoluble, or insoluble to freely soluble in organic solvents, and slightly soluble to practically insoluble, or insoluble in aqueous media over a wide range of pH values. The molecular formula is C ₂₅H₃₀N₆O ₂ and molecular weight is 446.56. Chemical structure of erdafitinib is as follows:

BALVERSA (erdafitinib) is supplied as 3 mg, 4 mg or 5 mg film-coated tablets for oral administration and contains the following inactive ingredients:

Tablet Core: Croscarmellose sodium, Magnesium stearate (from vegetable source), Mannitol, Meglumine, and Microcrystalline Cellulose.

Film Coating: (Opadry amb II): Glycerol monocaprylocaprate Type I, Polyvinyl alcohol-partially hydrolyzed, Sodium lauryl sulfate, Talc, Titanium dioxide, Iron oxide yellow, Iron oxide red (for the orange and brown tablets only), Ferrosoferric oxide/iron oxide black (for the brown tablets only).

CLINICAL PHARMACOLOGY
1. 12.1.Mechanism of Action

Erdafitinib is a kinase inhibitor that binds to and inhibits enzymatic activity of FGFR1, FGFR2, FGFR3 and FGFR4 based on in vitro data. Erdafitinib also binds to RET, CSF1R, PDGFRA, PDGFRB, FLT4, KIT, and VEGFR2. Erdafitinib inhibited FGFR phosphorylation and signaling and decreased cell viability in cell lines expressing FGFR genetic alterations, including point mutations, amplifications, and fusions. Erdafitinib demonstrated antitumor activity in FGFR-expressing cell lines and xenograft models derived from tumor types, including bladder cancer.

12.2.Pharmacodynamics

Cardiac Electrophysiology

Based on evaluation of QTc interval in an open-label, dose escalation and dose expansion study in 187 patients with cancer, erdafitinib had no large effect (i.e.,

> 20 ms) on the QTc interval.

Serum Phosphate

Erdafitinib increased serum phosphate level as a consequence of FGFR inhibition. BALVERSA should be increased to the maximum recommended dose to achieve target serum phosphate levels of 5.5–7.0 mg/dL in early cycles with continuous daily dosing [see Dosage and Administration (2.3)].

In erdafitinib clinical trials, the use of drugs which can increase serum phosphate levels, such as potassium phosphate supplements, vitamin D supplements, antacids, phosphate-containing enemas or laxatives, and medications known to have phosphate as an excipient were prohibited unless no alternatives exist. To manage phosphate elevation, phosphate binders were permitted. Avoid concomitant use with agents that can alter serum phosphate levels before the initial dose increase period based on serum phosphate levels [see Drug Interactions (7.1)].

12.3.Pharmacokinetics

Following administration of 8 mg once daily, the mean (coefficient of variation [CV%]) erdafitinib steady-state maximum observed plasma concentration (C _max), area under the curve (AUC_tau), and minimum observed plasma concentration (C _min) were 1,399 ng/mL (51%), 29,268 ng•h/mL (60%), and 936 ng/mL (65%), respectively.

Following single and repeat once daily dosing, erdafitinib exposure (maximum observed plasma concentration [C_max] and area under the plasma concentration time curve [AUC]) increased proportionally across the dose range of 0.5 to 12 mg (0.06 to 1.3 times the maximum approved recommended dose). Steady state was achieved after 2 weeks with once daily dosing and the mean accumulation ratio was 4-fold.

Absorption

Median time to achieve peak plasma concentration (t _max) was 2.5 hours (range: 2 to 6 hours).

Effect of Food

No clinically meaningful differences with erdafitinib pharmacokinetics were observed following administration of a high-fat and high-calorie meal (800 calories to 1,000 calories with approximately 50% of total caloric content of the meal from fat) in healthy subjects.

Distribution

The mean apparent volume of distribution of erdafitinib was 29 L in patients.

Erdafitinib protein binding was 99.8% in patients, primarily to alpha-1-acid glycoprotein.

Elimination

The mean total apparent clearance (CL/F) of erdafitinib was 0.362 L/h in patients. The mean effective half-life of erdafitinib was 59 hours in patients.

Metabolism

Erdafitinib is primarily metabolized by CYP2C9 and CYP3A4. The contribution of CYP2C9 and CYP3A4 in the total clearance of erdafitinib is estimated to be 39% and 20% respectively. Unchanged erdafitinib was the major drug-related moiety in plasma, there were no circulating metabolites.

Excretion

Following a single oral dose of radiolabeled erdafitinib, approximately 69% of the dose was recovered in feces (19% as unchanged) and 19% in urine (13% as unchanged).

Specific Populations

No clinically meaningful trends in the pharmacokinetics of erdafitinib were observed based on age (21-88 years), sex, race, body weight (36-132 kg), mild (eGFR [estimated glomerular filtration rate, using modification of diet in renal disease equation] 60 to 89 mL/min/1.73 m2) or moderate (eGFR 30-59 mL/min/1.73 m2) renal impairment or mild hepatic impairment (total bilirubin ≤ ULN and AST > ULN, or total bilirubin > 1.0–1.5 x ULN and any AST).

The pharmacokinetics of erdafitinib in patients with severe renal impairment, renal impairment requiring dialysis, moderate or severe hepatic impairment is unknown.

Drug Interaction Studies

Clinical Studies and Model-Based Approaches

Strong CYP2C9 Inhibitors:

Erdafitinib mean ratios (90% CI) for C_max and AUC _inf were 121% (99.9, 147) and 148% (120, 182), respectively, when co-administered with fluconazole, a strong CYP2C9 inhibitor and moderate CYP3A4 inhibitor, relative to erdafitinib alone.

Strong CYP3A4 Inhibitors:

Erdafitinib mean ratios (90% CI) for C_max and AUC_inf were 105% (86.7, 127) and 134% (109, 164), respectively, when co-administered with itraconazole (a strong CYP3A4 inhibitor and P-gp inhibitor) relative to erdafitinib alone.

Strong CYP3A4/2C9 Inducers:

Simulations suggested that rifampicin (a strong CYP3A4/2C9 inducer) may significantly decrease erdafitinib C_max and AUC.

In Vitro Studies

CYP Substrates:

Erdafitinib is a time dependent inhibitor and inducer of CYP3A4. The effect of erdafitinib on a sensitive CYP3A4 substrate is unknown. Erdafitinib is not an inhibitor of other major CYP isozymes at clinically relevant concentrations.

Transporters:

Erdafitinib is a substrate and inhibitor of P-gp. P-gp inhibitors are not expected to affect erdafitinib exposure to a clinically relevant extent. Erdafitinib is an inhibitor of OCT2.

Erdafitinib does not inhibit BCRP, OATP1B, OATP1B3, OAT1, OAT3, OCT1, MATE-1, or MATE-2K at clinically relevant concentrations.

Acid-Lowering Agents:

Erdafitinib has adequate solubility across the pH range of 1 to 7.4. Acid-lowering agents (e.g., antacids, H ₂-antagonists, proton pump inhibitors) are not expected to affect the bioavailability of erdafitinib.

12.5 Pharmacogenomics

CYP2C9 activity is reduced in individuals with genetic variants, such as the CYP2C9*2 and CYP2C9*3 polymorphisms. Erdafitinib exposure was similar in subjects with CYP2C9*1/*2 and *1/*3 genotypes relative to subjects with CYP2C9*1/*1 genotype (wild type). No data are available in subjects characterized by other genotypes (e.g., *2/*2, *2/*3, *3/*3). Simulation suggested no clinically meaningful differences in erdafitinib exposure in subjects with CYP2C9*2/*2 and

*2/*3 genotypes. The exposure of erdafitinib is predicted to be 50% higher in subjects with the CYP2C9*3/*3 genotype, estimated to be present in 0.4% to 3% of the population among various ethnic groups.

NONCLINICAL TOXICOLOGY
1. 13.1.Carcinogenesis, Mutagenesis, and Impairment of Fertility

Carcinogenicity studies have not been conducted with erdafitinib.

Erdafitinib was not mutagenic in a bacterial reverse mutation (Ames) assay and was not clastogenic in an in vitro micronucleus or an in vivo rat bone marrow micronucleus assay.

Fertility studies in animals have not been conducted with erdafitinib. In the 3-month repeat-dose toxicity study, erdafitinib showed effects on female reproductive organs (necrosis of the ovarian corpora lutea) in rats at an exposure less than the human exposure (AUC) at maximum recommended human dose.

CLINICAL STUDIES
1. 14.1.Urothelial Carcinoma with Susceptible FGFR Genetic Alterations

Study BLC2001 (NCT02365597) was a multicenter, open-label, single-arm study to evaluate the efficacy and safety of BALVERSA in patients with locally advanced or metastatic urothelial carcinoma (mUC). Fibroblast growth factor receptor (FGFR) mutation status for screening and enrollment of patients was determined by a clinical trial assay (CTA). The efficacy population consists of a cohort of eighty- seven patients who were enrolled in this study with disease that had progressed on or after at least one prior chemotherapy and that had at least 1 of the following genetic alterations: FGFR3 gene mutations (R248C, S249C, G370C, Y373C) or FGFR gene fusions (FGFR3-TACC3, FGFR3-BAIAP2L1, FGFR2-BICC1, FGFR2-CASP7), as

determined by the CTA performed at a central laboratory. Tumor samples from 69 patients were tested retrospectively by the QIAGEN therascreen ® FGFR RGQ RT-PCR Kit, which is the FDA-approved test for selection of patients with mUC for BALVERSA.

Patients received a starting dose of BALVERSA at 8 mg once daily with a dose increase to 9 mg once daily in patients whose serum phosphate levels were below the target of 5.5 mg/dL between days 14 and 17; a dose increase occurred in 41% of patients. BALVERSA was administered until disease progression or unacceptable toxicity. The major efficacy outcome measures were objective response rate (ORR) and duration of response (DoR), as determined by blinded independent review committee (BIRC) according to RECIST v1.1.

The median age was 67 years (range: 36 to 87 years), 79% were male, and 74% were Caucasian. Most patients (92%) had a baseline Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1. Sixty-six percent of patients had visceral metastases. Eighty-four (97%) patients received at least one of cisplatin or carboplatin previously. Fifty-six percent of patients only received prior cisplatin- based regimens, 29% received only prior carboplatin-based regimens, and 10% received both cisplatin and carboplatin-based regimens. Three (3%) patients had disease progression following prior platinum-containing neoadjuvant or adjuvant therapy only. Twenty-four percent of patients had been treated with prior anti PD-L1/PD-1 therapy.

Efficacy results are summarized in Table 7 and Table 8. Overall response rate was 32.2%. Responders included patients who had previously not responded to anti PD-L1/PD-1 therapy.

Table 7: Efficacy Results

Endpoint	BIRCa assessment
Endpoint	N=87
ORR (95% CI)	32.2% (22.4, 42.0)
Complete response (CR)	2.3%
Partial response (PR)	29.9%
Median DoR in months (95% CI)	5.4 (4.2, 6.9)

a BIRC: Blinded Independent Review Committee ORR = CR + PR

CI = Confidence Interval

Table 8: Efficacy Results by FGFR Genetic Alteration

	BIRCa assessment
FGFR3 Point Mutation	N=64
ORR (95% CI)	40.6% (28.6, 52.7)
FGFR3 Fusion b, c	N=18
ORR (95% CI)	11.1% (0, 25.6)
FGFR2 Fusion c	N=6
ORR	0

a BIRC: Blinded Independent Review Committee

b Both responders had FGFR3-TACC3_V1 fusion

c One patient with a FGFR2-CASP7/FGFR3-TACC3_V3 fusion is reported in both FGFR2 fusion and FGFR3 fusion above

ORR = CR + PR

CI = Confidence Interval

HOW SUPPLIED/STORAGE AND HANDLING

BALVERSA™ (erdafitinib) tablets are available in the strengths and packages listed below:

3 mg tablets: Yellow, round biconvex, film-coated, debossed with “3” on one side and “EF” on the other side.
Bottle of 56-tablets with child resistant closure (NDC 59676-030-56).
Bottle of 84-tablets with child resistant closure (NDC 59676-030-84).
4 mg tablets: Orange, round biconvex, film-coated, debossed with “4” on one side and “EF” on the other side.
Bottle of 28-tablets with child resistant closure (NDC 59676-040-28).
Bottle of 56-tablets with child resistant closure (NDC 59676-040-56).
5 mg tablets: Brown, round biconvex, film-coated, debossed with “5” on one side and “EF” on the other side.
Bottle of 28-tablets with child resistant closure (NDC 59676-050-28).

Store at 20°C-25°C (68°F-77°F); excursions permitted between 15°C and 30°C (59°F and 86°F) [see USP Controlled Room Temperature].

BALVERSATM (erdafitinib) tablets

PATIENT COUNSELING INFORMATION

Advise the patient to read the FDA-approved patient labeling (Patient Information).

FGFR genetic alterations: Advise patients that evidence of a susceptible FGFR3 or FGFR2 mutation or gene fusion within the tumor specimen is necessary to identify patients for whom treatment is indicated [see Dosage and Administration (2.1)].

Ocular disorders: Advise patients to contact their healthcare provider if they experience any visual changes [see Warnings and Precautions (5.1)]. In order to prevent or treat dry eyes, advise patients to use artificial tear substitutes, hydrating or lubricating eye gels or ointments frequently, at least every 2 hours during waking hours [see Dosage and Administration (2.3)].

Skin, mucous or nail disorders: Advise patients to contact their healthcare provider if they experience progressive or intolerable skin, mucous or nail disorders [see Adverse Reactions (6.1)].

Hyperphosphatemia: Advise patients that their healthcare provider will assess their serum phosphate level between 14 and 21 days of initiating treatment and will adjust the dose if needed [see Warnings and Precautions (5.2)]. During this initial phosphate-assessment period, advise patients to avoid concomitant use with agents that can alter serum phosphate levels. Advise patients that, after the initial phosphate assessment period, monthly phosphate level monitoring for hyperphosphatemia should be performed during treatment with BALVERSA [see Drug Interactions (7.1)].

Drug Interactions: Advise patients to inform their healthcare providers of all concomitant medications, including prescription medicines, over-the-counter drugs, and herbal products [see Drug Interactions (7.1, 7.2)].

Dosing Instructions: Instruct patients to swallow the tablets whole once daily with or without food. If vomiting occurs any time after taking BALVERSA, advise patients to take the next dose the next day. [see Dosage and Administration (2.1)].

Missed dose: If a dose is missed, advise patients to take the missed as soon as possible. Resume the regular daily dose schedule for BALVERSA the next day. Extra tablets should not be taken to make up for the missed dose [see Dosage and Administration (2.3)].

Embryo-Fetal Toxicity: Advise pregnant women and females of reproductive potential of the potential risk to the fetus. Advise females to inform their healthcare providers of a known or suspected pregnancy [see Warning and Precautions (5.3) and Use in Specific Population (8.1)].

Advise female patients of reproductive potential to use effective contraception during treatment and for one month after the last dose of BALVERSA. Advise male patients with female partners of reproductive potential to use effective contraception during treatment and for one month after the last dose of BALVERSA [see Use in Specific Populations (8.3)].

Lactation: Advise females not to breastfeed during treatment with BALVERSA and for one month after the last dose [see Use in Specific Populations (8.2)].

Product of Switzerland

Manufactured for: Janssen Products, LP Horsham, PA 19044

Under license from Astex Therapeutics Limited.

©2019 Janssen Pharmaceutical Companies

PATIENT INFORMATION

BALVERSA™ (bal-VER-sah) (erdafitinib) tablets

What is BALVERSA?

BALVERSA is a prescription medicine used to treat adults with bladder cancer (urothelial cancer) that has spread or cannot be removed by surgery:

which has a certain type of abnormal “FGFR” gene, and
who have tried at least one other chemotherapy medicine that contains platinum, and it did not work or is no longer working. Your healthcare provider will test your cancer for certain types of abnormal FGFR genes and make sure that BALVERSA is right for you.

It is not known if BALVERSA is safe and effective in children.

Before taking BALVERSA tell your healthcare provider about all of your medical conditions, including if you:

have vision or eye problems.
are pregnant or plan to become pregnant. BALVERSA can harm your unborn baby. You should not become pregnant during treatment with BALVERSA.

Females who can become pregnant:

° Your healthcare provider may do a pregnancy test before you start treatment with BALVERSA.

° You should use effective birth control during treatment and for 1 month after the last dose of BALVERSA. Talk to your healthcare provider about birth control methods that may be right for you.

° Tell your healthcare provider right away if you become pregnant or think you may be pregnant.

Males with female partners who can become pregnant:

° You should use effective birth control when sexually active during treatment with BALVERSA and for 1 month after the last dose.

are breastfeeding or plan to breastfeed. Do not breastfeed during treatment and for 1 month after the last dose of BALVERSA.

Tell your healthcare provider about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements.

How should I take BALVERSA?

Take BALVERSA exactly as your healthcare provider tells you.
Take BALVERSA 1 time each day.
Swallow BALVERSA tablets whole with or without food.
Your healthcare provider may change your dose of BALVERSA, temporarily stop or completely stop treatment if you get certain side effects.
If you miss a dose of BALVERSA, take the missed dose as soon as possible on the same day. Take your regular dose of BALVERSA the next day. Do not take more BALVERSA than prescribed to make up for the missed dose.
If you vomit after taking BALVERSA, do not take another BALVERSA tablet. Take your regular dose of BALVERSA the next day.

BALVERSATM (erdafitinib) tablets

What are the possible side effects of BALVERSA? BALVERSA may cause serious side effects, including:

Eye problems. Eye problems are common with BALVERSA but can also be serious. Eye problems include dry or inflamed eyes, inflamed cornea (front part of the eye) and disorders of the retina, an internal part of the eye. Tell your healthcare provider right away if you develop blurred vision, loss of vision or other visual changes. You should use artificial tear substitutes, hydrating or lubricating eye gels or ointments at least every 2 hours during waking hours to help prevent dry eyes. During treatment with BALVERSA, your healthcare provider will send you to see an eye specialist.
High phosphate levels in the blood (hyperphosphatemia). Hyperphosphatemia is common with BALVERSA but can also be serious. Your healthcare provider will check your blood phosphate level between 14 and 21 days after starting treatment with BALVERSA, and then monthly, and may change your dose if needed.

The most common side effects of BALVERSA include:

mouth sores • low red blood cells (anemia)
feeling tired • dry skin
change in kidney function • dry eyes
diarrhea • hair loss
dry mouth • redness, swelling, peeling or tenderness, mainly on the
nails separate from the bed or poor formation of the nail hands or feet (‘hand-foot syndrome’)
change in liver function • constipation
low salt (sodium) levels • stomach (abdominal) pain
decreased appetite • nausea
change in sense of taste • muscle pain

Tell your healthcare provider right away if you develop any nail or skin problems including nails separating from the nail bed, nail pain, nail bleeding, breaking of the nails, color or texture changes in your nails, infected skin around the nail, an itchy skin rash, dry skin, or cracks in the skin.

BALVERSA may affect fertility in females who are able to become pregnant. Talk to your healthcare provider if this is a concern for you. These are not all possible side effects of BALVERSA. For more information, ask your healthcare provider or pharmacist.

Call your healthcare provider for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

How should I store BALVERSA?

Store BALVERSA tablets at room temperature between 68°F to 77°F (20°C to 25°C).

Keep BALVERSA and all medicines out of the reach of children.

General information about the safe and effective use of BALVERSA.

Medicines are sometimes prescribed for purposes other than those listed in Patient Information leaflets. Do not use BALVERSA for a condition for which it was not prescribed. Do not give BALVERSA to other people, even if they have the same symptoms that you have. It may harm them. If you would like more information, talk with your healthcare provider. You can ask your healthcare provider for information about BALVERSA that is written for healthcare professionals.

What are the ingredients in BALVERSA? Active ingredient: erdafitinib

Inactive ingredients:

Tablet Core: Croscarmellose sodium, Magnesium stearate (from vegetable source), Mannitol, Meglumine, and Microcrystalline Cellulose. Film Coating (Opadry amb II): Glycerol monocaprylocaprate Type I, Polyvinyl alcohol-partially hydrolyzed, Sodium lauryl sulfate, Talc, Titanium dioxide, Iron oxide yellow, Iron oxide red (for the orange and brown tablets only), Ferrosoferric oxide/iron oxide black (for the brown tablets only).

Manufactured by: Janssen-Cilag SpA, Latina, Italy

Manufactured for: Janssen Products, LP, Horsham, PA 19044

© 2019 Janssen Pharmaceutical Companies

For more information call Janssen Products, LP at 1-800-526-7736 (1-800-JANSSEN) or go to www.BALVERSA.com.

This Patient Information has been approved by the U.S. Food and Drug Administration. Issued: April 2019

Published Date: April 16th, 2019

Endoscopic Approaches and Emerging Novel Treatments for Upper Tract Urothelial Carcinoma

Upper tract urothelial carcinoma, comprising either the renal pelvis or ureter, is rarer than urothelial carcinoma of the bladder accounting for only 5-10% of all urothelial carcinomas¹ (epidemiology of upper tract urothelial cancer, Wallis CJD). However, similar to bladder urothelial carcinoma, not all upper tract urothelial cancer is high-risk and/or patients may not be fit for radical surgery. Although a radical nephroureterectomy is the gold standard treatment for upper tract urothelial cancer, there has been an impetus for developing and assessing less aggressive, less invasive treatment modalities^2-4. As such, this article will discuss endoscopic (ureteroscopic and percutaneous), kidney-sparing treatment modalities for upper tract urothelial cancer, as well as focus on several emerging treatments.

Indications for Kidney Sparing/Endoscopic Management

Imperative – patients with contraindications for radical surgery: (i) a solitary functioning kidney, (ii) bilateral upper tract urothelial cancer, (iii) baseline renal insufficiency, (iv) poor candidacy for hemodialysis or renal transplantation, (v) significant comorbidities
Elective – patients with low-risk non-muscle invasive upper tract urothelial cancer. May be eligible for a partial nephrectomy, segmental ureterectomy, or endoscopic management

The 2017 European Association of Urology Guidelines on upper tract urothelial cancer⁵ suggest that ureteroscopic endoscopic ablation can be considered in patients with clinically low-risk cancer in addition to the following situations: (i) a laser generator and equipment is available for biopsies, (ii) when a flexible rather than rigid ureteroscope is available, (iii) the patient is informed of the need for earlier or closer surveillance, and (iv) complete tumor resection is achievable. Furthermore, the Guidelines suggest that percutaneous ablation can be considered for low-risk upper tract urothelial cancer in the renal pelvis, particularly for tumors in the lower calyceal system that are inaccessible or difficult to manage by flexible ureteroscopy.

Ureteroscopic Management

Endoscopic evaluation, typically by ureteroscopy, is crucial for the initial diagnosis, risk stratification, and subsequent treatment planning for patients with upper tract urothelial cancer. Information from endoscopy helps assess tumor location, multifocality, architecture and allows the clinician to obtain a tissue diagnosis. However, ureteroscopic biopsies can be technically challenging given the limited ureteroscopic biopsy instruments that can traverse the small working channel. Some experts have advocated that the visual characteristics of the tumor may be able to predict disease aggressiveness, such as sessile-appearing tumors being more likely to be higher grade/stage .⁶ Several techniques for achieving a tissue diagnosis have been described, including multiple urine and washing samples and multiple quality biopsies to ensure sufficient tissue for pathological assessment; the most commonly used biopsy tools include the Piranha forceps (Boston Scientific, Marlborough, MA) and the BIGopsy forceps (Cook Medical, Bloomington, IN).² For larger, papillary tumors, a stone basket (ie. nitinol) can be used for snaring and debulking the tumor.

One of the benefits of a ureteroscopic approach is that a single procedure can be both diagnostic and therapeutic. When possible, use of a ureteral access sheath is ideal in that it allows atraumatic multiple insertions of the ureteroscope, especially important when encountered with a large tumor volume⁷. Following multiple biopsies for tissue diagnosis, a laser can be used both for additional tumor resection and fulguration (for hemostasis) of the tumor bed. The most commonly used lasers are the holmium:yttrium-aluminum-garnet (YAG) laser and the neodymium-doped (Nd):YAG laser. The holmium laser is typically better suited for smaller tumors, however, it requires contact with the tissue in order to be effective. The Nd: YAG laser has a smaller wavelength, is able to penetrate deeper (5-6 mm), and does not require direct tissue contact. Although less readily available, electrocautery resection is also possible with a 10-13Fr rigid ureteral resectoscope (Karl Storz Endoscopy, Tuttlingen, Germany); this scope allows resection of tumors similar to a loop used for transurethral resection of bladder tumors².

Currently, there is no Level I evidence assessing oncologic outcomes of patients undergoing ureteroscopic management of upper tract urothelial cancer. Retrospective series to date are all limited to fewer than 100 patients. The largest retrospective series with more than two years of follow-up was published by Grasso and colleagues (n=82)⁸ noting 81% recurrence rate in the upper tract, 57% in the bladder, 19% of patients progressing to surgical resection, and a 74% and 87% overall and cancer-specific survival rate, respectively. Petros et al summarized these retrospective studies with the following outcomes:²

Median follow-up: 24-58 months
Upper tract recurrence rate: 65%
Bladder recurrence rate: 44%
Progression to surgical resection rate: 0-33%
Overall survival rate: 35-100%
Cancer-specific survival rate: 70-100%

In general, ureteroscopic management of upper tract urothelial cancer is associated with high risk of recurrence and a not insignificant rate of progression to more radical surgery.

Percutaneous Management

Antegrade percutaneous endoscopic treatment of upper tract urothelial carcinoma is typically reserved for patients with low-grade, large volume tumors that are either anatomically or technically challenging for ureteroscopic management, ie. lower pole tumors. This approach is particularly advantageous for patients that have had a prior cystectomy and urinary diversion. A major benefit of percutaneous management is the ability to use larger instruments that are able to fit through a nephroscope, including loop cautery for debulking large tumors. All of the laser biopsy instruments listed above for ureteroscopic management are also feasible for the percutaneous approach. The primary risk of percutaneous management of upper tract urothelial carcinoma (aside from those traditionally associated with percutaneous management of nephrolithiasis) is disruption of the urothelium, which may lead to a theoretically increased risk of tumor seeding into the retroperitoneum.²

Similar to ureteroscopic management of upper tract urothelial carcinoma, oncologic outcomes have relied on retrospective studies of fewer than 100 patients. However, one study by Motamedinia et al.⁹ identified 141 patients who underwent percutaneous resection with a median follow-up of 66 months. They noted that recurrence occurred in 37% of low-grade patients and 63% of high-grade patients, with a median time to recurrence of 71.4 vs 36.4 months, respectively. On multivariable analysis, grade was the only predictor of recurrence (HR 2.12, p = 0.018) and radical nephroureterectomy was avoided in 87% of patients. Petros and colleagues² summarized oncologic outcomes of percutaneous management among studies with a minimum 2-year follow-up (n=361):

Median follow-up: 24-66 months
Upper tract recurrence rate: 40%
Bladder recurrence rate: 24%
Progression to surgical resection rate: 6-50%
Overall survival rate: 40-90%
Cancer-specific survival rate: 75-100%

Emerging Novel Treatments

Several new and exciting treatments are under development with regards to minimally invasive treatment of upper tract urothelial cancer. As highlighted above, the recurrence rate for endoscopic management is high (40-65% on pooled analysis)² and these approaches are not well suited to treatment of multifocal disease or carcinoma in situ. Thus, much research has been directed for improving the deliverability of topical agents to the upper tracts. One of the challenges is difficulty concentrating therapeutic levels of these agents in the upper tract for more than a brief period of time secondary to ureteral peristalsis rapidly draining topical treatment from the pelvis and ureter. Specifically, mitomycin C exposure time to the urothelium is critical for efficacy.¹⁰ RTGel™ is a reverse-thermal hydrogel composed of a combination of polymers that allows it to exist as a liquid at cold temperatures but solidifies to a gel state at body temperature.¹¹ This product was developed to address the constraints of the upper urinary tract, where continuous urine production and ureteral peristalsis prevents drug retention in the upper tract. Subsequently, MitoGel Ôwas developed as a novel formulation of RTGel combined with mitomycin C. The hypothesis for MitoGel is that upon delivery to the upper urinary tract, MitoGel would gelatinize and urine would produce a slow dissolution of the gel, allowing a sustained release of mitomycin C into the upper tract allowing prolonged exposure to the urothelium. Using a preclinical swine animal model (n=23), Donin et al,¹¹ noted that after antegrade instillation of MitoGel, the product remained visible in the pelvicalyceal system on fluoroscopic and computed tomography imaging for 4-6 hours after instillation. Furthermore, on necropsy, they noted that mitomycin C plasma levels were well within acceptable safety thresholds and that there was no evidence of urinary obstruction, acute kidney injury, sepsis, or myelosuppression. Donin and colleagues subsequently confirmed these safety results in a study assessing six once-weekly unilateral retrograde instillations of Mitogel.¹²

The OLYMPUS study (NCT02793128) is a prospective single-arm ongoing clinical trial designed to assess the efficacy, safety, and tolerability of MitoGel in patients with low grade, noninvasive upper tract urothelial cancer. Eligible patients are treated with MitoGel once weekly for a total of six times in a retrograde fashion; patients demonstrating a complete response are treated with MitoGel once monthly for a total of 11 instillations as maintenance, or until the first recurrence. The primary outcomes are complete response rate defined as the percent of patients with complete response at the primary disease evaluation visit (~11 weeks), and adverse event rates (over ~2 years). Secondary outcomes include:

(i) Long-term durability of complete response (12 months)
(ii) Complete response rates at 3, 6, and 9 months
(iii) Partial response to treatment (~11 weeks)
(iv) Mitomycin C level in blood plasma

The target recruitment goal is 71 patients with an estimated study completion date of February 2020.

Previous studies assessing differential gene expression between upper tract and bladder urothelial carcinoma using microarray data suggest that upper tract tumors tend to have high expression of genes associated with a luminal subtype.¹³ Furthermore, one particular gene highly expressed in upper tract tumors is SLITRK6, an integral membrane protein known to have high levels of expression in certain carcinomas, but low levels in the majority of other tissues.¹⁴ An antibody to SLITRK6 protein has been developed and linked to a cytotoxic agent called monomethyl auristatin E (AGS15E), a microtubule-disrupting agent.^{15, 16} ASG-15C was chosen among seven anti-SLITRK6 antibodies and monomethyl auristatin E was chosen due to its efficacy in tumor inhibition and regression. Upon binding to SLITRK6, ASG-15ME is rapidly internalized and trafficked to lysosomes and early endosomes. An ongoing Phase I dose escalation trial of AGS15E in patients with metastatic urothelial carcinoma presented initial interim trial results at the ESMO 2016.¹⁷ This trial includes patients previously treated with ≥ 1 prior chemotherapy regimens; SLITRK6 expression was determined by immunohistochemistry. Disease assessments were performed every 8 weeks using RECIST v 1.1 criteria and ASG-15ME was administered IV weekly for 3 out of every 4 weeks until no further benefit. Six dose levels were assessed: 0.1, 0.25, 0.5, 0.75, 1, and 1.25 mg/kg. At the time of analysis, 51 pts were enrolled and 93% were SLITRK6 positive. Of 42 evaluable patients at doses considered active (doses ≥0.5 mg/kg), one had a complete response and 13 had a partial response (ORR =33%). Adverse event rate was high (91%) and the most common treatment-related adverse event was fatigue (44%). Serum concentrations of ASG-15ME decreased multi-exponentially and half-life was 3.1 days. In heavily pre-treated individuals, novel antibody-drug conjugates continue to be explored for therapeutic benefit.

Conclusions

Endoscopic management of upper tract urothelial cancer is technically feasible but associated with high rates of recurrence and non-insignificant rates of progression necessitating radical surgical treatment. Endoscopic management should be reserved for low-grade tumors and patients that have contraindications to radical nephroureterectomy. Research is ongoing, particularly for improving delivery of topical agents to decrease recurrence rates.

Published Date: April 15th, 2019

Written by: Zachary Klaassen, MD, MSc

References:

Siegel RL, Miller KD, Jemal A. Cancer statistics, 2019. CA Cancer J Clin. 2019;69:7-34.
Petros FG, Li R, Matin SF. Endoscopic Approaches to Upper Tract Urothelial Carcinoma. Urol Clin North Am. 2018;45:267-86.
Samson P, Smith AD, Hoenig D, Okeke Z. Endoscopic Management of Upper Urinary Tract Urothelial Carcinoma. J Endourol. 2018;32:S10-S6.
Cutress ML, Stewart GD, Zakikhani P, Phipps S, Thomas BG, Tolley DA. Ureteroscopic and percutaneous management of upper tract urothelial carcinoma (UTUC): systematic review. BJU Int. 2012;110:614-28.
Roupret M, Babjuk M, Comperat E, Zigeuner R, Sylvester RJ, Burger M, et al. European Association of Urology Guidelines on Upper Urinary Tract Urothelial Carcinoma: 2017 Update. Eur Urol. 2018;73:111-22.
Williams SK, Denton KJ, Minervini A, Oxley J, Khastigir J, Timoney AG, et al. Correlation of upper-tract cytology, retrograde pyelography, ureteroscopic appearance, and ureteroscopic biopsy with histologic examination of upper-tract transitional cell carcinoma. J Endourol. 2008;22:71-6.
Raman JD, Park R. Endoscopic management of upper-tract urothelial carcinoma. Expert Rev Anticancer Ther. 2017;17:545-54.
Grasso M, Fishman AI, Cohen J, Alexander B. Ureteroscopic and extirpative treatment of upper urinary tract urothelial carcinoma: a 15-year comprehensive review of 160 consecutive patients. BJU Int. 2012;110:1618-26.
Motamedinia P, Keheila M, Leavitt DA, Rastinehad AR, Okeke Z, Smith AD. The Expanded Use of Percutaneous Resection for Upper Tract Urothelial Carcinoma: A 30-Year Comprehensive Experience. J Endourol. 2016;30:262-7.
De Bruijn EA, Sleeboom HP, van Helsdingen PJ, van Oosterom AT, Tjaden UR, Maes RA. Pharmacodynamics and pharmacokinetics of intravesical mitomycin C upon different dwelling times. Int J Cancer. 1992;51:359-64.
Donin NM, Duarte S, Lenis AT, Caliliw R, Torres C, Smithson A, et al. Sustained-release Formulation of Mitomycin C to the Upper Urinary Tract Using a Thermosensitive Polymer: A Preclinical Study. Urology. 2017;99:270-7.
Donin NM, Strauss-Ayali D, Agmon-Gerstein Y, Malchi N, Lenis AT, Holden S, et al. Serial retrograde instillations of sustained release formulation of mitomycin C to the upper urinary tract of the Yorkshire swine using a thermosensitive polymer: Safety and feasibility. Urol Oncol. 2017;35:272-8.
Sanford T, Porten S, Meng MV. Molecular Analysis of Upper Tract and Bladder Urothelial Carcinoma: Results from a Microarray Comparison. PLoS One. 2015;10:e0137141.
Aruga J, Yokota N, Mikoshiba K. Human SLITRK family genes: genomic organization and expression profiling in normal brain and brain tumor tissue. Gene. 2003;315:87-94.
Vlachostergios PJ, Jakubowski CD, Niaz MJ, Lee A, Thomas C, Hackett AL, et al. Antibody-Drug Conjugates in Bladder Cancer. Bladder Cancer. 2018;4:247-59.
Morrison K, Challita-Eid PM, Raitano A, An Z, Yang P, Abad JD, et al. Development of ASG-15ME, a Novel Antibody-Drug Conjugate Targeting SLITRK6, a New Urothelial Cancer Biomarker. Mol Cancer Ther. 2016;15:1301-10.
Petrylak D, Heath E, Sonpavde G, George S, Morgans AK, Eigl BJ. Interim analysis of phase 1 dose escalation trial of the antibody-drug conjugate (ADC) ASG15E (ASG15ME) in patients (Pts) with metastatic urothelial cancer (mUC). Ann Oncol. 2016;27:266-95.

An Update on Muscle Invasive Bladder Cancer and Metastatic Bladder Cancer

Introduction

Bladder cancer was one of the top five leading causes of cancer death in 2015.¹ Most of these cases are of urothelial histologic origin. For about 35% of patients, bladder cancer is either muscle-invasive or metastatic at disease presentation. In addition, non-muscle invasive disease can progress to become muscle-invasive bladder cancer later on in the disease course. Preceding chapters discussed the diagnosis and staging of bladder cancer. This chapter will focus on the management of muscle-invasive urothelial bladder cancer as well as metastatic bladder cancer.

Muscle Invasive Bladder Cancer

Patients with muscle-invasive bladder cancer have the best outcomes when they are treated with a multidisciplinary approach.

Neoadjuvant Chemotherapy
Neoadjuvant cisplatin-based regimens improve survival outcomes for patients with invasive bladder cancer.^2,3 This has been shown in randomized trials and meta-analyses.^4-9 The Advanced Bladder Cancer Meta-analysis Collaboration found a significant disease (9%) and overall survival (5%) benefit with platinum-based chemotherapy regimens.² A recently updated meta-analysis (2016) with mature data on these randomized clinical trials revealed a 13% improvement in survival.³ Thus, neoadjuvant chemotherapy should be offered to all patients with muscle-invasive disease.

In patients who are not eligible for cisplatinum-based regimens (eg. creatinine clearance (<60 ml/min), ECOG performance status ≥2, New York Heart Association class ≥III heart failure, grade ≥2 hearing loss, ≥2 neuropathy, proceeding directly to extirpative local therapy or XRT is sometimes appropriate.¹⁰ Among the chemotherapy regimens studied, the most effective are MVAC: methotrexate, vinblastine, doxorubicin, and cisplatin and GC: Gemcitabine and Cisplatinum (note: there is no role for Carboplatin in this disease). There has been no head to head studies but some meta-analyses have shown a decreased survival benefit for GC when compared to dose-dense MVAC. Dose-dense MVAC is tolerated well and offers the advantage of shortened time for waiting to undergo surgery.^11-13 Additional advantages of neoadjuvant chemotherapy include the downstaging with ≤pT1N0 (49%).¹² These chemotherapy regimens not only provide an improved overall survival but also are associated with a complete pathologic response in about 25%-30% of patients.^12,14 In the future molecular subtypes may play a role in determining which patients would benefit from neoadjuvant chemotherapy.^15,16 For example, Seiler et al found that tumors classified as basal tumors had the most improvement in overall survival with neoadjuvant chemotherapy.¹⁵ These studies remain hypothesis generating at this point; studies to validate them are needed before they can be used in clinical practice. Until that time we, at MD Anderson, use a risk-adapted approach to avoid chemotherapy in patients who might derive minimal benefit.¹⁷ This strategy is shown in Figure 1.¹⁷

Culp et al. performed a retrospective study to define in high-risk muscle-invasive bladder cancer (≥cT3b or histologic lymphovascular invasion, micropapillary or neuroendocrine features) patients who underwent chemotherapy and compared outcomes in those who did and did not undergo neoadjuvant chemotherapy.¹⁸ This study concluded that patients who are most likely to benefit from chemotherapy are those who are high risk due to the worse prognosis compared to low-risk muscle-invasive bladder cancer.¹⁸

A few studies have evaluated the role of immunotherapy in the neoadjuvant setting. The ABACUS trial showed a downstaging of 39% and a pathologic complete response in 29% of patients ¹⁹ The PURE study also showed a pathologic complete response in 40% of patients and downstaging in 51%.²⁰

Radical Cystectomy
Radical cystectomy with urinary diversion is an essential part of the curative strategy for patients with non-metastatic bladder cancer. It is a complex surgery and is often associated with morbidity; however, enhanced recovery (ERAS) programs have helped improve patient’s surgical course outcomes.^21,22 ERAS programs focus on the preoperative, intraoperative, and postoperative continuum of care. Preoperative phases focus on preparation physically and mentally for surgery. Intraoperative phases work to decrease postoperative infection and limit fluid overload. Lastly, postoperative efforts are focused on early self-care and ambulation and feeding allowing for early discharge. An integral medication has been alvimopan (Entereg) in reducing the GI-related toxicity induced by opioid medications in the perioperative setting.²³

Radical cystectomy should include a bilateral pelvic lymph node dissection, this should include at a minimum the standard node dissection: internal iliac, external iliac, an obturator with consideration of an extended node template in high-risk patients (to include common iliac, presacral lymph nodes).²⁴ While several retrospective studies have shown the importance of removing more lymph node, we await the results of SWOG trial S1011 to answer whether an extended lymph node dissection is truly needed.^25-29

The approach to surgery (whether open or robotic) is less important than the skill of the surgeon.³⁰ The International Radical Cystectomy Consortium has reported that robotic cystectomy and diversions can be performed with similar outcomes to open surgery.³¹ The recent randomized trial comparing open to robotic cystectomy (RAZOR) showed no difference in intermediate oncologic outcomes.³¹ While operative time was longer with the robotic approach, there was reduced blood loss and transfusions, and shorter hospital stay.³¹ To date there no randomized trials comparing intracorporeal urinary diversion to open urinary diversion.

Partial cystectomy is only appropriate in a highly selected patient population such as tumor only in a bladder diverticulum or urachal adenocarcinoma. ²⁴

Urinary Diversion
The choice of urinary diversion is an important, life-altering one for patients undergoing radical surgery.³² Common urinary diversions include the ileal conduit, right-sided colon pouch (Indiana pouch) and orthotopic neobladder. Most studies have found no difference in the quality of life for the different urinary diversions, however, females may have a greater decrease in quality of life compared to men.^33-35 There are certain factors which may limit continent urinary diversions such as dexterity, cognition, previous radiation, preexisting incontinence and bladder tumor proximity to the urethra. Patients should have skills to manage their urinary diversion prior to discharge from the hospital after cystectomy.²⁴

Trimodal Therapy
Trimodal therapy (TMT) with chemotherapy, radiation and maximal TURBT offers a curative option to appropriately selected patients with radical cystectomy as a salvage option.^36,37 It is also an option in patients with multiple medical comorbidities, or those unwilling to undergo radical cystectomy.³⁸ Traditional selection criteria for TMT are patients with no variant histology, minimal T2 disease, no tumor associated hydronephrosis and absence of carcinoma-in-situ.^38,39 Patients should not always be offered radiation in conjunction with chemotherapy when the goal is curative intent.⁴⁰ A recent large retrospective study from the NCDB using a propensity-matched analysis found median overall survival 2.7 years (RC) vs 3 years (TMT).⁴¹ However, another study using the SEER-Medicare database also using a propensity-matched analysis found that radical cystectomy was less expensive and had better survival compared to TMT with almost 50% worse overall and cancer-specific survival.⁴²

Adjuvant Treatments

Adjuvant Chemotherapy
In patients with high-risk features such as ≥T3 disease and/or ≥N1 may benefit from adjuvant chemotherapy.^43,44 In a recent systematic review and meta-analysis of over 1500 patients from 11 clinical trials.⁴³ There was significant progression-free and overall survival associated with adjuvant chemotherapy compared with radical cystectomy alone with a 35% improvement in progression-free survival and 20% improvement in overall survival.⁴³ An additional retrospective study by Galsky et al also showed a benefit in overall survival.⁴⁴ Adjuvant chemotherapy regimens have been studied with the addition of adjuvant radiation, this found improved two year outcomes of locoregional recurrence-free survival of 96% compared to those without adjuvant chemotherapy and RT of 69%.⁴⁵ Patients who are chemotherapy naïve seem to benefit more than patients who underwent neoadjuvant chemotherapy.⁴⁶ The most benefit is again seen with cisplatinum containing regimens.⁴⁷

Adjuvant Radiotherapy
Adjuvant radiotherapy has had limited success due to toxicity to normal structures (eg bowel), but renewed interest has shown there may be a potential role for adjuvant radiation after radical cystectomy in high-risk patients and this is an ongoing area of study.^48-51 Baumann et al and Reddy et al have both published data on the contouring and target volumes of adjuvant radiation in patients after cystectomy to help alleviate some of the previous issues with post-cystectomy anatomical changes. In addition, there are multiple ongoing trials of adjuvant therapy in patients with ≥T3 disease.⁵⁰

Metastatic Urothelial Cancer

Chemotherapy
Cisplatin-based regimens remain the mainstay of treatment for patients that are eligible for chemotherapy.⁵² The area of immunotherapy in metastatic urothelial cancer is rapidly expanding.⁵³ In addition, for elderly patients, cisplatin-based chemotherapy regimens can be difficult to tolerate and carry a high rate of patient elected discontinuation.⁵⁴ For these reasons, immunotherapy may provide a treatment option for those who cannot tolerate cisplatin therapy.

Surgery
In select patients who have responded to chemotherapy, surgery may be a reasonable step, however, this is based on retrospective data, thus selection bias must heavily influence the decision on which patients may benefit from salvage surgery.⁵⁵ Salvage surgery may have a higher likelihood of complications, however, this has not been an area well studied. Surgical consolidation may be reasonable in patients who have a good response to chemotherapy and have small lesions. ⁵⁶ In addition, metastasectomy has been shown to be effective in solitary pulmonary lesions in retrospective studies.^55,57 In a SEER-Medicare study, a select group of patients underwent metastasectomy and over one third were still alive at three years, thus prolonging cancer survival.⁵⁸ In a meta-analysis, survival was improved by 37% with a metastasectomy.⁵⁹

Immunotherapy
There has been a recent deluge in the realm of immunotherapy.⁶⁰ Multiple drugs have been approved with agents available for patients who fail cisplatinum therapy as second-line therapy and in those who are cisplatin-ineligible patients as first-line treatment (Table 1), .⁶¹ Combinations of immunotherapy with traditional chemotherapy are currently being investigated.

table-1-muscle-invasive-bladder-cancer@2x.jpg

It is noteworthy that the administration of these immunotherapeutic agents has also been associated with multiple forms of immune-mediated reactions (colitis, pneumonitis, thyroiditis, hypophysitis, etc.) that can be life-threatening. Patients undergoing immunotherapy have to be watched vigilantly for adverse immune-mediated reactions, if not addressed immediately, these can lead to serious adverse outcomes.

Published Date: April 16th, 2019

Written by: Janet Baack Kukreja, MD, MPH and Ashish Kamat, MD, MBBS

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Bellmunt J, de Wit R, Vaughn DJ, et al. Pembrolizumab as Second-Line Therapy for Advanced Urothelial Carcinoma. N Engl J Med. 2017;376(11):1015-1026.
Balar AV, Castellano D, O'Donnell PH, et al. First-line pembrolizumab in cisplatin-ineligible patients with locally advanced and unresectable or metastatic urothelial cancer (KEYNOTE-052): a multicentre, single-arm, phase 2 study. Lancet Oncol. 2017;18(11):1483-1492.
Rosenberg JE, Hoffman-Censits J, Powles T, et al. Atezolizumab in patients with locally advanced and metastatic urothelial carcinoma who have progressed following treatment with platinum-based chemotherapy: a single-arm, multicentre, phase 2 trial. Lancet. 2016;387(10031):1909-1920.
Powles T, Duran I, van der Heijden MS, et al. Atezolizumab versus chemotherapy in patients with platinum-treated locally advanced or metastatic urothelial carcinoma (IMvigor211): a multicentre, open-label, phase 3 randomised controlled trial. Lancet. 2018;391(10122):748-757.

First Line Therapy of Metastatic Clear Cell RCC

Background

Kidney cancer represents 5% of all new cancer diagnoses in the United States, with approximately 64,000 new cases and 14,970 deaths in 2018.^1,2 The most common type of kidney cancer is renal cell carcinoma (RCC) and the most common histologic subtype of RCC is clear cell RCC, accounting for over 80% of cases.³ RCC is more common in men than women and typically occurs in the sixth to eighth decade of life.¹ Localized kidney cancer can often be cured with definitive surgery, with 5-year survival reaching over 90%.⁴However, for patients with advanced disease, 5-year survival remains poor at 11.7% and much progress is needed to develop novel therapies for advanced RCC.⁴

Risk Stratification

The current treatment paradigm for metastatic clear cell RCC requires stratification of patients into favorable, intermediate, or poor risk disease. Several validated models for risk stratification exist, including the International Metastatic Renal Cell Carcinoma Database Consortium model (IMDC)⁵ and Memorial Sloan Kettering Cancer Center model (MSKCC).⁶ Both criteria include time from diagnosis to systemic treatment of less than one year, performance status, as well as hemoglobin and calcium (Table 1). The main differences between these models are that the MSKCC model includes LDH and the IMDC includes neutrophil and platelet count as unique risk factors. Patients with no risk factors fall into the favorable risk group, patients with one to two risk factors are in the intermediate risk group, and those with three or more risk factors are in the high-risk group for both prognostic models. Contemporary clinical trials have found that drug effectiveness may vary depending on risk stratification which has led the FDA to approve some therapies for only certain risk groups.⁷ Thus, risk stratification is important for the clinician, not only for discussing prognosis with patients, but also for treatment selection.
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Favorable Risk Patients

For patients with no adverse risk factors, sunitinib and pazopanib are the preferred first line treatment options, recommended by both the National Comprehensive Cancer Network (NCCN) as well as the European Association of Urology (EAU).^8,9 Sunitinib is an oral multikinase inhibitor which targets vascular endothelial growth factor receptors (VEGFR) and platelet-derived growth factor receptors (PDGFR). A phase III trial comparing sunitinib to interferon-Î± showed that sunitinib significantly improved median progression free survival (11 months vs 5 months) and had a higher overall response rate as well when compared with interferon alfa (31% vs 6%).¹⁰ Sunitinib also demonstrated longer overall survival in a follow up study, 26.4 months vs 21.8 months.¹¹ Severe adverse events (grade 3-4 toxicities) were minimal, and the most common adverse events were diarrhea, fatigue, and nausea. Hypertension was one notable side effect of sunitinib, which was not seen with interferon alfa. Based on the data above, sunitinib was granted FDA approval in 2007 and has been the benchmark for many future clinical trials in the mRCC space.

Pazopanib is another oral multikinase inhibitor, which targets VEGFR-1,2,3, PDGFR- and , and c-KIT.¹² Pazopanib was established as a safe and efficacious therapy for mRCC based on a large randomized, placebo controlled trial in patients who were treatment naive or cytokine pretreated.¹² In this trial of 435 patients, pazopanib increased progression-free survival (9.2 months vs 4.2 months) compared with placebo, both in the treatment naÃ¯ve cohort as well as the cytokine pretreated cohort. The objective response rate to pazopanib was 30% and pazopanib was well tolerated. Unique toxicities of pazopanib included notable grade 3 hepatotoxicity 30% of patients had elevated ALT and 21% had elevated AST. These results granted pazopanib FDA approval in October 2009. A subsequent phase III study (COMPARZ) with 1,110 patients compared sunitinib to pazopanib, and pazopanib was found to be noninferior to sunitinib with respect to progression-free survival and overall survival.¹³ Median overall survival was 28.4 months in the pazopanib arm compared with 29.3 months in the sunitinib arm. In terms of safety, similar percentages of patients in both sunitinib and pazopanib experienced dose interruptions of one week or greater, 44% and 49% respectively. Patients in the pazopanib arm more frequently discontinued therapy based on abnormal liver function tests. Patients taking sunitinib had a higher risk of abnormal hematologic labs including leukopenia, thrombocytopenia, neutropenia, and anemia.

Additional FDA approved therapies for first line management of favorable risk patients include high dose interleukin 2 (HD IL-2)^14-17, interferon plus bevacizumab¹⁸, and sorafenib.¹⁹ These therapies are less commonly used given their tolerability and toxicity profiles. HD IL-2 deserves special mention here given its ability to induce complete responses in a small subset of patients. A recent abstract describing overall survival from the PROCLAIM database show that of favorable risk patients, median overall survival is 63.3 months and 2 year overall survival is 77.6%.¹⁴ Of course, patients who are given HD IL-2 are a very carefully selected robust cohort, and cross-trial comparisons are challenging to make.

Intermediate and Poor Risk

Per the IMDC and MSKCC prognostic models, patients with one or two risk factors are classified as intermediate risk, and poor risk if they have three or more risk factors. Currently, the two major newcomers in this space are cabozantinib and the combination of ipilimumab and nivolumab. Cabozantinib is a multikinase inhibitor of VEGFR, MET, and AXL.²⁰ In the phase II CABOSUN study, 157 intermediate or poor risk patients were randomized to cabozantinib or sunitinib. In this population, cabozantinib increased median progression free survival (8.2 months vs 5.6 months) and improved overall response rate (33% vs to 12%) compared with sunitinib. Both sunitinib and cabozantinib had about a 67% grade 3/4 adverse event rate and had a similar toxicity profile, including fatigue, hypertension, and diarrhea. Sunitinib had a lower incidence of hand foot syndrome and weight loss compared with cabozantinib, but higher rates of neutropenia and thrombocytopenia. Given this data, Cabozantinib obtained FDA approval for the front-line treatment of mRCC in December 2017.

The newest therapy to obtain FDA approval is the combination checkpoint inhibitor duo Ipilimumab and Nivolumab (Ipi/Nivo); it was approved in April of 2018, based on the results of CheckMate214.⁷ CheckMate 214 was a randomized, open-label trial comparing sunitinib with Ipi/Nivo. 1096 patients were enrolled, of which 847 were intermediate or poor risk. This study had a coprimary endpoint of overall survival, objective response rate, and progression free survival among patients who were intermediate or poor risk. The overall response rate was 42% with ipi/nivo vs 27% with sunitinib, with a complete response rate of 9% vs 1%. Median overall survival has not been reached with ipi/nivo vs 26 months for sunitinib. Progression free survival was 11.6 months for ipi/nivo compared with 8.4 months for sunitinib. 46% of patients receiving ipi/nivo experienced grade 3/4 toxicities compared with 63% of patients receiving sunitinib. The most common grade 3/4 adverse events with ipi/nivo was fatigue, diarrhea, and elevated lipase compared with hypertension, hand-foot syndrome, and increased lipase with sunitinib. 35% of patients required high dose corticosteroids for immune related toxicities with ipi/nivo. Â With this data, the European Association of Urology has recommended that ipi/nivo be the new standard of care for patients with intermediate and poor risk disease, and the NCCN has also listed ipi/nivo as a category 1, preferred treatment option for patients with intermediate and poor risk disease.^8,9
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Future Therapies

Front-line treatment options for mRCC are rapidly evolving.²⁴ Data shown at ASCO and GU ASCO has demonstrated that antiangiogenic agents in combination with checkpoint inhibitors may prolong progression-free survival when compared with kinase inhibitors.²⁵ Several phase III trials exploring this hypothesis are now underway (Table 3). IMmotion 151 is a randomized phase III trial comparing the combination of atezolizumab + bevacizumab vs sunitinib. Progression-free survival was 11.2 months in the intention to treat analysis for patients atezolizumab and bevacizumab, compared with 8.4 months in the sunitinib arm. JAVELIN Renal 100 is investigating avelumab in combination with axitinib and phase I results show a promising overall response rate of 54.5% out of 55 patients.²⁶ KEYNOTE-426 is investigating pembrolizumab in combination with axitinib, compared with sunitinib alone.²⁷ These trials are important and exciting for our patients with mRCC and their future results may alter the standard of care for frontline mRCC.
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Published Date: January 29th, 2019

Written by: Jason Zhu, MD

References:

Siegel RL, Miller KD, Jemal A. Cancer statistics, 2018. CA: A Cancer Journal for Clinicians 2018;68:7-30.2018. at https://www.cancer.org/cancer/kidney-cancer/about/key-statistics.html.)
Moch H, Gasser T, Amin MB, Torhorst J, Sauter G, Mihatsch MJ. Prognostic utility of the recently recommended histologic classification and revised TNM staging system of renal cell carcinoma. Cancer 2000;89:604-14.
Motzer RJ, Jonasch E, Agarwal N, et al. Kidney cancer, version 2.2017, NCCN clinical practice guidelines in oncology. Journal of the National Comprehensive Cancer Network 2017;15:804-34.
Heng DY, Xie W, Regan MM, et al. External validation and comparison with other models of the International Metastatic Renal-Cell Carcinoma Database Consortium prognostic model: a population-based study. The lancet oncology 2013;14:141-8.
Motzer RJ, Mazumdar M, Bacik J, Berg W, Amsterdam A, Ferrara J. Survival and prognostic stratification of 670 patients with advanced renal cell carcinoma. Journal of clinical oncology 1999;17:2530-.
Motzer RJ, Tannir NM, McDermott DF, et al. Nivolumab plus Ipilimumab versus Sunitinib in Advanced Renal-Cell Carcinoma. New England Journal of Medicine 2018;378:1277-90.
Motzer R, Jonasch E, Agarwal N. Kidney Cancer: NCCN Evidence Blocks, Version 2.2018, NCCN Clinical Practice Guidelines in Oncology. 2017.
Powles T, Albiges L, Staehler M, et al. Updated European Association of Urology Guidelines: Recommendations for the Treatment of First-line Metastatic Clear Cell Renal Cancer. European Urology 2018;73:311-5.
Motzer RJ, Hutson TE, Tomczak P, et al. Sunitinib versus Interferon Alfa in Metastatic Renal-Cell Carcinoma. New England Journal of Medicine 2007;356:115-24.
Motzer RJ, Hutson TE, Tomczak P, et al. Overall Survival and Updated Results for Sunitinib Compared With Interferon Alfa in Patients With Metastatic Renal Cell Carcinoma. Journal of Clinical Oncology 2009;27:3584-90.
Sternberg CN, Davis ID, Mardiak J, et al. Pazopanib in Locally Advanced or Metastatic Renal Cell Carcinoma: Results of a Randomized Phase III Trial. Journal of Clinical Oncology 2010;28:1061-8.
Motzer RJ, Hutson TE, Cella D, et al. Pazopanib versus Sunitinib in Metastatic Renal-Cell Carcinoma. New England Journal of Medicine 2013;369:722-31.
Fishman MN, Clark JI, Alva AS, et al. Overall survival (OS) by clinical risk category for high dose interleukin-2 (HD IL-2) treated metastatic renal cell cancer (RCC): Data from PROCLAIM. Journal of Clinical Oncology 2018;36:4578-.
Amin A, White RL. Interleukin-2 in Renal Cell Carcinoma: A Has-Been or a Still-Viable Option? Journal of Kidney Cancer and VHL 2014;1:74-83.
Alva A, Daniels GA, Wong MKK, et al. Contemporary experience with high-dose interleukin-2 therapy and impact on survival in patients with metastatic melanoma and metastatic renal cell carcinoma. Cancer Immunology, Immunotherapy 2016;65:1533-44.
Fyfe G, Fisher RI, Rosenberg SA, Sznol M, Parkinson DR, Louie AC. Results of treatment of 255 patients with metastatic renal cell carcinoma who received high-dose recombinant interleukin-2 therapy. Journal of clinical oncology 1995;13:688-96.
Escudier B, Pluzanska A, Koralewski P, et al. Bevacizumab plus interferon alfa-2a for treatment of metastatic renal cell carcinoma: a randomised, double-blind phase III trial. The Lancet 2007;370:2103-11.
Escudier B, Szczylik C, Hutson TE, et al. Randomized Phase II Trial of First-Line Treatment With Sorafenib Versus Interferon Alfa-2a in Patients With Metastatic Renal Cell Carcinoma. Journal of Clinical Oncology 2009;27:1280-9.
Choueiri TK, Escudier B, Powles T, et al. Cabozantinib versus everolimus in advanced renal cell carcinoma. The New England journal of medicine 2015;373:1814-23.
Escudier B, Bellmunt J, Négrier S, et al. Phase III trial of bevacizumab plus interferon alfa-2a in patients with metastatic renal cell carcinoma (AVOREN): final analysis of overall survival. J Clin Oncol 2010;28:2144-50.
Hudes G, Carducci M, Tomczak P, et al. Temsirolimus, Interferon Alfa, or Both for Advanced Renal-Cell Carcinoma. New England Journal of Medicine 2007;356:2271-81.
Choueiri TK, Halabi S, Sanford BL, et al. Cabozantinib Versus Sunitinib As Initial Targeted Therapy for Patients With Metastatic Renal Cell Carcinoma of Poor or Intermediate Risk: The Alliance A031203 CABOSUN Trial. Journal of Clinical Oncology 2017;35:591-7.
Zarrabi K, Wu S. Current and emerging therapeutic targets for metastatic renal cell carcinoma. Current oncology reports 2018;20:41.
Motzer RJ, Powles T, Atkins MB, et al. IMmotion151: A Randomized Phase III Study of Atezolizumab Plus Bevacizumab vs Sunitinib in Untreated Metastatic Renal Cell Carcinoma (mRCC). Journal of Clinical Oncology 2018;36:578-.
Choueiri TK, Larkin JMG, Oya M, et al. First-line avelumab + axitinib therapy in patients (pts) with advanced renal cell carcinoma (aRCC): Results from a phase Ib trial. Journal of Clinical Oncology 2017;35:4504-.
Rini BI, Powles T, Chen M, Puhlmann M, Atkins MB. Phase 3 KEYNOTE-426 trial: Pembrolizumab (pembro) plus axitinib versus sunitinib alone in treatment-naive advanced/metastatic renal cell carcinoma (mRCC). Journal of Clinical Oncology 2017;35:TPS4597-TPS.

Management of Non-Muscle Invasive Bladder Cancer

In the previous sections, we have covered Epidemiology, Diagnosis, and Pathology of Bladder Cancers. As noted, most patients present at a potentially curative stage non-muscle invasive bladder cancer (NMIBC). Although NMIBC can generally be managed with endoscopic resections followed by some form of intravesical therapy, some have the potential to progress to muscle-invasive bladder cancer (MIBC) or develop metastases. Key to the management of NMIBC is making the distinction between tumors likely to progress vs. those that will not, and for the appropriate personalized therapy for each patient.

Endoscopic Surgical Management

Cystoscopic Resection

NMIBC is usually diagnosed with cystoscopic evaluation. Upon diagnosis, the location, number, and morphology of the tumors are recorded. Urinary cytology is sent and upper tract imaging performed to assess for extravesical urothelial tumors and staging purposes.

Transurethral resection of bladder tumor (TURBT) is the initial treatment. Bimanual exam under anesthesia should be performed to complete clinical staging. It is imperative that deeper resections are obtained to ensure adequate muscle sampling and en bloc resection or at least sending the base separately can help pathologists make the best diagnosis. Resecting tumors within a bladder diverticulum may be easily complicated by bladder perforation. Invasion beyond the lamina propria in diverticula should be categorized as cT3a disease. When resecting near the ureteral orifice caution is advised and using pure cutting current is important to minimize scarring which may lead to ureteral obstruction. Alternatively, small tumors may be resected using the cold-cup biopsy forceps.

To improve the quality of TUR and reporting, a 10-item checklist designed to encompass both the description of tumor characteristics associated with oncologic outcomes (e.g. tumor number, size, and characteristics) and steps ensuring adequate tumor evaluation and treatment (e.g. bimanual exam, visually complete resection) has been proposed. The implementation of this checklist enhanced surgeon attention to the critical aspects of the procedure, improving surgical quality.¹

Expected side effects of TURBT include minor bleeding and irritative symptoms. Excessive bleeding and bladder perforation are uncommon (<5% of cases). Fortunately, in cases of perforation, the risk of tumor seeding appears to be low.² Extraperitoneal perforations can usually be managed with prolonged catheterization, while intraperitoneal rupture often requires surgical repair. TUR syndrome may occur due to the absorption of hypotonic fluid if due diligence is not observed.³ As long as minimal energy is applied to the ureteral orifice, the incidence of scarring is low.⁴

Additional Strategies

Concurrent with resection of the tumor, any suspicious area within the lower urinary tract should be sampled, either with formal resection or with cold cup biopsy. Prostatic urethral biopsies are recommended in patients with a multifocal tumor or visible abnormalities. Repeat TUR within 2-4 weeks is recommended when primary resection is incomplete or in the presence of high-grade T1 tumors.⁵

Laser therapy is sometimes used, not only for tumor coagulation but also for en bloc resection. In a recent meta-analysis of en bloc resection series, 96% of the cases demonstrated the presence of detrusor muscle within the specimen and residual disease was present on re-TUR in only 1/119 cases.⁶ Treatment should be under direct visualization and discontinued as soon as a coagulative effect is observed around the tumor base.⁷

Narrowband imaging (NBI) and blue light cystoscopy (BLC) has been used to enhance visualization of bladder tumors. BLC is a technique that identifies cancer through the selective accumulation of photosensitizing drugs (5-aminolevulinic acid and hexyl-aminolevulinate) in the malignant cells. When used in conjunction with white light cystoscopy, BLC provides enhanced detection rates of non-muscle invasive lesions.^8-10 In a meta-analysis consisting of 12 randomized controlled trials with a total 2258 patients, a lower recurrence rate (OR 0.5; p<0.0001) with a delayed time to the first occurrence (by 7.39 weeks, p<0.0001) was seen with BLC.¹¹ As a result, recommendations for its use have been incorporated into the NCCN guidelines. Recently, flexible blue light cystoscopy was also demonstrated to detect additional malignant lesions in 63% of the patients with recurrence after primary therapy and in 21% of the patients with lesions not otherwise seen on white light cystoscopy.¹²

In NMIBC, the most important prognostic factor for progression is grade.¹³ While high-grade tumors often appear sessile and broad-based, low-grade tumors typically exhibit papillary architecture on a thin stalk. In conjunction, LG tumorsâ€™ low likelihood of progression and favorable morphology lend themselves to biopsy and fulgurations that can be accomplished in the outpatient setting.¹⁴ Adopting this strategy can significantly reduce the therapeutic burden associated with bladder cancer treatment.

Perioperative Intravesical Chemotherapy

The most widely studied agent has been Mitomycin C (MMC), used as a single dose immediately after TURBT. Although MMC was shown to reduce the risk of recurrence by 35% (HR: 0.65; 95% CI, 0.58-0.74; p<0.001), it was not efficacious in patients with a prior recurrence rate of more than one per year or in patients with EORTC recurrence score 5.¹⁵ A recent prospective randomized trial using perioperative infusion of gemcitabine demonstrated a reduction of recurrence from 47% to 35% (p<0.001). Corroborating the findings in a previous meta-analysis of perioperative instillation of Mitomycin C, among the target population with low-grade, non-muscle invasive cancer, the reduction was even more dramatic (from 54% to 34%, p-0.001). There were also minimal complications (2.4% â‰¥Grade 3).¹⁶

Adjuvant Intravesical Therapy

Immunotherapy

Bacillus Calmette-Guerin is an attenuated mycobacterium with proven efficacy in reducing recurrences, progression and death from Â NMIBC.¹⁷ Therapy is usually started 2-4 weeks after tumor resection.¹⁸ Therapeutic protocol includes induction with 6 weeks followed by maintenance therapy (3 weekly maintenances at 3mo, 6mo, 12mo, 18mo, 24mo, 30mo, and 36mo). This is now accepted as standard of care in patients with high-risk disease, with one year maintenance as an alternative for intermediate risk patients (Figure 2).¹⁹ If tumor recurrence is found after induction therapy, an additional induction course may be attempted.

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Although side-effects are usually temporary and self-limited, significant morbidity can occur with fevers, lung infections, and sepsis. While most can be treated with symptomatic therapy, in the case of severe infections or BCG-osis, addition of steroids should be considered in addition to anti-tuberculosis therapy. In a randomized study by the EORTC, reduced dose was compared to full dose BCG, and 1 compared to 3 years. While full dose for 3 years was associated with the best reduction in recurrences, there was no significant difference with regards to progression.²⁰ Interestingly, there was no difference in local or systemic side effects between low dose or full dose BCG.²⁰ Â Nonetheless in clinical practice, reduction of dose for cause - i.e. when side effects are reported - Â has been noted to allow patients to continue on therapy and finish the duration of maintenance.

A number of other immunogenic agents have been tested for the treatment of NMIBC, some in the setting of BCG failure. These include keyhole limpet hemocyanin (KLH), mycobacterial cell wall DNA extract (MCNA), IL-2, and IFN-Î±. None of these, however, proved to be as effective as treatment with BCG.

Chemotherapy

In general, intravesical chemotherapy may improve recurrence-free rates, but these are not as effective as BCG in preventing progression (Table 1). They are, however, better tolerated. MMC, the most extensively studied intravesical chemotherapy agent, was associated with 9. 4% progression rate, compared to 7.7% after BCG.²¹Â Strategies such as electromotive therapy have been seeking to enhance the efficacy of MMC, although results have been mixed thus far. In studies limited to high-risk NMIBC, recurrence-free rates following chemohyperthermia ranged from 29-71%.²² Gemcitabine and the taxanes paclitaxel and docetaxel may be used in combination, even in the treatment of BCG-Unresponsive disease (Figure 2).

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BCG Unresponsive Disease

Recurrent tumors after intravesical BCG treatment confer a high risk of progression and salvage radical cystectomy is recommended.²³Â In practice, many patients may need to resort to less radical treatment options due to their physical frailty or rejection of complete bladder removal. Alternate options for these patients remain scarce. Valrubicin, the only approved agent for recurrent CIS after intravesical BCG treatment, has only an 8% complete response rate at 30-month follow-up.²⁴ Alternative options include other intravesical chemotherapies including gemcitabine, docetaxel and sequential or combination therapy (Table 2). Gene therapies options include the use of InstiladrinÂ®, an IFN-Î± expressing recombinant adenoviral vector, which has recently achieved 35% 12-month relapse-free survival in a cohort of high risk, BCG-Unresponsive NMIBC patients (Figure 2).²⁵ Ongoing trials in this space are listed in Table 3.

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Strategies for Surveillance

Due to its high recurrence rate and the need for vigilant cystoscopic surveillance, the management of bladder cancer is the most costly amongst all cancers in the US; $2.2 billion was spent in 2003.²⁶Â Surveillance relies on cystoscopy and urine cytology, with most recommending this every 3 months up to 24 months after initial diagnosis, followed by every 6 months up to 5 years.¹⁹

Although generally regarded as the urinary test of choice, urine cytology has very low sensitivity (48%), especially in detecting a low-grade tumor (16%).²⁷ Recent studies have also demonstrated the decreased performance of cytology for high-grade tumors â€“ for example in a recent multicenter study, as many as 40% of CIS were not detected by cytology. Thus, caution must be exercised when relying on cytology alone.²⁸Â Other urinary markers available today include BTA stat and BTA TRAK (detect human complement factor H-related protein), ImmunoCyt (fluorescent-labeled monoclonal antibodies), NMP22 (detection of nuclear matrix protein 22), UroVysion (FISH of DNA probes specific for bladder cancer aneuploidy) and Cxbladder (measures the expression of 5 biomarkers). However, none are recommended for use in the management guidelines other than potential use of Urovysion FISH in clarifying atypical cytology or in predicting response to BCG. A positive FISH result after BCG induction confers an increased risk of recurrence (3-5 fold) and progression (5-13 fold), depending on the timing of FISH positivity. Â For example in one study; at the 3-month time point, patients with a positive FISH result had a 58% risk of recurrence compared to 15% with a negative result (p < 0.001). For disease progression, the incidence was 25% with a positive FISH compared to 7% with a negative result (p < 0.013).²⁹ Since many patients who have a positive FISH test have no visible tumor at the time of assessment but subsequently develop recurrence in 6-24 months, this phenomenon has been categorized as a molecular failure and such patients can be considered for clinical trials for salvage therapies.³⁰

In addition, cytokines and biomarkers have been assessed to predict response to BCG. However, due to the complexity of the immune response to BCG, no single marker is likely to definitively predict a positive or negative response. We have prospectively tested the hypothesis that a panel of urinary cytokines can accurately assess the multifaceted immune response generated by intravesical BCG.³¹ A nomogram (CyPRIT, Cytokine Panel for Response to Intravesical Therapy) using a panel of 9 cytokines (IL-2, IL-6, IL-8, IL-18, IL-1ra, TRAIL, IFN-g, IL-12[p70], and TNF-a) was found to have an accuracy of 85.5% in predicting response to BCG (95% CI 77.9–93.1%). Efforts to validate the use of CyPRIT are currently underway.

Published Date: April 16th, 2019

Written by: Roger Li, MD and Ashish Kamat, MD, MBBS

References:

Anderson C, Weber R, Patel D, Lowrance W, Mellis A, Cookson M, et al. A 10-Item Checklist Improves Reporting of Critical Procedural Elements during Transurethral Resection of Bladder Tumor. J Urol. 2016;196(4):1014-20.
Balbay MD, Ã‡imentepe E, ÃœNsal A, Bayrak Ã–, KoÃ‡ A, Akbulut Z. The actual incidence of bladder perforation following transurethral bladder surgery. The Journal of urology. 2005;174(6):2260-3.
Bolat D, Gunlusoy B, Aydogdu O, Aydin ME, Dincel C. Comparing the short - term outcomes and complications of monopolar and bipolar transurethral resection of bladder tumors in patients with coronary artery disease: a prospective, randomized, controlled study. Int Braz J Urol. 2018;44(4):717-25.
Mano R, Shoshany O, Baniel J, Yossepowitch O. Resection of ureteral orifice during transurethral resection of bladder tumor: functional and oncologic implications. J Urol. 2012;188(6):2129-33.
Cumberbatch MGK, Foerster B, Catto JWF, Kamat AM, Kassouf W, Jubber I, et al. Repeat Transurethral Resection in Non-muscle-invasive Bladder Cancer: A Systematic Review. Eur Urol. 2018;73(6):925-33.
Naselli A, Puppo P. En bloc transurethral resection of bladder tumors: a new standard? J Endourol. 2017;31(S1):S-20-S-4.
Liem EI, de Reijke TM. Can we improve transurethral resection of the bladder tumour for nonmuscle invasive bladder cancer? Current opinion in urology. 2017;27(2):149-55.
Fradet Y, Grossman HB, Gomella L, Lerner S, Cookson M, Albala D, et al. A comparison of hexaminolevulinate fluorescence cystoscopy and white light cystoscopy for the detection of carcinoma in situ in patients with bladder cancer: a phase III, multicenter study. The Journal of urology. 2007;178(1):68-73.
Grossman HB, Gomella L, Fradet Y, Morales A, Presti J, Ritenour C, et al. A phase III, multicenter comparison of hexaminolevulinate fluorescence cystoscopy and white light cystoscopy for the detection of superficial papillary lesions in patients with bladder cancer. The Journal of urology. 2007;178(1):62-7.
Hermann GG, Mogensen K, Carlsson S, Marcussen N, Duun S. Fluorescence-guided transurethral resection of bladder tumours reduces bladder tumour recurrence due to less residual tumour tissue in T a/T1 patients: a randomized twoâ€centre study. BJU Int. 2011;108(8b):E297-E303.
Yuan H, Qiu J, Liu L, Zheng S, Yang L, Liu Z, et al. Therapeutic outcome of fluorescence cystoscopy guided transurethral resection in patients with non-muscle invasive bladder cancer: a meta-analysis of randomized controlled trials. PLoS One. 2013;8(9):e74142.
Daneshmand S, Patel S, Lotan Y, Pohar K, Trabulsi E, Woods M, et al. Efficacy and Safety of Blue Light Flexible Cystoscopy with Hexaminolevulinate in the Surveillance of Bladder Cancer: A Phase III, Comparative, Multicenter Study. J Urol. 2018;199(5):1158-65.
Fernandez-Gomez J, Solsona E, Unda M, Martinez-Pineiro L, Gonzalez M, Hernandez R, et al. Prognostic factors in patients with non-muscle-invasive bladder cancer treated with bacillus Calmette-Guerin: multivariate analysis of data from four randomized CUETO trials. Eur Urol. 2008;53(5):992-1001.
Sabir EF, HolmÃ¤ng S. TaG1 Bladder Cancer: A Third of All Primary Tumors and 80% of All Recurrences Can Be Treated in the Office Using Local Anesthesia. Urology Practice. 2014;1(4):184-8.
Sylvester RJ, Oosterlinck W, Holmang S, Sydes MR, Birtle A, Gudjonsson S, et al. Systematic review and individual patient data meta-analysis of randomized trials comparing a single immediate instillation of chemotherapy after transurethral resection with transurethral resection alone in patients with stage pTaâ€“pT1 urothelial carcinoma of the bladder: which patients benefit from the instillation? Eur Urol. 2016;69(2):231-44.
Messing EM, Tangen CM, Lerner SP, Sahasrabudhe DM, Koppie TM, Wood DP, Jr., et al. Effect of Intravesical Instillation of Gemcitabine vs Saline Immediately Following Resection of Suspected Low-Grade Non-Muscle-Invasive Bladder Cancer on Tumor Recurrence: SWOG S0337 Randomized Clinical Trial. JAMA. 2018;319(18):1880-8.
Morales A, Eidinger D, Bruce AW. Intracavitary Bacillus Calmette-Guerin in the treatment of superficial bladder tumors. J Urol. 1976;116(2):180-3.
Lamm DL, Van Der Meijden AP, Morales A, Brosman SA, Catalona WJ, Herr HW, et al. Incidence and treatment of complications of bacillus Calmette-Guerin intravesical therapy in superficial bladder cancer. The Journal of urology. 1992;147(3):596-600.
Babjuk M, Bohle A, Burger M, Capoun O, Cohen D, Comperat EM, et al. EAU Guidelines on Non-Muscle-invasive Urothelial Carcinoma of the Bladder: Update 2016. Eur Urol. 2016.
Oddens J, Brausi M, Sylvester R, Bono A, van de Beek C, van Andel G, et al. Final results of an EORTC-GU cancers group randomized study of maintenance bacillus Calmette-Guerin in intermediate- and high-risk Ta, T1 papillary carcinoma of the urinary bladder: one-third dose versus full dose and 1 year versus 3 years of maintenance. Eur Urol. 2013;63(3):462-72.
BÃ¶hle A, Jocham D, Bock P. Intravesical bacillus Calmette-Guerin versus mitomycin C for superficial bladder cancer: a formal meta-analysis of comparative studies on recurrence and toxicity. The Journal of urology. 2003;169(1):90-5.
Liem EI, Crezee H, de la Rosette JJ, de Reijke TM. Chemohyperthermia in non-muscle-invasive bladder cancer: An overview of the literature and recommendations. Int J Hyperthermia. 2016;32(4):363-73.
Babjuk M, BÃ¶hle A, Burger M, Capoun O, Cohen D, CompÃ©rat EM, et al. EAU Guidelines on Non-Muscle-invasive Urothelial Carcinoma of the Bladder: Update 2016. Eur Urol. 2017;71(3):447-61.
Steinberg G, Bahnson R, Brosman S, Middleton R, Wajsman Z, Wehle M. Efficacy and safety of valrubicin for the treatment of Bacillus Calmette-Guerin refractory carcinoma in situ of the bladder. The Valrubicin Study Group. J Urol. 2000;163(3):761-7.
Shore ND, Boorjian SA, Canter DJ, Ogan K, Karsh LI, Downs TM, et al. Intravesical rAd-IFNalpha/Syn3 for Patients With High-Grade, Bacillus Calmette-Guerin-Refractory or Relapsed Non-Muscle-Invasive Bladder Cancer: A Phase II Randomized Study. J Clin Oncol. 2017;35(30):3410-6.
Donat SM. Evaluation and follow-up strategies for superficial bladder cancer. The Urologic clinics of North America. 2003;30(4):765-76.
Yafi FA, Brimo F, Steinberg J, Aprikian AG, Tanguay S, Kassouf W. Prospective analysis of sensitivity and specificity of urinary cytology and other urinary biomarkers for bladder cancer. Urologic Oncology: Seminars and Original Investigations. 2015;33(2):66.e25-66.e31.
Tan WS, Sarpong R, Khetrapal P, Rodney S, Mostafid H, Cresswell J, et al. Does urinary cytology have a role in haematuria investigations? BJU Int. 2018.
Kamat AM, Dickstein RJ, Messetti F, Anderson R, Pretzsch SM, Gonzalez GN, et al. Use of fluorescence in situ hybridization to predict response to bacillus Calmette-Guerin therapy for bladder cancer: results of a prospective trial. The Journal of urology. 2012;187(3):862-7.
Kamat AM, Willis DL, Dickstein RJ, Anderson R, Nogueras-Gonzalez G, Katz RL, et al. Novel fluorescence in situ hybridization-based definition of bacille Calmette-Guerin (BCG) failure for use in enhancing recruitment into clinical trials of intravesical therapies. BJU international. 2016;117(5):754-60.
Kamat AM, Briggman J, Urbauer DL, Svatek R, Nogueras Gonzalez GM, Anderson R, et al. Cytokine Panel for Response to Intravesical Therapy (CyPRIT): Nomogram of Changes in Urinary Cytokine Levels Predicts Patient Response to Bacillus Calmette-Guerin. Eur Urol. 2016;69(2):197-200.

Upper Tract Urothelial Carcinoma

Upper tract urothelial carcinoma (UTUC) comprises any malignancies arising from the urothelium between the level of the renal pelvis and the distal ureter. Owing to their relatively rarity, there is generally little data to guide the management of patients with these tumors and much of practice is extrapolated from the management of urothelial cancer of the bladder. A recent genomic assessment of UTUC demonstrates novel mutations and distributions of mutations, compared with bladder cancer.¹ Further, anatomic differences between the upper urinary tract and the bladder affect the validity of extrapolating data from one disease site to the other. In the ureter, the muscular layer surrounding the urothelium is marked attenuated compared to the detrusor. Additionally, in the renal pelvis, the urothelium may directly about the renal parenchyma.

Epidemiology

Upper tract disease represents approximately 5-10% of all urothelial malignancies.² There is significant geographic variation in the incidence of these cancers, likely due to differences in the prevalence of underlying risk factors. In Balkan nations, UTUC may represent up to 40% of all kidney-related cancers. In Western nations, the incidence is approximately 2 per 100,000 population.³ As with bladder cancer, the incidence of these cancers peaks in individuals in their 8^th and 9^th decades of life.

Interestingly, the incidence of UTUC appears to be increasing. Accompanying this has been a change in tumor stage, with an increasing proportion of earlier stage neoplasms.⁴

While bladder common is nearly 4 times as common in men as in women, the differential is closer to 2:1 for UTUC. Data is mixed on the association between patient gender and outcomes in UTUC. While some authors have reported that women are more likely to have advanced stage of disease⁵, other have not demonstrated this.⁶ Similarly, some groups report worse outcomes among women⁵ following nephroureterectomy, while other analyses have demonstrated no difference.⁶

Utilizing a large, multi-institutional cohort, Raman et al. examined predictors of recurrence and cancer-specific mortality among patients undergoing radical nephroureterectomy.⁷ They found that pathological tumor stage, nodal involvement, and tumor grade were associated with survival. Tumor location, whether in the renal pelvis or ureter, was not significantly associated with oncologic outcomes.

Etiology

Most, though not all, risk factors for the develop of UTUC are similar to the development of bladder cancer. Particular focus here is made of the unique risk factors including hereditary syndromes and uncommon environmental exposures.

Genetic and environmental risk factors may contribute to the development of UTUC. Hereditary UTUC is associated with hereditary nonpolyposis colorectal carcinoma (HNPCC) syndrome, or Lynch syndrome.⁸ These patients may also have an increased risk of bladder cancers⁸, though whether this is from a urothelial field defect or seeding from the upper tract is unclear. HNPCC should be suspected among younger patients or those with a personal or family (two first-degree relatives) history of HNPCC-associated cancers, including colon or endometrial cancers.

A number of environmental risk factors are known for UTUC. First among these is aristolochic acid nephropathy. This is felt to be the common pathway between both Balkan endemic nephropathy and Chinese herb nephropathy (associated with consumption of Aristolochia fangchi) and UTUC.⁹ In Western countries, smoking is a much more common risk factor. This is associated with the production of N-hydroxylamine from aromatic amines. For reasons that are poorly understood, smoking seems to confer a higher risk of ureteral tumors than renal pelvic lesions.¹⁰ Previous reports suggested that coffee consumption may also be associated with UTUC but further work has suggested that these results likely represent Berkson's bias, due to the relationship between smoking and coffee consumption. Analgesic abuse, particularly of phenacetin, has also been well documented to be associated with the development of UTUC. However, the frequency of this exposure is rapidly declining and, as such, associated cases are relatively rare today. Arsenic exposure, typically through contaminated water, has also demonstrated an association with the development of UTUC. Interestingly, arsenic-associated UTUC demonstrates a female preponderance, unlike the general epidemiologic trends. As with bladder cancer, occupational exposures to aromatic hydrocarbons have been associated with a significantly increased risk of UTUC. Alkylating chemotherapy and chemic laxatives also appear to be associated with increased rates of UTUC. Finally, chronic inflammation may predispose to non-urothelial (squamous cell cancer or adenocarcinoma) of the upper urinary tract.

Association Between UTUC and Bladder Cancer

Significant focus has been directed to the relationship between UTUC and urothelial bladder cancer as a result of their shared tissue of origin. UTUC may occur in approximately 2 to 4% of patients with bladder cancer. However, there is wide variability in this quoted risk owing to differences in bladder cancer pathology and duration of follow-up. UTUC recurrence following bladder cancer treatment is reportedly more common among patients with carcinoma in situ (CIS) of the bladder¹¹ and among those with more advanced (T1 vs Ta) disease.¹²

Among patients with UTUC, recurrence in the bladder is relatively common. Depending on the report, estimates range from 15 to 75% at 5 years. Thus, routine cystoscopic surveillance is recommended following treatment for UTUC.

Histologic Considerations

The vast majority of upper tract tumors are urothelial in origin (>90%). As with bladder cancer, this may present as CIS, as papillary or sessile lesions, and as solitary lesions or in a multifocal pattern. Histological variants, now relatively well recognized in bladder cancer, may also be found in UTUC. Squamous cell cancers and adenocarcinomas make up a small proportion of upper tract malignancies. Other lesions including benign fibroepithelial polyps and neurofibromas as well as neuroendocrine tumors, hematopoietic tumors, and sarcomas have been reported.

Two benign lesions, papillomas and inverted papillomas, have been associated with synchronous and metachronous development of UTUC. Thus, surveillance is recommended for patients with these lesions.

Clinical Assessment and Evaluation

The majority of patients with UTUC present with gross or microscopic hematuria. In fact, depending on estimates, up to 98% of all patients with UTUC will have hematuria. However, UTUC remains uncommon among patients presenting with hematuria. Â Flank pain may also occur and is typically felt to be due to obstruction of the collecting system. UTUC may also present entirely without symptoms as an incidental finding.

Today, triphasic computed tomography (so called CT urography (CTU)) is the imaging modality of choice for the diagnosis of upper tract lesions. The sensitivity of CTU, as well as the negative predictive value, is reported to near 100%.¹³ Most upper tract lesions present with a filling defect. To distinguish from other causes of such a defect, UTUC typically have a density between 10 and 70 hounsfield units, less than radiolucent stones. In equivocal cases, retrography pyelography, selective ureteric washings for cytology, or ureteroscopy may be necessary.

Due to the association between UTUC and bladder cancer, cystoscopy is necessary to rule-out concomitant bladder cancer. Further, in the workup of a patient with hematuria, bladder cancer is a much more common underlying etiology than UTUC.

In addition to visualizing the lesion, ureteroscopy can allow for histologic diagnosis with biopsy or brushings. However, these biopsies are limited in the amount of tissue that may be samples and, as such, tumor grade is more reliable than stage based on these samples. Staging requires integration of imaging studies as tumor grade.

Cytology may be employed in the work-up of UTUC. While cytology is highly specific, it lacks sensitivity.

Staging, as detailed in the chart below, according to the TNM classification, parallels that of bladder cancer.
table 1 upper tract urothelial carcinoma2x

table 1 upper tract urothelial carcinoma2x

Upper tract tumors disseminate via lymphatic and hematogenous spread as well as direct extension. The most common sites of metastasis are lungs, liver, bones and lymph nodes. Thus, preoperative staging, depending on primary tumor characteristics, comprises thoracic imaging (CXR or CT), abdominal CT, liver function testing, and bone scan. In addition, for patients for whom nephroureterectomy is being considered, assessment of the contralateral renal function is necessary.

Prognostic Factors

Stage is the most important predictor. Unfortunately, it is sometimes difficult to ascertain stage preoperatively. Certainly, nodal involvement is independently associated with worse survival outcomes. Tumor location, whether in the renal pelvis or ureter, has proven controversial with regards to prognosis. While some studies have suggested no difference¹⁴, others have found improved survival among patients with renal pelvic tumors.¹⁵ Likely through its association with tumor stage, the presence of hydronephrosis has been shown to be associated with worse survival.¹⁶ Larger tumors (typically defined as greater than 3 or 4 cm) are also associated with worse outcomes. Other factors including tumor multifocality, tumor necrosis, and lymphovascular invasion have also been associated with worse outcomes though the data is somewhat contradictory.

A number of molecular markers have been evaluated for prognostication in patients with UTUC. These include cytogentic abnormalities, oncogenes (c-MET and RON), as well as markers of apoptosis (Bcl-2 and surviving), markers of cell migration and invasion (E-cadherin and MMPs), cell cycle progression (p53 and CDKN1B), angiogenesis (HIF-1Î±), cell proliferation (Ki-67, EGFR, and NF-ÎºB), cell differentiation (uroplakin III and snail), mitosis (aurora-A), and microsatellite instability.

Treatment

The relative rarity of UTUC has precluded many large trials to guide treatment for these patients. As an overarching principle, the least invasive treatment necessary for safe oncologic control of the tumor should be preferred. Depending on tumor characteristics, this may include radical nephroureterectomy (whether open or laparoscopic), segmental ureterectomy, and endoscopic/percutaneous tumor ablations.

Radical nephroureterectomy remains the gold standard for large, high-grade and suspected invasive tumors of the renal pelvis and proximal ureter. A variety of techniques exist for management of the distal ureter though formal excision of a bladder cuff is the gold standard approach.

For patients with low-grade, non-invasive tumors, retrograde endoscopic or percutaneous ablation offer the potential for nephron-sparing treatment.

Perhaps the most notable advance in the treatment of patients with UTUC comes with the recent publication of the POUT trial which assessed the role of adjuvant chemotherapy following nephroureterectomy. Among 248 patients with pT2-4 N0-3 UTUC, Birtle and colleagues randomized patients to 4 cycles of adjuvant gemcitabine-cisplatin or surveillance. They demonstrated a significant improvement in disease-free survival and progression-free survival.

The multifocal and recurrence nature of urothelial carcinoma makes ongoing follow-up critical following any treatment. For patients opting for endoscopic approaches, repeated surveillance ureteroscopy is required. For other patients, cystoscopy, urine cytology and upper tract imaging are required. For patients at increased risk of metastases, thoracic imaging, biochemical studies including liver function testing, and bone scan may be indicated.

Published Date: January 28th, 2019

References:

Moss TJ, Qi Y, Xi L, et al. Comprehensive Genomic Characterization of Upper Tract Urothelial Carcinoma. European urology 2017;72:641-9.
Siegel RL, Miller KD, Jemal A. Cancer statistics, 2018. CA: a cancer journal for clinicians 2018;68:7-30.
Roupret M, Zigeuner R, Palou J, et al. European guidelines for the diagnosis and management of upper urinary tract urothelial cell carcinomas: 2011 update. European urology 2011;59:584-94.
David KA, Mallin K, Milowsky MI, Ritchey J, Carroll PR, Nanus DM. Surveillance of urothelial carcinoma: stage and grade migration, 1993-2005 and survival trends, 1993-2000. Cancer 2009;115:1435-47.
Mohamad Al-Ali B, Madersbacher S, Zielonke N, Schauer I, Waldhoer T, Haidinger G. Impact of gender on tumor stage and survival of upper urinary tract urothelial cancer : A population-based study. Wien Klin Wochenschr 2017;129:385-90.
Shariat SF, Favaretto RL, Gupta A, et al. Gender differences in radical nephroureterectomy for upper tract urothelial carcinoma. World journal of urology 2011;29:481-6.
Raman JD, Ng CK, Scherr DS, et al. Impact of tumor location on prognosis for patients with upper tract urothelial carcinoma managed by radical nephroureterectomy. European urology 2010;57:1072-9.
Skeldon SC, Semotiuk K, Aronson M, et al. Patients with Lynch syndrome mismatch repair gene mutations are at higher risk for not only upper tract urothelial cancer but also bladder cancer. European urology 2013;63:379-85.
Grollman AP, Shibutani S, Moriya M, et al. Aristolochic acid and the etiology of endemic (Balkan) nephropathy. Proceedings of the National Academy of Sciences of the United States of America 2007;104:12129-34.
McLaughlin JK, Silverman DT, Hsing AW, et al. Cigarette smoking and cancers of the renal pelvis and ureter. Cancer research 1992;52:254-7.
Slaton JW, Swanson DA, Grossman HB, Dinney CP. A stage specific approach to tumor surveillance after radical cystectomy for transitional cell carcinoma of the bladder. The Journal of urology 1999;162:710-4.
Wright JL, Hotaling J, Porter MP. Predictors of upper tract urothelial cell carcinoma after primary bladder cancer: a population based analysis. The Journal of urology 2009;181:1035-9; discussion 9.
Caoili EM, Cohan RH, Korobkin M, et al. Urinary tract abnormalities: initial experience with multi-detector row CT urography. Radiology 2002;222:353-60.
Isbarn H, Jeldres C, Shariat SF, et al. Location of the primary tumor is not an independent predictor of cancer specific mortality in patients with upper urinary tract urothelial carcinoma. The Journal of urology 2009;182:2177-81.
Ouzzane A, Colin P, Xylinas E, et al. Ureteral and multifocal tumours have worse prognosis than renal pelvic tumours in urothelial carcinoma of the upper urinary tract treated by nephroureterectomy. European urology 2011;60:1258-65.
Ng CK, Shariat SF, Lucas SM, et al. Does the presence of hydronephrosis on preoperative axial CT imaging predict worse outcomes for patients undergoing nephroureterectomy for upper-tract urothelial carcinoma? Urologic oncology 2011;29:27-32

Diagnosis and Pathology of Bladder Cancer

Diagnosis:

Clinical Presentation

There are no reliable screening tests available for detecting bladder cancer; hence the diagnosis is usually made based on clinical signs and symptoms. Painless hematuria – microscopic or gross – is the most common presentation and a hematuria investigation in an otherwise asymptomatic patient detects bladder neoplasm in roughly 20% of gross and 5% of microscopic cases.^1,2

Approach to Adrenal Masses

The small size and, in benign states, almost inconspicuous appearance of the adrenals belies both their physiologic and pathophysiologic complexity. As a result of this complexity, management of adrenal disorders often requires the involvement of endocrinologists, cardiologists, nephrologists, and anesthesiologists in addition to urologists. In this article, we will focus on non-functional and functional adrenal disorders. Though there are pathophysiologic states characterized by decreased adrenal function, these are typically beyond the purview of the urologist.

Brief Overview of Adrenal Physiology

The adrenal is histologically divided into a three zoned cortex and the inner medulla. The adrenal cortex is involved in the multistep process of steroidogenesis. Each region of the cortex (glomerulosa, fasciculata, and reticularis) produces different steroidal end-products (mineralocorticoids, glucocorticoids, and androgens, respectively) as a result of differing ratios and types of enzymes that catalyze steroidogenesis. The adrenal medulla produces catecholamines (norepinephrine, epinephrine, and dopamine) under the control of the sympathetic branch of the autonomic nervous system.

Adrenal Pathology

The differential diagnosis of an adrenal mass is broad, including a number of benign and malignant conditions as summarized in Table 1. In patients with bilateral adrenal masses, the differential diagnosis is somewhat shorter but includes metastases, congenital adrenal hyperplasia, adenomas, lymphoma, infectious causes, hemorrhage, pheochromocytoma, and amyloidosis, and ACTH-dependent Cushing's disease.
table-1-approach-to-adrenal-masses@2x.jpg

table-1-approach-to-adrenal-masses@2x.jpg

In urologic practice, many adrenal masses represent adrenal incidentalomas, masses >1 cm found on imaging performed for other reasons. While incidentally detected, a relatively large proportion (up to 20%) of these lesions may warrant surgical resection.¹ Additionally, more than 10% of these lesions will prove to be biologically active. Therefore, metabolic testing (as detailed below) is recommended for all adrenal incidentalomas.²

Primary adrenal malignancies are uncommon. Adrenocortical carcinoma (ACC) has an incidence of less than 2 per million population.³ While there are associated hereditary syndromes, the majority of ACCs are sporadic. ACC may be biochemically functional or non-functional. Among functional lesions, hypercortisolism is the most common.

From an oncologic perspective, metastases are a much more common cause of adrenal lesions than primary adrenal pathology. Primary cancers with a particular predilection for adrenal metastases including melanoma, lung cancer, renal cell carcinoma, breast cancer, and medullary thyroid cancer.⁴ However, a wide variety of other cancer may also spread to the adrenal. In patients with known extra-adrenal malignancy, a new adrenal mass is likely to represent metastasis in approximately 50% of cases⁴. Thus, standard functional assessment is advocated.⁴

While we will not dwell on it further, a brief mention of congenital adrenal hyperplasia is warranted. This is an autosomal recessive congenital condition characterized by low cortisol production as a result of enzymatic defects in the steroidogenesis pathway. Deficiency in 21-hydroxylase is the cause of nearly 95% of cases. Due to a lack of feedback, there is overproduction of ACTH and resulting overproduction of adrenal androgens. This condition is most often diagnosed and managed in childhood, thus, it will be uncommon as a presentation for adults with newly diagnosed adrenal lesions.

Investigation of Adrenal Lesion

With a newly identified adrenal lesion, there are two primary questions which will guide further management. First, could this mass be malignant? Second, is this mass functional? That is, are there any physical signs and symptoms or biochemical evidence of excess hormonal activity that could be attributed to excess secretion of an adrenally derived hormone.

Imaging is warranted (and likely the reason for assessment) for patients with adrenal lesions. Ultrasound is relatively poor at visualizing and characterizing adrenal lesions. Therefore, axial imaging using CT or MRI is advised. Unenhanced CT scan is the first line test of choice. In more than 70% of cases, it is possible to identify adrenal adenomas on the basis of this test alone. Low attenuation (<10 HU) is the characteristic finding on this study. Enhanced CT with adrenal washout protocols may be used where unenhanced CT is unclear. Adenomas exhibit characteristic rapid enhancement washout after administration of CT contrast. MRI is an alternative to CT scan. Again, there are characteristic findings of adrenal adenomas including a loss of signal intensity of out-of-phase sequences.⁵

Imaging findings help to guide the answer to the question of whether a given adrenal lesion may be malignant. There is a relationship between the size of an adrenal lesion and the likelihood of malignancy. Thus, all lesions larger than 6 cm should be considered malignant until proven otherwise. Due to diagnostic uncertainty, may would advocate resection for lesions 4 cm or larger.¹ Additionally, as the incidence of benign lesions increases with age, additional concern should be taken for younger patients with even small adrenal lesions. On axial imaging, ACC exhibit increase attenuation on non-contrast CT, irregular borders and enhancement, and calcification and necrosis.

Functional assessment of adrenal lesions begins with history and physical examination. Cushing's syndrome, caused by excess production of glucocorticoids, may present with central obesity, proximal muscle weakness, thinning of the skin, a so-called buffalo hump, or moon facies. Primary hyperaldosteronism, also known as Connâ€™s disease, may present with hypertension and hypokalemia. In many patients, hypertension is quite severe with mean blood pressures in the range of 180/110⁶. Pheochromocytomas, which secrete catecholamines, may present with hypertension, arrhythmia, anxiety, headache, pallor, diaphoresis, and tremor. The classic triad comprised headache, episodic sudden perspiration and tachycardia.⁷ Adrenocortical carcinoma may produce functional syndromes as described above or may also cause mass-related effects including abdominal fullness, back pain, nausea, and vomiting.

Biochemical assays are employed to confirm functional lesions. For Cushing's syndrome, the diagnosis may be confirmed with a 24-hour urinary free cortisol test or a low-dose dexamethasone suppression test. Following diagnosis, a number of subsequent tests may be performed to ascertain the underlying etiology. While these are typically coordinated by an endocrinologist, they will be briefly summarized here. Determination of serum ACTH (adrenocorticotropic hormone) can distinguish ACTH-dependent Cushingâ€™s from ACTH-independent causes. Among patients with elevated ACTH, determination of the anatomic source, whether pituitary or ectopic, can drive further management. However, modern imaging remains relatively insensitive and non-specific for the detection of both pituitary and ectopic sources of ACTH.^8,9 Therefore, direct measurement of venous levels of ACTH in the inferior petrosal sinus following CRH stimulation has been accepted to distinguish pituitary and ectopic sources of ACTH.⁸ High-dose dexamethasone suppression testing is no longer routinely used.⁸

Due to the underlying pathophysiology, patients must stop mineralocorticoid receptor antagonist antihypertensives prior to investigation for primary hyperaldosteronism. Further, hypokalemia should be corrected. For these patients, it is critical to determine whether this is a primary process or driven by perturbations in renin levels. Thus, determination of the ratio of serum aldosterone to plasma renin activity (PRA) is critical. This is known as the aldosterone to renin ratio (ARR). For patients with a positive ARR screening test, confirmatory testing typically seeks to identify suppression of aldosterone production following sodium loading. Options include fludrocortisone suppression testing, oral sodium loading, and intravenous saline infusion. Other, less commonly utilized, tests include captopril suppression testing, the furosemide-upright test, and the ACTH stimulation test. However, a number of etiologies may contribute to primary hyperaldosteronism including bilateral or unilateral hyperplasia, adenomas, and tumors. Therefore, following confirmation, subtype investigations may be undertaken among patients who are surgical candidates. This is typically performed with cross-sectional imaging. For patients without identified unilateral nodules, adrenal venous sampling may allow lateralization of the lesion. In the case of a non-diagnostic sampling, other optics including nuclear scintigraphy and postural stimulation testing.

Pheochromocytomas are potentially the most worrisome of functional adrenal lesions given the potential for significant cardiovascular instability if they are not recognized prior to intervention. Evaluation of these masses should include both biochemical and radiographic studies. Biochemical studies assess catecholamines and their metabolites including plasma free metanephrines, catecholamines, urinary fractionated metanephrines, total metanephrines, and vanillylmandelic acid. Each of these tests have varying sensitivity and specificity. Today, most advocate testing of plasma free metanephrine levels¹⁰ as this is more sensitive than serum levels of catecholamines. For patients with equivocal findings, use of the clonidine suppression test has been suggested by some.¹¹ Chromogranin A is an alternative confirmatory test though the sensitivity is somewhat poor for this function.

As with all adrenal lesions, imaging of pheochromocytoma begins with computed tomography (CT). Unlike adrenal adenomas, pheochromocytoma typically has an increased attenuation (mean 35 HU).¹² Magnetic resonance imaging (MRI) is an alternative. Classically, these lesions have a bright signal, termed the "light bulb" sign. Functional imaging may be undertaken using ¹⁸F-FDG PET scanning or metaiodobenzylguanidine (MIBG) scintigraphy.

As hereditary lesions account for nearly 1/3 cases of pheochromocytoma, familial testing has been suggested among patients who have a family history, present at age <50 years, have multiple lesions, malignant pheochromocytoma, or bilateral pheochromocytoma.¹³

Investigations to assess the functionality of adrenal lesions are summarized in Table 2.
table-2-approach-to-adrenal-masses@2x.jpg

table-2-approach-to-adrenal-masses@2x.jpg

Investigation of suspected ACC should assess excesses of glucocorticoids, sex steroids, catecholamines, and mineralocorticoids. The Weiss pathologic criteria are used to distinguish benign and malignant adrenal lesions (Table 3).¹⁴ The presence of three or more of these criteria is highly associated with malignancy.

Treatment of Adrenal Lesions

For patients with small non-functional adrenal lesions with benign imaging findings, surveillance may be appropriate. However, surgery is the mainstay for patients with adrenal lesions. There are particular nuances on the basis of the underlying histology and functional status. In general, laparoscopic adrenalectomy is considered the gold standard as, in experienced hands, oncologic outcomes are equivalent with improved convalescence.

For patients with adrenocortical carcinoma, surgical resection is the standard of care. In these cases, wide margins are critical. Thus, for larger tumors with possible adjacent organ involvement, some authors advocate that these cases should be performed open in order to ensure negative margins given the potential need for adjacent organ resection. Unfortunately, recurrence is common following even aggressive resection. Radiotherapy can be used in an adjuvant setting for patients with positive margins and for treatment of bone or central nervous system metastases. Systemic therapy may be undertaken with mitotane, a synthetic derivative of DDT.

For patients with Cushing's disease, the management varies widely based on underlying etiology. The overall goals included correction of the cortisol excess, restoration of the underlying hormonal axis, and management of the sequelae. Approaches to this, depending on underlying etiology, include weaning of exogenous steroids, transsphenoidal resection of pituitary lesions, unilateral or bilateral adrenalectomy, resection of ectopic sources of ACTH, and medical therapy with blockers of steroidogenesis.

Treatment of primary aldosteronism seeks to control blood pressure and prevent sequelae of hormonal excess. This may be accomplished medically or surgically depending on the underlying cause and patient suitability for operation. Medical treatment may be undertaken with aldosterone receptor antagonists such as spironolactone or eplerenone.

Pheochromocytoma is primarily a surgical disease. However, extensive medical consultation and optimization is required to prevent significant intraoperative cardiovascular complications. Further, these patients are at risk of cardiomyopathy and, therefore, consultation with a cardiologist or anesthesiologist prior to surgery is advisable. Catecholamine blockade is required prior to surgery on pheochromocytoma. Classically, this has been achieved with the non-competitive alpha-blocker phenoxybenzamine. However, selective reversible alpha-blockers including doxazosin or terazosin are alternatives. Following alpha-blockade, beta-blockade may be undertaken due to the risk of reflex tachycardia or arrhythmia.¹³ An alternative to alpha- and beta-blockade which has been proposed utilized calcium channel blockade.¹⁵ Finally, catecholamine synthesis blockade through the use of alpha-methyltyrosine (metyrosine) may be added. In the perioperative period, repletion of the intravascular volume is critical. This may be achieved through liberal consumption of salt and liquid or intravenous resuscitation. Careful postoperative monitoring is key as these patients are at risk for hypotension and hypoglycemia. Additionally, as these lesions have a predilection for recurrence, ongoing monitoring is required.

Published Date: January 28th, 2019

References:

Young WF, Jr. Clinical practice. The incidentally discovered adrenal mass. The New England journal of medicine 2007;356:601-10.
Grumbach MM, Biller BM, Braunstein GD, et al. Management of the clinically inapparent adrenal mass ("incidentaloma"). Ann Intern Med 2003;138:424-9.
Fassnacht M, Kroiss M, Allolio B. Update in adrenocortical carcinoma. The Journal of clinical endocrinology and metabolism 2013;98:4551-64.
Lenert JT, Barnett CC, Jr., Kudelka AP, et al. Evaluation and surgical resection of adrenal masses in patients with a history of extra-adrenal malignancy. Surgery 2001;130:1060-7.
Namimoto T, Yamashita Y, Mitsuzaki K, et al. Adrenal masses: quantification of fat content with double-echo chemical shift in-phase and opposed-phase FLASH MR images for differentiation of adrenal adenomas. Radiology 2001;218:642-6.
Young WF, Jr., Klee GG. Primary aldosteronism. Diagnostic evaluation. Endocrinol Metab Clin North Am 1988;17:367-95.
Bravo EL, Tagle R. Pheochromocytoma: state-of-the-art and future prospects. Endocr Rev 2003;24:539-53.
Porterfield JR, Thompson GB, Young WF, Jr., et al. Surgery for Cushing's syndrome: an historical review and recent ten-year experience. World J Surg 2008;32:659-77.
Newell-Price J, Bertagna X, Grossman AB, Nieman LK. Cushing's syndrome. Lancet 2006;367:1605-17.
Lenders JW, Pacak K, Walther MM, et al. Biochemical diagnosis of pheochromocytoma: which test is best? JAMA : the Journal of the American Medical Association 2002;287:1427-34.
Eisenhofer G, Goldstein DS, Walther MM, et al. Biochemical diagnosis of pheochromocytoma: how to distinguish true- from false-positive test results. The Journal of clinical endocrinology and metabolism 2003;88:2656-66.
Motta-Ramirez GA, Remer EM, Herts BR, Gill IS, Hamrahian AH. Comparison of CT findings in symptomatic and incidentally discovered pheochromocytomas. AJR Am J Roentgenol 2005;185:684-8.
Pacak K. Preoperative management of the pheochromocytoma patient. The Journal of Clinical Endocrinology and metabolism 2007;92:4069-79.
Weiss LM. Comparative histologic study of 43 metastasizing and nonmetastasizing adrenocortical tumors. Am J Surg Pathol 1984;8:163-9.
Ulchaker JC, Goldfarb DA, Bravo EL, Novick AC. Successful outcomes in pheochromocytoma surgery in the modern era. The Journal of Urology 1999;161:764-7.

The Impact of Visceral Metastasis in Prostate Cancer Patients

Introduction and Epidemiology

In 2018 in the United States, there will be an estimated 164,690 new cases of prostate cancer (19% of all male cancer incident cases, 1st) and an estimated 29,430 prostate cancer mortalities (9% of all male cancer deaths, 2nd only to lung/bronchus cancer).¹ For the last 30 or more years, prostate cancer has been the most common noncutaneous malignancy among men in the United States, with 1 in 7 men being diagnosed with the disease.² De-novo metastatic prostate cancer incidence seems to vary by geographical region and ranges from 4.4 to 9.9 per 100,000 men. A recent study found that over the last several decades, the incidence of de novo metastatic prostate cancer was decreasing in the United States (12.0 to 4.4 per 100,000 men) but increasing in Denmark (6.7 to 9.9 per 100,000 men).³ The exact mechanism for these epidemiologic differences is not clear, but likely related to varying uptake and utilization of PSA surveillance.

With improvements in the treatment of advanced prostate cancer over the last decade, men with advanced disease are living longer and developing non-lymph node visceral metastases. In a single-institution Japanese study (from 2000-2014), among 1,038 prostate cancer patients, there were 144 (19.8 %) men with castration-resistant prostate cancer (CRPC) and 43 (33.1%) patients developing visceral metastases after CRPC progression.⁴ At diagnosis, the sites of visceral metastases included lung (89.5%), liver (5.3%), and adrenal glands (5.3%). After CRPC progression, new visceral metastases were found in the lung (47.3%), liver (43.6%), and adrenal gland (9.1%). Among 359 CRPC patients in the UK (June 2003 to December 2011), the frequency of radiologically detected visceral metastases before death was 32%; among the 92 patients with a CT scan performed within 3 months of death, 49% had visceral metastases, most commonly involving the liver (20%) and lung (13%).⁵ These findings confirm a large autopsy study that found among 1,500 prostate cancer patients, 25% of men had liver metastases and 46% had lung metastases.⁶ Of men participating in first-line studies for metastatic CRPC (mCRPC), ~20% of patients had non-lymph node soft tissue visceral metastases.^7,8 As such, leaders in the field have suggested that men with visceral metastases have been an underestimated and understudied subgroup of patients with advanced and heavily treated mCRPC.^9,10 The objective of this article is to discuss the biology of visceral metastases, assess the impact of visceral metastases on survival, highlight several large trials that have performed subgroup analyses of visceral metastases patients, and discuss emerging therapeutic regimens for these patients, specifically radioligand targeted therapy.

The Biology of Visceral Metastases

We are likely only beginning to understand the biology of visceral metastases, particularly as it differs from that of bone metastases. There are several interrelated factors leading to differing pathophysiology between visceral and bone metastases, namely intrinsic cellular factors, the tumor microenvironment, and systemic factors.

1. Cellular Factors: Immunohistochemical analysis of tissue microarrays examining the antiapoptotic pathways expressed in visceral vs bone metastases found that soft-tissue metastases are more likely to express nuclear survivin, whereas bone lesions demonstrate relative overexpression of cytoplasmic survivin, B-cell lymphoma 2, and myeloid cell leukemia 1.¹¹
2. Tumor Microenvironment: microarray studies have found physiologically and clinically important differences between bone, liver, and lymph node metastases. Visceral lesions derived from liver and lymph nodes were found to express an angiogenic profile different from that of liver metastases alone, with significant relative overexpression of the proangiogenic factor angiopoietin-2.¹²
3. Systemic Factors: serum cytokine levels are associated with prognosis as well as with the presence of liver metastases among prostate cancer patients.^9,13 A number of studies have examined levels of TGF-β and interleukin-6 (IL-6) as prognostic markers, finding that the addition of TGF-β and soluble IL-6 receptor levels to a preoperative nomogram significantly improved the ability to predict biochemical progression of the disease.¹⁴

Impact of Visceral Metastases on Survival

Patients with visceral metastases invariably have a worse prognosis than patients with bone-only metastases, likely secondary to an overall increased disease burden.^5,10,15-26 In a study including patients in the SEER database (2010-2013), patients with de-novo bone-metastases plus visceral metastases had significantly worse prostate cancer-specific mortality (vs bone only): bone + brain metastases HR 1.48, 95%CI 1.05-2.10; bone + liver metastases HR 2.18, 95%CI 1.79-2.65; bone + lung metastases HR 1.33, 95%CI 1.13-1.56.²⁷

Several large phase III randomized controlled trials (RCTs) have assessed the impact of visceral metastases on survival outcomes using post-hoc analysis of the trial data. The TAX 327 trial found that docetaxel plus prednisone improved OS, pain scores, PSA level, and quality of life compared to mitoxantrone plus prednisone among patients with mCRPC.⁸ A decade after this publication, Pond et al.²⁵ performed a post-hoc analysis of this data stratified by metastasis site. They found that men with liver metastases with or without other metastases had a shorter median OS (10.0 months; 95%CI 5.4-11.5) than men with lung metastases with or without bone or nodal metastases (median OS: 14.4 months; 95%CI 11.5-22.4). The AFFIRM trial showed that treatment with the androgen receptor inhibitor enzalutamide led to significant improvements in outcomes for patients with mCRPC.²⁸ A subsequent study assessed patients in the AFFIRM trial who had liver and/or lung metastases.²⁰ In patients with liver metastases (n = 92), enzalutamide treatment was associated with a lower risk of radiographic progression (HR 0.645, 95%CI 0.413-1.008), improved 12-month OS (37.7% vs 20.6%) and radiographic progression-free survival (rPFS) (11.6% vs 3.0%) rates compared to those on placebo. Furthermore, patients treated with enzalutamide had higher PSA response rates (35.1% vs 4.8%) compared with placebo. Similarly, patients with lung metastases (n = 104) treated with enzalutamide also had an improved median OS (HR 0.848, 95%CI 0.510-1.410), reduced risk of radiographic progression (HR, 0.386, 95%CI 0.259-0.577), improved 12-month OS (65.1% vs 55.3%) and rPFS (30.9% vs 8.2%) rates, and a better PSA response rate (52.1% vs 4.9%) compared with those who received placebo. The PREVAIL clinical trial tested enzalutamide in men with mCRPC prior to chemotherapy, finding a decreased risk of radiographic progression and death among those taking enzalutamide compared to placebo.²⁹ Of the 1,717 patients in PREVAIL, 12% had visceral metastases: 74 with liver-only or liver/lung metastases and 130 with lung only metastases.¹⁹ In patients with liver metastases, treatment with enzalutamide was associated with an improvement in rPFS (HR 0.44, 95%CI 0.22-0.90) but not OS. Among patients with lung metastases only, enzalutamide significantly improved rPFS (HR 0.14, 95%CI 0.06-0.36) and OS (HR 0.59, 95%CI 0.33-1.06). Patients with liver metastases had worse outcomes than those with lung metastases, regardless of treatment.

Results of post-hoc analyses of phase III RCTs showing poor outcomes among patients with visceral metastases have also been confirmed using population-level studies. Gandaglia et al.²⁴ utilized the SEER-Medicare database (1991-2009) to assess outcomes of 3,857 patients presenting with metastatic prostate cancer. Among these patients, 80.2% had bone metastases, 10.9% had bone plus visceral metastases, 6.1% had visceral only metastases, and 2.8% had lymph node only metastases. Patients with bone plus visceral metastases had the worst cancer-specific survival (median 19 months), following by visceral only metastases (median 26 months), bone-only metastases (median 32 months) and lymph node only metastases (median 61 months). Patients with visceral metastases had a significantly higher risk of overall and cancer-specific mortality compared to those with exclusively lymph node metastases (p<0.001), and the unfavorable impact of visceral metastases persisted in the oligometastatic subgroup. Whitney et al.¹⁸ studied 494 men with M0 CRPC (diagnosed after 1999) from five Veterans Affairs hospitals in the Shared Equal Access Regional Cancer Hospital (SEARCH) database who later developed metastases. Among these patients, 236 men had a CT scan performed, of which 38 (16%) had visceral metastases, including 19 patients with liver metastases, 8 patients with lung metastases, and 16 patients with other locations of metastases. The authors found that visceral metastases were a predictor of OS on univariate analysis and after risk adjustment (HR 1.84, 95%CI 1.24-2.72).

To further assess the impact of metastatic site on OS among men with mCRPC, a collaborative group performed an individual patient data meta-analysis of 8,820 men with mCRPC who received docetaxel chemotherapy in nine phase III RCTs.²² Site of metastases was categorized as lymph node only, bone with or without lymph node involvement (with no visceral metastases), and lung metastases (but no liver), and any liver metastases. 72.8% of patients had a bone with or without lymph node metastases, 20.8% had a visceral disease, and 6.4% had lymph node-only disease. Men with lymph node-only disease had the best survival with a median OS of 31.6 months, followed by men with non-visceral bone metastases (median OS 21.3 months), men lung metastases (median OS 19.4 months), and those with liver metastases (median OS 13.5 months).

There are several take-home messages from these studies assessing survival outcomes among patients with visceral metastases:

1. Patients with any degree of liver metastases typically have the worst survival outcomes compared to those with bone metastases or other sites of visceral metastases
2. Patients with visceral metastases do have a response to enzalutamide (either in the pre- or post-chemotherapy setting), although their prognosis remains poor

Radioligand Therapy for mCRPC Patients

The recent uptake in the utilization of PSMA-PET/CT imaging has led to a new field of therapy among heavily pretreated mCRPC patients: radioligand directed therapy. The high PSMA expression in prostate cancer metastases makes it a promising approach to developing new tracers for targeted radionuclide therapies. Since 2015, several institutional studies have reported promising results for response rates and a favorable safety profile after radioligand therapy with 177Lu-PSMA-617 in patients with mCRPC,^30-34, however, these studies have suffered from small sample sizes and thus poor generalizability. In an effort to overcome these issues, Rahbar and colleagues³⁵ performed a multicenter German analysis among a cohort of patients treated with 177Lu-PSMA-617. There were 145 patients with mCRPC treated with 177Lu-PSMA-617 at 12 centers undergoing 1-4 therapy cycles with an activity range of 2-8 GBq per cycle. Among these patients, 87% had bone, 77% lymph node, 20% liver, 14% lung, and 2% other sites of metastases. The study reported an overall biochemical response rate of 45% after all therapy cycles, including 40% of patients who responded after a single cycle. Notably, negative predictors of biochemical response include elevated alkaline phosphatase and the presence of visceral metastases.

A study published last month reported on 100 consecutive patients at a single institution receiving 177Lu-PSMA-I&T, treated with a median of two cycles of therapy (range 1-6).³⁶ Among these 100 patients, 57 had received ≥3 prior treatment regimens for mCRPC. There were 87 patients that had lymph metastases and 35 with visceral metastases, including 18 with liver, 11 with lung and 8 with adrenal metastases. A PSA decline of ≥50% was achieved in 38 patients, the median clinical progression-free survival was 4.1 months, and median OS was 12.9 months. The presence of visceral metastasis was the only variable associated with a poor PSA response (p = 0.049), as only nine of 35 (26%) patients with visceral metastasis achieved a maximum PSA decline of ≥50%. The authors concluded that the presence of visceral metastases and rising LDH were associated with worse treatment outcome.

Although 177Lu-PSMA-617 is the most well-studied radioligand to date, there are several other compounds in development and undergoing initial testing. These compounds include: 177Lu-J591, 90Y-J591, 131I-MIP 1095, 177Lu-PSMA-I&T, and 225Ac-PSMA-617.³⁷

Conclusions

Secondary to the improved treatment options available for patients with mCRPC, these men are living longer and thus increasing the prevalence of mCRPC patients with visceral metastases. Although post-hoc studies of enzalutamide trials in the pre- and post-chemotherapy mCRPC setting demonstrate a degree of response, visceral metastases are associated with poor survival outcomes. Initial radioligand therapy studies, primarily with 177Lu-PSMA-617, show promise for heavily treated mCRPC patients, although subgroup analyses of these studies also demonstrate worse survival among patients with visceral metastases. For the future design of phase II and phase III clinical trials among men with mCRPC, patients should be stratified by metastasis site to preclude patients with visceral metastases being inadvertently randomized to an unbalanced trial arm. Further efficacious treatment options for these patients are in dire need. The treatment of visceral metastases is one of the new therapeutic frontiers for prolonging not only quantity but also the quality of life.

Published Date: April 16th, 2019

Written by: Zachary Klaassen, MD

References:

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Systemic Therapy for Advanced Renal Cell Carcinoma

As highlighted in prior articles on the Etiology and Epidemiology of Kidney Cancer, cancers of the kidney and renal pelvis comprise the 6^th most common newly diagnosed tumors in men and 10^th most common in women¹ and account for an estimated 65,340 people new diagnoses and 14,970 cancer-related deaths in 2018 in the United States. Despite a previously mentioned stage migration due to an increase in incidental detection, a large proportion (up to 35%) of patients present with advanced disease, including metastases.² Historically, metastatic RCC has been early uniformly fatal, with 10-year survival rates less than 5%.³

As emphasized in the article on Malignant Renal Tumors, clear cell renal cell carcinoma (ccRCC) is the most common histologic subtype of renal cell carcinoma (RCC). Likely due to its much higher prevalence, the vast majority of systemic therapies for RCC have been investigated among patients with ccRCC. Historically, treatment for metastatic RCC (mRCC) had been limited to cytokine therapies (interleukin-2 and interferon-alfa). However, the development of tyrosine kinase inhibitors (TKIs), which target vascular endothelial growth factors (VEGF), and mammalian target of rapamycin (mTOR) inhibitors have replaced cytokine-based therapies as the standard of care. More recently, immunotherapy-based approaches using checkpoint inhibitors have demonstrated significant benefits and have joined the repertoire of available agents for patients with metastatic RCC.

Cytokine Therapies for Advanced ccRCC

The host immune system has long been implicated with RCC tumor biology. As a result, modulators of the immune system were among the first therapeutic targets for advanced ccRCC.

Interferon-α was one of the first cytokines assessed for the treatment of metastatic ccRCC. Interferons have a range of biologic functions, including immunomodulation. Early data demonstrated response rates in the range of 10 to 15% for patients treated with interferon-α.⁴ Compared with other available systemic therapies available at the time, interferon therapy conferred a survival benefit.⁵

An alternative form of immunologic modulation was examined using interleukin-2. While response rates were similar to interferon-based therapies (~15 to 20%)⁶, interleukin-2 was distinct in that durable complete responses were observed in approximately 7 to 9% of patients.⁷ On the basis of these data, high-dose IL-2 was approved by the U.S. Food and Drug Administration (FDA) in 1992. However, IL-2 is associated with considerable toxicity which has limited its widespread utilization. Most worrisome is vascular leak syndrome which leads to intravascular depletion, hypovolemia, respiratory compromise and multi-organ failure. Alternatives to the high-dose intravenous bolus administration were explored but lead to worse oncologic outcomes. Thus, high-dose IL-2 is the only recommended approach for patients undergoing cytokine therapy.

Subsequently, combinations of interferon and interleukin therapies were explored. These demonstrated some improvement in response rate but no difference in overall survival.⁸ Combination therapy resulted in significantly increased toxicity compared to monotherapy with either agent.

With the introduction of VEGF and mTOR targeting agents, interferon is no longer utilized as first-line therapy. However, IL-2 remains an available, though not widely utilized, option on the basis of its ability to induce durable complete responses which these new agents lack.

Inhibitors of the VEGF Pathway for Advanced ccRCC

Based on work into the molecular biology underlying ccRCC led to “rational targeted therapeutics” including targeting of the VEGF pathway.

The first inhibitor of the VEGF pathway used in clinical trials was bevacizumab, a humanized monoclonal antibody against VEGF-A. While this approach was first explored in patients who had progressed on cytokine-based therapies, it was soon evaluated head-to-head against interferon in previously untreated patients.^9,10 The addition of bevacizumab to interferon resulted in significant improvements in response rate and progression-free survival. Today, bevacizumab is uncommonly used as monotherapy in untreated patients but is considered as second-line therapy in patients who have failed prior therapy with tyrosine kinase inhibitors.

Tyrosine-kinase inhibitors also target the VEGF pathway, through inhibition of a combination of VEGFR-2, PDGFR-Î², raf-1 c-Kit, and Flt3 (sunitinib and sorafenib). In 2006, sorafenib was shown to have biologic activity in ccRCC. Subsequent studies demonstrated improvements in progression-free survival compared with placebo in patients who have previously failed cytokine therapy and improvements in tumor regression compared to interferon in previously untreated patients. Despite FDA approval, sorafenib is rarely used as first-line therapy today. More widely used is sunitinib. As with agents discussed, sunitinib was first evaluated among patients who had previously received cytokine treatment. Subsequently, it was compared to interferon-Î± in a large phase III randomized trial.¹¹ While the initial analysis demonstrated significant improvement in progression-free survival and overall response rate, subsequent follow-up has demonstrated a strong trend towards improved overall survival. On account of these data, sunitinib is widely used as first-line treatment of RCC.

Tyrosine-kinase inhibitors exhibit a class-based toxicity profile including gastrointestinal events, dermatologic complications including hand-foot desquamation, hypertension, and general malaise. However, quality of life appears to be better with these agents than with interferon.¹¹

Subsequently, a number of more targeted tyrosine kinase inhibitors have been developed with the goal to decrease the toxicity of this treatment strategy. Such agents include pazopanib, axitinib, and tivozanib. Comparative data of pazopanib and sunitinib have demonstrated non-inferior oncologic outcomes with decreased toxicity among patients receiving pazopanib.¹² Axitinib was evaluated as second-line therapy compared to sorafenib among patients who had previously received sunitinib, bevacizumab, temsirolimus, or cytokine therapy. Axitinib was associated with improved progression-free survival; on the basis of these data, this agent was approved for second-line therapy of metastatic RCC.¹³ Finally, tivozanib has been compared to sorafenib among patients who had not previously received VEGF or mTOR-targeting therapies. While this study demonstrated tivozanibâ€™s activity, it was not FDA approved and is therefore not used.

Most recently, a multikinase inhibitor, cabozantinib, has been approved for the first-line treatment of mRCC. In the phase II CABOSUN trial, cabozantinib demonstrated improved progression-free survival compared to sunitinib.¹⁴ However, these results have proven controversial, with a number of concerns raised including a potential exaggerated effect due to the poor efficacy of sunitinib compared to what would be expected based on previous reports.¹⁵

Despite the efficacy of VEGF targeted therapies, resistance to VEGF-inhibition almost inevitably results. Therefore, research into the development of these resistance mechanisms and ways to target these pathways has been undertaken. Agents including nintedanib and dovitinib have been explored though these are not yet in routine practice.

Inhibitors of mTOR for Advanced ccRCC

Mammalian target of rapamycin (mTOR) plays a key role in regulating HIF-Î±, thus modulating the pathway between abnormalities in VHF and proliferation. Two analogous of sirolimus have demonstrated efficacy in treating advanced RCC, temsirolimus and everolimus.

A three-arm trial comparing temsirolimus, interferon, and the combination was undertaken among patients with pre-defined poor risk disease who had not previously received systemic therapy for RCC.¹⁶ This demonstrated improvements in progression-free survival and overall survival for patients receiving temsirolimus. Notably, the combination arm did not offer a benefit compared to interferon alone. Unlike temsirolimus which must be administered intravenously, everolimus is an oral agent. Among patients progressing on sunitinib and/or sorafenib, everolimus demonstrated significantly improved progression-free survival compared to placebo.¹⁷

Checkpoint Inhibitors for Advanced ccRCC

The immunologic basis for treatment of advanced RCC has been well established, including the aforementioned cytokine therapies. Recently, immune checkpoint inhibitors have been examined in the treatment of advanced RCC. Two particular regimes warrant focus â€“ nivolumab and ipilimumab and atezolizumab.

First presented at ESMO in the fall of 2017 and subsequently published in the spring of 2018, CheckMate 214 demonstrated an overall survival (OS) benefit for first-line nivolumab plus ipilimumab vs. sunitinib.¹⁸ More details regarding this study may be found in the UroToday coverage of ESMO 2017. In short, among the subgroup of patients with intermediate or poor-risk RCC, treatment with nivolumab plus ipilimumab resulted in significantly improved overall response rate, comparable progression-free survival, and significantly improved overall survival.

Similarly, first presented at GU ASCO in the spring of 2018 and subsequently published, IMmotion151 reported a progression-free survival (PFS) benefit for first-line atezolizumab + bevacizumab vs. sunitinib.¹⁹ This regime was active with a significant benefit in progression-free survival among the whole cohort of patients, as well as a subset of PD-L1+ patients. More details regarding this study may be found in the UroToday coverage of GU ASCO 2018.

These trials are notable in that they demonstrated improved outcomes in first-line treatment, compared to the current standard of care, sunitinib.

Other Agents for Advanced ccRCC

Numerous chemotherapeutic agents have been explored in ccRCC. These include 5-FU, gemcitabine, vinblastine, bleomysin, and platinums. Meta-analyses of these data demonstrate poor response²⁰ and thus cytotoxic chemotherapy is not indicated in the treatment of advanced RCC. Similarly, hormonal therapies including medroxyprogesterone have been explored but have no role in modern management of advanced RCC.

Treatment of Advanced non-ccRCC

There is a relative dearth of data for treatment of advanced non-clear cell RCC. Therefore, patients with these tumors may receive agents on the basis of their activity in ccRCC. However, VEGF-receptor inhibitors have been shown to have relatively low activity in patients with papillary RCC.²¹ Responses were somewhat better in patients with chromophobe RCC. Temsirolimus and everolimus appear to have some activity in patients with non-clear cell histology. Similarly, nivolumab monotherapy appears to have biologic activity in patients with non-ccRCC.²²

Integration of treatment options for patients with advanced RCC

With so many active agents available for the treatment of advanced RCC, it may be difficult to ascertain which treatment to offer patients who present in clinic. There are a number of ways to approach this issue â€“ first, one may take a quantitative approach, utilizing the available comparative data in a network meta-analysis; second, one may rely upon eminence, as in expert-informed guidelines; finally, one may rely on individual clinical experience. In this setting, all three options are available.

First, assessing this in a quantitative fashion, we performed a network meta-analysis of agents for the treatment of advanced RCC.²³ While there are limitations to this approach including the reliance on the assumption of transitivity between studies, interesting conclusions may be drawn. First, assessing progression-free survival, we found that it was highly likely (91% chance) that cabozantinib provided the greatest benefit. However, when assessing overall survival, nivolumab plus ipilimumab had the highest likelihood of being the preferred treatment choice. Finally, when assessing adverse events, it was highly likely that nivolumab plus ipilimumab had the most favorable toxicity profile.

Second, considering a panel of expert opinion, the European Association of Urology updated their guidelines on the treatment of renal cell carcinoma recently. Their recommendations are highlighted in the following figure, taken from the EAU guidelines:

Finally, we may rely on the guidance of individual clinical experience. Anil Kapoor, MD who has extensive experience in the treatment of both localized and advanced RCC, offered his treatment approach recently to UroToday.

Published Date: January 21st, 2019

References:

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