SES AUA 2022: Implications of Postponing Cancer Treatment During the Pandemic

(UroToday.com) The 86^th Annual Meeting of the Southeastern Section of the American Urological Association was host to a State-of-the-Art Lecture by Dr. Zachary Klaassen, MD, MSc discussing implications of postponing cancer treatment during the Coronavirus Disease 2019 (COVID-19) pandemic.

Dr. Klaassen began his talk by highlighting the heavy demand for resources during the current pandemic, which has been further exacerbated by a limited health system capacity leading to overwhelmed hospitals. Furthermore, medical governing bodies have recommended re-prioritizing surgical cases, attempting to balance the risks of potential increased COVID-19 infections with those of delayed surgery.

This is of particular significance in the genitourinary oncology field as patients with such malignancies have baseline characteristics similar to high risk COVID-19 patients. In an early study from Lombardy, Italy published in 2020, 1,591 patients admitted to intensive care units had a median age of 63 years, 82% were male, 68% had at least one comorbidity, and 26% eventually experienced a COVID-19 related mortality.¹ Subsequently, the mortality and pulmonary complication rates in patients undergoing surgery with perioperative COVID-19 infections was evaluated in 1,128 patients undergoing surgery (835 emergent, 280 elective). Two hundred and ninety-four patients (26.1%) tested positive pre-operatively. The 30-day mortality rate was 23.8% with a pulmonary complication rate of 51.2%. Significantly, patients undergoing an oncology operation had increased odds of experiencing 30-day mortality (OR: 1.55, 95% CI: 1.01 – 2.39).² Dr. Klaassen acknowledged that while these issues were most relevant at the start of the pandemic in the Spring of 2020, these concerns remain significant today due to the continued emergence of novel viral strains with periodic, crippling COVID-19 surges.

In 2020, led by Drs. Christopher Wallis and Klaassen, European Urology published a collaborative review to aid in the triage and management of genitourinary malignancies during the COVID-19 pandemic.³ Dr. Klaassen emphasized that the recommendations from this collaborative review are not necessarily guideline-based and should strictly be used for triaging operative cases when resources/operative time are at a premium.

Beginning with low-grade non-muscle invasive bladder cancer (NMIBC), Dr. Klaassen highlighted its indolent natural history with long-term bladder cancer-specific mortality rates of 1-2%. This contrasts with patients with high-grade NMIBC who have high rates of progression (21-53%) and bladder cancer-specific mortality rates of 14-34%. Importantly, this group of patients also benefits from:

• Prolonged intravesical therapy with maintenance BCG regimens which have shown to significantly improve recurrence-free survival from a median of 36 to 77 months
• Re-resection with residual tumor found in 17-71% of Ta-T1 tumors and muscle invasive disease in 8% of initial pTa and 32% of initial pT1 cases. Re-resection is furthermore associated with lower recurrence rates.

Based on this evidence, the collaborative review had the following recommendations for NMIBC:

• Management of low-grade NIMBC (low-or intermediate-EORTC risk) may safely be deferred
• Patients with high-grade NIMBC should receive at least induction and one maintenance course of BCG
• Re-resection can be considered on a case-by-case basis but is particularly valuable in those with pT1 disease or no muscle in the original specimen

Next, Dr. Klaassen addressed the management of patients with muscle-invasive bladder cancer (MIBC). A systematic review and meta-analysis of 19 studies with 17,532 patients assessed the association between time to cystectomy and survival outcomes.⁴

• A longer delay between bladder cancer diagnosis and radical cystectomy resulted in a pooled hazard ratio of 1.34 (95% CI: 1.18 – 1.53) for overall death.
• A longer delay between transurethral resection and cystectomy resulted in a pooled hazard ratio of 1.18 (95% CI: 0.99-1.41) for overall death.
• A longer delay between neoadjuvant chemotherapy and radical cystectomy was associated with a pooled hazard ratio of 1.04 (95% CI: 0.93-1.16).

Patients with variant histology and cT2-4 bladder cancer managed without neoadjuvant chemotherapy similarly had worse survival outcomes if radical cystectomy was delayed beyond eight weeks.

Based on this evidence, the collaborative review had the following recommendations for MIBC:

• Delays up to 12 weeks before cystectomy may be safe for patients with MIBC (<8 weeks for variant histology)
• Oncologic principles, including the importance of neoadjuvant chemotherapy, should be considered at this time while acknowledging the risks of neutropenia
• Trimodal therapy could be considered based on patient and hospital factors

With regards to advanced/metastatic bladder cancer, the collaborative review had the following recommendations:

• Cytotoxic chemotherapy remains preferred
• Gemcitabine/Cisplatin may be preferred to MVAC due to lower rates of neutropenia
• Immune checkpoint inhibitors can be considered

Dr. Klaassen next addressed the management of low-risk prostate cancer patients. Long-term follow up of Dr. Klotz’s Sunnybrook active surveillance cohort of 993 men with low- or intermediate-risk prostate cancer demonstrated low rates (1.3%) of metastasis or prostate cancer mortality with long-term (15 years) follow up.⁵ Notably, the rate of metastases was significantly higher in intermediate versus low-risk prostate cancer patients undergoing active surveillance.

Next, timing of surgical treatment for patients with localized, intermediate/high risk disease was addressed. Using a cohort of 2,303 patients treated with radical prostatectomy at Johns Hopkins University, Gupta et al. compared outcomes of patients treated less than three months from diagnosis to those treated 3-6 months from diagnosis.⁶ No significant differences were noted for:

• Pathologic outcomes: positive surgical margin rates, extraprostatic extension, seminal vesicle invasion, lymph node invasion or use of adjuvant therapy
• Two- or five-year biochemical recurrence rates
• Two-, five-, or ten-year metastasis free survival

Another report by Fossati et al. evaluated the association between time from prostate cancer diagnosis to radical prostatectomy and biochemical/clinical recurrence in 2,653 patients treated with radical prostatectomy at San Raffaele. Worse biochemical recurrence rates were restricted to patients with high-risk disease only:⁷

There does not appear to be a role for neoadjuvant androgen deprivation prior to local treatments, as such an approach has:

• Marginal benefit for recurrence (OR 0.74, 95% CI 0.55 – 1.00)
• No difference in prostate cancer-specific mortality (OR 0.99, 95% CI 0.75-1.32)
• No difference in overall survival (OR 1.11, 95% CI 0.67 – 1.85)

With regards to localized prostate cancer, the collaborative review had the following recommendations:

• Patients with low-risk prostate cancer should receive active surveillance
• Patients with intermediate/high-risk prostate cancer may safely defer treatment for 3-6 months

With regards to metastatic prostate cancer, the collaborative review acknowledged that there is very little data to guide decision making and had the following recommendations:

• Androgen receptor-targeted agents may be preferable to docetaxel due to oral administration and decreased risk of neutropenia
• Longer formulations of ADT are preferable

Next, Dr. Klaassen addressed the management of localized (cT1-T2) kidney cancer. Using data from the Delayed Intervention and Surveillance for Small Renal Masses (DISSRM) registry, Pierorazio et al. evaluated 497 patients with small renal masses (i.e. <4 cm) who underwent primary intervention versus active surveillance. Although five-year overall survival was superior in the primary intervention group (92% versus 75%), there was no significant difference in cancer-specific survival rates (99% versus 100%).⁸ Next, the significance of growth kinetics of small renal masses was addressed. In 2014, Mehrazin et al. assessed 68 patients with small renal masses initially undergoing active surveillance, of whom 23 underwent delayed intervention. Amongst patients who opted for delayed intervention, the annual growth rate was significantly higher (0.73 versus 0.37 cm/year). After a mean follow up of 38.9 months, none of the patient had progressed to metastatic disease and 13% died of other causes.⁹

The collaborative review recommendations for localized (cT1-2) kidney cancer are accordingly as follows:

• Surveillance of small renal masses is safe
• When treatment is necessary (mass growth) – delayed during COVID-19
• cT1b/cT1b: delays of 3-6 months appear safe

The same does not apply to locally advanced (cT3) kidney cancer, where the impact of delayed intervention is unknown and such patient undergo expedited surgery. The collaborative review acknowledged the paucity of such data and recommended prioritizing such patients for surgical intervention both to maximize oncologic outcomes while minimizing symptomatic complications from bleeding or IVC occlusion.

The role and timing of cytoreductive nephrectomy (CN) remains an evolving subject of interest. SURTIME, which randomized 99 patients to immediate CN followed by sunitinib therapy versus three cycles of sunitinib followed by CN in the absence of disease progression, found no difference in 28-week progression-free rates (42-43%).¹⁰ CARMENA, which randomized 450 patients in a 1:1 fashion to CN + sunitinib versus sunitinib alone, demonstrated non-inferior median overall survival in the sunitinib alone arm (18.4 months) compared to the CN + sunitinib arm (13.9 months).¹¹

The collaborative review recommendations regarding the role CN in metastatic kidney cancer are accordingly as follows:

• Upfront systemic therapy: prioritized over CN in asymptomatic patients with metastatic kidney cancer
• Nephrectomy: reserved for symptomatic patients

Dr. Klaassen went on to discuss the management of upper tract urothelial carcinoma (UTUC) patients. Management of UTUC is guided by disease grade and patient comorbidity status. Numerous studies have demonstrated that endoscopic management of low-grade UTUC is safe. However, impact of delayed radical nephroureterectomy (RNU) for those requiring intervention remains less clear. A retrospective analysis by Waldert et al. evaluated the impact of a three-month RNU delay. Forty-one patients underwent RNU at least three months after diagnosis (median time to RNU: 110 days) whereas 146 patients underwent RNU less than three months after diagnosis (median time to RNU: 33 days). There was no significant difference in risk of disease recurrence and cancer-specific mortality. However, the delayed intervention group had worse pathologic stage, increased lymph node involvement, lymphovascular invasion, tumor necros and infiltrative tumor architecture.¹² A similar analysis of the MD Anderson cohort evaluated 54 and 186 patients undergoing delayed (≥3 month) and early RNU, respectively, with a median follow up of 29 months. There was no significant difference in five-year cancer-specific (71-72%) or overall survival (59-60%) rates].¹³ Dr. Klaassen next highlighted results from the recent published POUT trial that randomized pT2-4 or pN1-3 UTUC patients to either surveillance (n=129) or adjuvant gemcitabine + cisplatin/carboplatin (n=132) within 90 days of RNU. Adjuvant chemotherapy led to improved disease-free survival (HR 0.45, 95% CI 0.30-0.68).¹⁴

The collaborative review recommendations regarding the management of UTUC are thus as follows:

• Patients with suspected UTUC may be initially investigated with urine cytology and CT urogram – forgo diagnostic ureteroscopy
• Low-grade UTUC: often managed by nephron-sparing approaches – likely to have no/minimal risk of surgical delay
• High-grade UTUC: delays up to 12 weeks may not be associated with changes in survival, but may have worse pathological outcomes
• First-line treatment for metastatic disease should be commenced when possible
• Likely feasible to delay adjuvant chemo for 90 days

With regards to the management of localized testicular cancer, it is widely accepted that one must proceed expediently with an orchiectomy. Following surgical treatment, active surveillance remains the standard of care for the management of clinical stage 1 germ cell tumors. Chemotherapy remains the preferred initial approach for N+ non-seminomatous germ cell tumors. Post-chemotherapy masses <1 cm are typically observed, however the impact of delaying post-chemotherapy RPLNDs for masses >1cm remains unknown.

The collaborative review recommendations regarding the management of testicular cancer are thus as follows:

• Guidelines and expert opinion: avoid surgical delays for radical orchiectomy, particularly given the minimal burden on the healthcare system (same-day surgery)
• Surveillance: preferred for most/all patients with clinical stage 1 disease
• Insufficient data to provide guidance on the effects of delaying post-chemotherapy RPLND

Dr. Klaassen next went on to discuss the management of primary penile cancer. There are no studies assessing the effect of delayed partial, total or radical penectomy. Due to social stigma concerns, there have long been known delays between the initial appearance of a penile lesion and first consultation. A single center study in Italy of 113 patients identified a period of 53 days between the known appearance of a penile lesion and first consultation. With regards to the management of inguinal nodes, the EAU guidelines recommend a modified inguinal lymphadenectomy or dynamic sentinel-node biopsy in all patients with intermediate/high-risk tumors and non-palpable nodes. In a report of 84 patients from the Moffitt Cancer Center evaluating the impact of delayed inguinal lymphadenectomy (ILD) more than three months following treatment of primary disease, it was demonstrated that delayed ILD was associated with significantly worse five-year recurrence-free (37.8% versus 77.0%) and disease-free survival (39.5% versus 64.1%).¹⁵

The collaborative review recommendations regarding the management of penile cancer are thus as follows:

• Given the rarity, symptomatology and high-risk of metastatic progression: avoid delays in primary surgery

Dr. Klaassen next went on to present a report from the European Urology team that provides an evidence-informed, expert-derived review of genitourinary cancer management moving forward following the initial COVID-19 pandemic.¹⁶

Telemedicine was uncommonly used in urology prior to the pandemic. One of the limitations of telemedicine is the inability to perform a physical exam. This is potentially less troublesome in the follow up of prostate cancer patients (rectal exam less critical in the MRI era) and kidney/bladder cancer patients. In contrast, the clinical exam component is a significant component of the work up/follow up of testes and penile cancer patients.

Advantages of telemedicine include:

• Improved access for those with long commutes, full-time employment
• Less time consuming
• Enables tertiary level care for remote patients
• Decreases carbon emissions

Notable disadvantages are:

• Makes delivering “bad news” more difficult
• Patient nonverbal clues may be lost
• May exacerbate health care disparities
  • Need sufficient technology
  • Many platforms only available in English
  • More challenging for elderly patients
• Concerns regarding privacy and confidentiality
• Challenges with billing and remuneration

Other potential virtual avenues include:

• Remote multi-disciplinary tumor boards
• Electronic consults – improve specialty expertise
• Virtual education:
  • Urology collaborative online video didactics
  • EMPIRE
  • Virtual conferences (ASCO, ESMO, EAU, AUA, etc.)

Dr. Klaassen went on to discuss potential avenues to optimize treatment selection during the current pandemic:

• Encourage active surveillance for:
  • Low/favorable intermediate risk prostate cancer
  • Small renal mass
  • Low grade NMIBC
• Hypofractionation for prostate cancer radiotherapy (equivalent oncologic outcomes as longer regimens)
• Long duration ADT formulations (3-6 months)
• Prioritize BCG induction and only early maintenance BCG for high grade NMIBC
• Use of filtration for CO2 release during laparoscopic/robotic surgery (SAGES recommendation)
• Less frequent surveillance cystoscopies for low grade NMIBC
• Fewer biopsies and MRIs in active surveillance for prostate cancer
• De-intensification of imaging surveillance post-nephrectomies

It is important to acknowledge the mental health effects of this pandemic. Social distancing is associated with significant stress and loss of motivation, meaning, and self-worth, with women and younger patients at significantly higher risk. Increased uptake of expectant management may be associated with added psychological burden due to the concept of “forgoing treatment”. Dr. Klaassen went on to reference his work from Ontario-based administrate datasets that examined patients with pre-existing psychiatric disorders and found an association with worse cancer related outcomes, particularly patients with a pre-cancer diagnosis psychiatric hospitalization who had a wore cancer-specific mortality (HR 1.73).¹⁷

Dr. Klaassen concluded his talk with the following messages:

• It is unlikely that COVID-19 will disappear – we will likely have intermittent spikes, resulting in increases in hospitalizations, that will affect operating room resources
• Risk of viral transmission will continue to affect the practice of medicine
• Within the constraints of COVID-19: we need to consider how to best optimize the care of patients with genitourinary cancer

Presented By: Zachary Klaassen, MD, MSc, Assistant Professor of Urology, Ronald W. Lewis Endowed Chair in Urologic Education, Augusta University, Georgia Cancer Center, Augusta, GA

Written By: Rashid Sayyid, MD, MSc – Urology Chief Resident, Augusta University/Medical College of Georgia, @rksayyid on Twitter during the 86th Annual Meeting of the Southeastern Section of the American Urological Association, San Juan, PR, Mar 16 – 19, 2022

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