(UroToday.com) The 2022 Annual Meeting of the American Urological Association was host to a debate regarding the role of focal ablation versus active surveillance in a 65-year-old male with Gleason Grade Group two (GG2) disease and MRI concordant unilateral prostate cancer. This debate was moderated by Dr. Kirsten Greene and was contested between Drs. Robert Reiter and Dipen Parekh.
Dr. Greene began the discussion by presenting a case scenario of a:
- 65-year-old man undergoing his first prostate biopsy for a PSA level of 5 ng/ml
- Gleason Score 3+4 in 10% each of 2 cores for the MRI lesion
- 2/16 cores positive, no cribriform or intraductal pathology seen
- MRI shows a unilateral PIRADS 4 lesion
- Patient is otherwise relatively healthy on a statin for his hypercholesterolemia and has a negative family history for prostate, colon, and breast cancer
- AUA symptom score of 3, with a quality-of-life domain score of 1 and SHIM of 22 not on any erectile dysfunction medications
Dr. Reiter was tasked with arguing in favor of active surveillance (AS) for this patient with GG2 disease. He emphasized that AS, but not focal therapy, is supported by the current guidelines. Many GG2 cancers have an indolent natural history akin to GG1 cancers. AS may reduce overtreatment in men who may never require it and may delay need for radical or other treatment without compromising oncologic or quality of life outcomes.
Dr. Reiter went on to present data by Huang et al. that evaluated pathologic outcomes in patients with GG2 disease and low volume Gleason pattern 4 at time of biopsy who underwent a radical prostatectomy. These patients had non-significantly different risks of GG1 (63.6%-65.9%) and GG2 (26.2%-31.9%) disease at time of radical prostatectomy. Thus, we can conclude that biopsies with low percentage pattern 4 disease are associated with increased rates of downstaging to GG1 disease at time of prostatectomy. Perrera et al. have also recently demonstrated that the biochemical recurrence rate is a function of percent Gleason Pattern 4 disease on biopsy.
Dr. Reiter next cited data from Dr. Klotz’s AS Sunnybrook cohort which included 1400 men on AS, ~22% of whom were intermediate risk. Although overall and cancer-specific survivals were inferior in the intermediate risk groups (51% versus 67% and 89% versus 97%, respectively), the absolute differences were not as significant as one would anticipate, even after accounting for the fact that the intermediate risk group enrolment was not restricted to patients with low-volume Gleason pattern 4 disease. Thus, one would expect these differences to be even smaller if stricter inclusion/exclusion criteria were enforced.
Long-term data from the UCSF cohort has similarly demonstrated no significant difference in metastasis-free survival in patients with GG2 compared to those with GG1 disease.
Results from the Canary PASS cohort have demonstrated similar reclassification rates for GG2 and GG1 cancers.
With regards to treatment-free survival in the UCSF cohort, patients with GG2 disease and any PSA density (PSAD) level had non-significantly different treatment-free survival rates compared to patients with GGG1 disease and PSAD>=0.15.
Dr. Reiter next presented combined data from his group and the National Cancer Institute that evaluated 519 men with low- or intermediate-risk prostate cancer diagnosed via an MRI-targeted prostate biopsy and underwent MRI-guided confirmatory and surveillance biopsies. The primary outcome of interest was upgrading to GG3 disease or worse. After a median follow up of 4.8 years, 92 men were upgraded to GG3 disease, and the upgrade-free probability was 0.85 (95% CI 0.81-0.88).
Based on the results from the above Kaplan Meier curve, Dr. Reiter argued should we treat everyone or just those that progress? This is supported by studies demonstrating that recurrence free survival is the same for immediate versus delayed surgery after upgrading on AS. A recent report of 531 men on AS after Gleason Grade progression, of whom 192 underwent early radical prostatectomy (median time to surgery 3.5 months) and 25 underwent late radical prostatectomy (median time to surgery 17 months), demonstrated non-significant differences in recurrence rates and adverse pathology outcomes.
These results contrast with the report by Balakrishnan et al. that demonstrated that recurrence free survival after delayed surgery in men with initial GG2 cancer was worse. Dr. Reiter argued that these results were mostly limited to men with two or more cores of Gleason Pattern 4 disease, but this pre-dated the use of targeted biopsies, so this may not be similar as those with two targeted cores. Furthermore, it is not known whether earlier intervention would have led to lower rates of disease recurrence.
Dr. Reiter went on to emphasize the important role of emerging genomic tests in risk stratification of GG2 cancers and selection for AS. Imaging results at time of MRI may also predict adverse outcomes. Faena et al. have demonstrated that a PIRADS 5 lesion is associated with adverse pathology and biochemical recurrence in patients with biopsy Gleason 3+4 disease, independent of biopsy method (systematic or targeted).
Dr. Reiter concluded the first portion of the discussion as follows:
- Many GG2 cancers are candidates for AS
- Natural history of these cancers is long and can be indolent
- We should strive to avoid overtreatment
- 50% or more of men can avoid any treatment when properly selected
- Many of these men chose treatment despite absence of progression
- However, not all men with GG2 cancers can avoid need for treatments (which does not mean focal therapy is their answer)
- In those for whom treatment is needed, pathologic and biochemical recurrence free survival appears comparable to men undergoing immediate treatment
- Genomics, imaging, and other tools may further aid risk stratification to identify patients unlikely to require treatment in the future
Next, Dr. Parekh began his argument in favor of focal therapy by outlining the following management options for this patient:
- Radical treatment
- Unnecessary for indolent cancer
- Leads to treatment-related morbidity
- Active Surveillance
- Misclassification risk
- May escape cancer control
- Associated with anxiety
- Focal therapy
- Cancer control
- Reducing treatment related morbidity
- Reducing anxiety
Dr. Parekh argued that long-term data by Albertsen et al. published in 2005 has long demonstrated that GG2 disease is a potentially lethal disease variant.1 Focal therapy is based on treatment of the index lesion with GG2 disease or worse which is known to drive clinical progression. Although prostate cancer is multifocal in 86% of cases, >90% of satellite lesions are low risk/GG1 disease and 87% are <0.5 ml in volume.
Focal therapy can be in the form of:
- Cryotherapy
- High-intensity focused ultrasound (HIFU)
- Irreversible electroporation
- Lase ablation therapy
- Vascular-targeted photodynamic therapy
- Brachytherapy
Dr. Parekh went on to present results from the landmark CLIN1001 PCM301 randomized controlled trial, that randomized 413 patients with localized, low-risk prostate cancer from 37 centers in Europe to padeliporfin vascular-targeted photodynamic therapy versus AS. After a median follow up of 24 months, the authors demonstrated that progression was significantly lower in the treatment arm (28% versus 58%, HR 0.34, p<0.001) and rates of a negative biopsy at 24 months was much higher (49% versus 14%, HR 3.67, p<0.001).2 Notably, rate of grade 3 or worse adverse events were non-significantly different. Dr. Parekh argued that if the outcomes for focal therapy versus AS are clearly superior for low-risk cancer, then the superiority of focal therapy versus AS in GG2 disease is a “no brainer”.
There has clearly been an increased uptake of focal therapy for GG2 disease. From 1996-2015, 76% of patients treated with focal therapy were GG1, whereas in the last 5 years, 51% were GG2 or GG3 patients. Dr. Parekh next presented long-term outcomes from the HEAT registry of 13 centers in the UK, including 1,379 patients with a minimum 6 months follow up (62% GG2 disease). The 5- and 7-year failure free survival rates for intermediate risk disease were 83% and 68%, respectively.3 A report by Oishi et al of 160 men (106 intermediate risk) who underwent hemigland cyroablation demonstrated 5-year cancer-specific and metastasis-free survival rates of 100%. The radical treatment-free survival at 5 years was 83%. Prostate cancer treatment with irreversible electroporation in 88 patients with intermediate risk cancer has similarly demonstrated 5-year recurrence-free survival rates of 85.4%.
With regards to HIFU functional outcomes, Rischmann et al. published in 2017 their report of 111 patients with a median follow up of 2 years. 26% of such patients had GG2 disease. 95% had a follow up biopsy negative for significant cancer. Additional therapy was needed in 28% of patients. 97% of patients were pad free and 78.4% had preserved erectile function. A combined analysis of three prospective HIFU trials (HEMI, FOCAL, LESION-CONTROL) demonstrated an initial worsening of erectile function at one month, however by nine months this is almost completely recovered.
What if focal therapy does not work? Dr. Parekh argued that robotic radical prostatectomy after focal therapy appears to be safe with similar outcomes as per multiple reports.
The discussion was turned back over to Dr. Retier who explained the rationale of focal therapy:
- Index tumor can be visualized, mapped, and ablated with minimal side effects compared to radical therapies.
- May also delay need for radical therapy in those for whom it is not successful
Certain questions remain though:
- How good are we at selecting patients?
- How good are we at delineating and ablating the entire tumor?
- What are the outcomes and how are they defined?
- How do these outcomes/endpoints compare to those of active surveillance?
- How effective/safe is salvage treatment?
Dr. Reiter next addressed the issue of whether contemporary imaging and biopsy techniques reliably identify unilateral prostate cancer. His group reported on 92 patients who were deemed to be excellent candidates for hemiablation based on biopsy/clinical/imaging findings and subsequently underwent radical prostatectomy. Almost half (48%) of these supposedly, “excellent” candidates were found to be ineligible for hemiablation based on the final pathology results: 41 patients had discordant laterality of clinically significant prostate cancer, with 21 having a tumor crossing the midline, 20 with undetected distinct contralateral tumors, and 3 with ipsilateral upgrading. 24% of patients had unidentified contralateral clinically significant GG2 disease with tertiary pattern 5.
Dr. Reiter’s group has also attempted to predict pathologic tumor size in prostate cancer based on mp-MRI and pre-operative findings. The overall correlation between radiographic and pathologic tumor size was r=0.4. This implies that 16% of the variability in pathologic tumor size could be explained by radiographic tumor size alone.
Dr. Reiter next argued that the outcomes of focal therapy are dependent on the definition of failure used:
- Radical treatment free survival
- Focal re-treatment free survival
- Biochemical recurrence free survival
- ASTRA nadir + 2
- Stuttgart nadir + 1.2
- Biopsy (in-field and/or out-of-field)
- How many and how often?
- How sensitive?
- Ability to detect residual tumor that measures in mm in a large, treated area?
- Imaging
- MRI
- PSMA
Dr. Reiter presented data by Reddy et al. that reported on cancer control outcomes following HIFU in 1,379 men with non-metastatic prostate cancer. After a median follow up of 32 months, failure-free survival at 5, 6, and 7 years was 83%, 75% and 68% , respectively. Notably, failure was defined as need for a third HIFU, whole gland therapy, metastasis, or death. Residual cancer was found in 488 biopsies in 314 patients, and 92 patients had salvage whole gland treatment. Dr. Reiter argued: Is freedom from radical therapy a valid endpoint? Is it similar to radiation therapy endpoints of nadir+2 with failures detected only at a later stage?
Tourinho-Barbosa et al. reported on 309 men with unilateral low- or intermediate-risk prostate cancer who underwent focal therapy with either HIFU or cryoablation. Failure was defined in two ways:
- Composite of local or systemic salvage, positive biopsy of GG2 disease or higher in-field or out-of-field
- Radical treatment free survival, metastasis, or death
Patients were followed up with PSA tests every six months, yearly MRI, and mandated one year biopsy and for-cause biopsy (abnormal MRI or 2 PSA rises). The mean follow up was 5 years.3
The figure above demonstrates how the definition of failure significantly changes the corresponding outcomes.
Although Dr. Parekh had highlighted results demonstrating that salvage radical therapy after focal therapy is oncologically safe and feasible, Dr. Reiter highlighted the results of a propensity-score matched analysis that demonstrated that biochemical recurrence for patients undergoing delayed salvage after focal therapy was significantly worse compared to patients undergoing primary radical therapy. One must obviously consider the biases inherent to such analyses, however the discrepancy is quite alarming.
Marconi et al. reported on the oncologic, functional outcomes and predictors of recurrence in 82 patients undergoing a salvage robotic radical prostatectomy after focal therapy. The progression-free survival was 74%, 48%, and 36% at 12, 24, and 36 months, respectively. The 12-month continence rate was 83% and potency rate declined from 67% to 4%. The question arises: would delayed surgery after surveillance have had similar outcomes? Thompson et al. similarly reported on 53 men failing focal therapy. The pad free rates were 100% pre-HIFU, followed by 95.3% post-HIFU, and 65.5% 12 months post-prostatectomy. Correspondingly, the potency rates were 90.9%, 73% and 0%, respectively. Almost 2/3 of patients had pT3a-b disease, 44% had positive surgical margins, and freedom from radiation/hormone therapy at 12 months was 66.7%. The question that arises here is: Is salvage too late after focal therapy using freedom from radical therapy endpoint?
Dr. Reiter concluded this portion of the debate as follows:
- Focal therapy is desirable
- However, when compared to AS:
- By definition at least twice as many men receive treatment with focal therapy versus AS
- Success rate is highly sensitive to definition of failure
- Radical treatment free survival is not a validated endpoint and may detect failures too late
- Using biopsy to define progression (AS) or recurrence (focal therapy), “failure” rates are similar for AS and focal therapy at 5 years
- Is focal therapy just a form of active surveillance?
The final chance of a rebuttal was given to Dr. Parekh who addressed the questions likely to be asked by a 65-year-old healthy male with GG2 disease:
- Is my cancer harmless?
- Can cancer progression be reliably monitored?
- If cancer progresses, will it still be curable?
- Will active treatment be required or significantly delayed?
- Will outcomes be similar if receiving delayed versus initial active treatment?
Again, risk of AS in GG2 disease are:
- Misclassification
- Oncologic outcomes
- Limitations of MRI and biomarkers to predict progression
- Adverse outcomes with delayed intervention in patients failing AS
- Anxiety
The risk of upgrading and upstaging for clinical GG2 disease from biopsy to radical prostatectomy specimens is significant with nearly 1 in 3 patients with GG2 disease harboring disease of higher grade or stage on prostatectomy specimens. Widely available clinical information is insufficient for predicting the risk of more advanced disease. Dr. Parekh next presented results from the Miami MAST AS trial:
29-year data from SPCG-43 demonstrate a benefit to curative treatment in 281 patients with intermediate-risk prostate cancer with an improvement in:
- Overall mortality (15.5% absolute benefit)
- Prostate cancer mortality (24.2%)
- Risk of metastasis (19.9%)
Most AS protocols do not currently include GG2 patients with long-term follow-up (excluding the Toronto cohort) and thus results from these cohorts should not be directly extrapolated to GG2 patients.
Long-term outcomes of patients placed on AS in the screening arm of the Goteborg screening trial demonstrated that intermediate-risk patients (defined as GG<=2, cT1-2N0M0, PSA<20 ng.ml) had a lower 10-year failure free survival (73%) compared to patients with low- (85%) and very low-risk (95%) disease. Long-term results from population-based datasets have further demonstrated worse mortality outcomes for intermediate-risk prostate cancer patients managed with AS:
Dr. Parekh next highlighted work from Dr. Reiter’s own group that evaluated the reliability of serial prostate MRI to detect prostate cancer progression during AS and concluded that while reliance on MRI in 100 men would result in the avoidance of follow-up biopsy in up to 683 patients, 12 cases of prostate cancer progression would be missed. Dr. Parekh pointed out as well that there are currently no biomarkers or genomic studies currently validated to reliably predict progression.
His biggest concern however is the risk associated with delayed radical treatment in patients who fail focal therapy. Results from the SEARCH database recently published have demonstrated that a delay in radical prostatectomy >9 months is associated with worse biochemical recurrence rates even for subsets of patients with “lower-risk” intermediate disease. These findings are likely to increase anxiety in AS patients with results from Memorial Sloan Kettering demonstrating that after 1 year on AS, the estimated risk of anxiety was 29%, which remained at 14% even after 7.5 years.
He next referred to the AUA 2022 guidelines, which noted the following
- For patients with favorable intermediate-risk prostate cancer, clinicians should discuss AS, radiation therapy and radical prostatectomy
- The Panel does recognize the noted increased risk of disease progression with AS among intermediate risk patients, particularly those with GG2 disease, as well as the relatively limited data on very long-term follow-up of such patients, and thereby emphasize the importance of shared decision making.
Dr. Parekh concluded the debate with the following points regarding the risk of AS in GG2 disease:
- Misclassification: High
- Oncologic outcomes: Poor
- Limitations of MRI and biomarkers to predict progression: Severe
- Adverse outcomes with delayed intervention in patients failing AS: High
- Anxiety: High
Kirsten Greene, MD, MAS, Professor and Chair of Urology, University of Virginia, Charlottesville, VA
Robert E. Reiter, MD, MBA, Professor and Chief of Urologic Oncology, University of California in Los Angeles, Los Angeles, CA, Dipen J Parekh, MD, Professor and Chair, Desai Sethi Urology Institute, University of Miami, Miami, FL
Written By: Rashid Sayyid, MD, MSc – Urology Chief Resident, Augusta University/Medical College of Georgia, @rksayyid on Twitter during the 2022 American Urological Association (AUA) Annual Meeting, New Orleans, LA, Fri, May 13 – Mon, May 16, 2022.
References:
- Albertsen PC, Hanley JA, Fine J. 20-year outcomes following conservative management of clinically localized prostate cancer. JAMA. 2005;293(17):2095-101.
- Azzouzi A, Vincendeau S, Barret E, et al. Padeliporfin vascular-targeted photodynamic therapy versus active surveillance in men with low-risk prostate cancer (CLIN1001 PCM301): an open-label, phase 3, randomised controlled trial. Lancet Oncol. 2017;18(2):181-191.
- Bill-Axelson, Holmberg L, Garmo H, et al. Radical Prostatectomy or Watchful Waiting in Prostate Cancer - 29-Year Follow-up. N Engl J Med. 2018;379(24):2319-2329.