SAN FRANCISCO, CA USA (UroToday.com) - This session included audience participation through online and text voting on clinical scenarios, with commentary by a panel of experts.
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The panel was moderated by Fred Saad, MD, FRCS and included Scott Tomlins, MD, PhD (pathologist), A. Oliver Sartor, MD (medical oncologist), Paul L. Nguyen, MD (radiation oncologist), and Ganesh S. Palapattu, MD (urologist), each commenting from their own unique perspectives.
The first clinical scenario involved a healthy 40-year-old male with an PSA of 51, a normal digital rectal examination (DRE), with no symptoms and no family history, who, on MRI, had tumor seen on the right with extension into the right seminal vesicle, and on biopsy had high-volume bilateral Gleason 3+4=7 disease with biopsy-proven seminal vesicle disease. Metastatic work up was negative. The majority of the audience favored multi-modality treatment with radical prostatectomy (RP), with or without adjuvant radiation therapy, and androgen deprivation therapy (ADT) (57%). The panel discussed the bias that exists with trying to maximize local control, through radical prostatectomy, in young patients with high risk-disease, and all agreed that they would likely recommend up front radical prostatectomy for this patient. They also all emphasized the importance of informing the patient that the use of multiple therapies would likely be necessary. Dr. Nguyen pointed out that in this particular patient he would have a low threshold for the use of adjuvant radiation therapy, as opposed to salvage therapy, depending on the final pathologic diagnosis, and though there is no randomized controlled data, he would give consideration to the use of ADT, as well, given the patient’s age and likely aggressiveness of disease.
The second clinical scenario dealt with whether a known BRCA germline mutation has any effect on treatment choice. The patient presented was a 52-year-old male with 3 out of 12 cores positive for Gleason 6 disease, with a known BRCA germline mutation. The audience was split between radical prostatectomy (46%) and active surveillance (40%). The panel agreed that the effect of a known germline mutation on treatment choice is a bit of a gray area. While evidence exists that BRCA1 and BRCA2 mutations portend more aggressive disease, in this particular patient—who could be considered a candidate for active surveillance depending on the criteria used—there is no data as to what the appropriate approach should be. The panel agreed that there is some concern for under grading of the disease with the patient. Drs. Nguyen and Sartor both pointed out the potential for gaining further information with MRI and the potential for MRI-targeted biopsy changing the treatment decision in this patient.
The final clinical scenario discussed took the audience through the prostate cancer history of a single patient. This patient was a 72-year-old man with clinical stage T3 disease diagnosed at age 66. The patient’s PSA at diagnosis was 35, and on biopsy he had a Gleason score of 4+4=8 in 7 out of 12 cores. Metastatic work up was negative and the patient underwent external beam radiation therapy (EBRT) with 24 months of ADT, which resulted in a PSA nadir of 0.3ng/ml.
A discussion was had regarding the appropriate length of ADT in this patient, and Dr. Nguyen pointed out that based on previous randomized controlled trials (RCTs), the correct answers were 36 and 28 months. He pointed out the RTOG has moved to 24 months in its current RCTs. A discussion ensued on whether or not the standard of care may change to 18 months given recent data showing no difference when compared to 36 months, while there was an improved quality of life with shorter duration of therapy. Several members of the panel discussed that the determination of length of ADT in this scenario would likely be driven by patient age. In a younger patient, who is more likely to benefit from a survival standpoint with longer periods of ADT, and more likely to have a quicker return to normal testosterone levels post-therapy, members of the panel agreed that they were more likely to administer 36 months of ADT. In an older patient, who is more likely to be hypogonadal and symptomatic at baseline, 18 months of ADT would more likely be considered.
The scenario continued with the patient developing a PSA recurrence, increasing to 6.2ng/ml with a PSA doubling time (PSADT) of 9 months. In the setting of a negative metastatic work up, the audience was completely split on the next step with regards to pursuing local therapy, observing, or initiating ADT, whether continuous or intermittent. The panel agreed that local therapy in this patient with a short PSADT and high-risk disease prior to EBRT was unlikely to be efficacious. Dr. Sartor discussed that there is no good data that a patient experiencing PSA failure with no evidence of metastatic disease would benefit from immediate ADT initiation. He acknowledged that there is an element of “PSA anxiety” and that ADT may be initiated in some patients, in the absence of metastatic disease, on the basis of that. He stated that in this clinical scenario, the patient may be asymptomatic from his disease for a prolonged period of time off ADT, and, thus, initiation of ADT with its potential adverse effects would cause more harm than good. The panel consensus was that observation was likely the best course of action for this patient at this time.
The panel then went on to discuss the role of local salvage therapy in patients who demonstrate a single bony metastasis or positive lymph node on metastatic work up. The consensus of the panel was that local salvage therapy data is very immature at this point, and while the concept is intriguing, it is far from being a proven concept that can be applied outside of a trial basis.
The scenario continued with the patient’s PSA rising to 22ng/ml on observation, now with a PSADT of 4 months, but still with a negative metastatic work up. The consensus of the panel was that ADT would be initiated and some discussion was had regarding whether intermittent therapy would be considered in this patient. Most agreed that intermittent therapy should be considered given the potential for improved QOL and the lack of a difference in survival in intermittent versus continuous ADT in patients with M0 disease. Dr. Saad stressed, however, that he would not consider intermittent therapy if the patient did not have a very good initial response to ADT, which he defined as a PSA level less than 1.
The scenario continued with the patient responding initially to ADT and then subsequently becoming castrate resistant with a PSA of 5 after a nadir of 2.5. In a discussion regarding the next step in treatment, Dr. Sartor said that he would favor observation at this time as long as the patient is asymptomatic. He stated that no trial currently exists that addresses the appropriate time to initiate the new therapies for castrate resistant prostate cancer (CRPC). He cautioned against the assumption that earlier initiation of therapy is better and stressed the need to wait for trial data before this conclusion can be made. The scenario picked up 6 months later with the patient’s PSA increased to 18. He now demonstrated slight spinal discomfort, and had a 3cm retroperitoneal lymph node and 3 new bony metastases on metastatic workup. The audience favored initiating abiraterone at this time. Dr. Sartor said that based on recent data presented at the meeting, enzalutamide should be considered, particularly given it does not need to be administered with prednisone.
The final question addressed what the appropriate next step would be in the absence of any response to abiraterone. While the audience favored initiation of docetaxel, Dr. Sartor cautioned against this approach as evidence in small studies has demonstrated that patients with primary abiraterone resistance potentially may also display a lack of response to docetaxel. He also stressed that resistance to abiraterone did not necessarily predict resistance to enzalutamide. He said the appropriate timing of the use of the new agents in this setting was undefined at this time and stressed the need for RCTs to establish optimal drug sequencing in CRPC.
Dr. Tomlins concluded the session with a discussion of the role of molecular profiling in prostate cancer treatment. He presented work that he was involved with at the University of Michigan which focused on molecular profiling in real-time biopsies. He presented examples which demonstrated androgen receptor (AR) signaling activation in CRPC. He also highlighted the potential role for molecular profiling in identifying non-AR based alterations (e.g.mutations in AKT and BRAF) in biopsied metastatic sites that may indicate a potential response to targeted therapies.
Highlights of a panel discussion at the 2014 Genitourinary Cancers Symposium - January 30 - February 1, 2014 - San Francisco Marriott Marquis - San Francisco, California USA