CHICAGO, IL USA (UroToday.com) - Maha Hussain, Professor of Medicine and Urology at the University of Michigan, and Howard Scher, Chief of the Genitourinary Oncology Service at Memorial Sloan Kettering Cancer Center artfully presented point and counterpoint debating the timing of docetaxel chemotherapy in advanced prostate cancer given the changing therapeutic landscape. Dr. Hussain argued for earlier treatment with docetaxel, and Dr. Scher argued the counterpoint supporting later incorporation of chemotherapy into the treatment algorithm.
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Late treatment with docetaxel chemotherapy
Dr. Howard Scher provided the counterpoint in the debate with Dr. Hussain regarding the optimal timing of treatment with chemotherapy. His argument detailed how the current evidence base suggests that delayed or late treatment with docetaxel chemotherapy is the best way to practice, particularly because the recently reported data from the ECOG CHAARTED trial has not yet been peer- reviewed or published. He cautioned that clinical trial results that have not undergone thorough peer-review should not be used to quickly change clinical practice without carefully evaluating the risk/benefit ratio of treatment. He urged us to remember that there are a plethora of well-tolerated treatment options available for use in men with advanced prostate cancer, and until an optimal sequencing algorithm has been defined, there is no clear answer to this question.
One important reason to consider later treatment with docetaxel chemotherapy, the preferred approach, is that there was discordance in the reported data between the GETUG-AFU 15 and CHAARTED studies. While both enrolled men with metastatic hormone-sensitive prostate cancer and randomized them to hormonal therapy with or without docetaxel chemotherapy up front, GETUG-AFU 15 reported no difference in overall survival between groups at 83 months follow-up, while CHAARTED demonstrated an increase in median overall survival associated with the ADT plus docetaxel arm at 29 months follow-up. Importantly he pointed out that patients in the GETUG-AFU 15 study received 9 rather than 6 cycles of chemotherapy, though he did acknowledge that there were fewer men with high volume disease (visceral mestastases or ≥ 4 bone metastases with ≥ 1 area outside of the axial skeleton) in the GETUG-AFU 15 study. Similar to Dr. Hussain’s previous demonstration, Dr. Scher placed the survival curves for the two studies next to each other for the audience to review, and pointed out that the separation in the GETUG-AFU 15 study was minimal and not similar to that seen in the CHAARTED study.
A second reason to use docetaxel late in the disease course rather than early on is that clinical trial enrollees are not identical to patients in the wider prostate cancer community. Thus treatments that may be tolerable and efficacious in clinical trials may ultimately be less effective and associated with prohibitive side effects when used in the “real world.” Dr. Scher reviewed that patients in the clinical trials discussed had an excellent performance statuses that are superior to many patients seen in typical oncology clinics. Additionally, simply being in a clinical trial can result in superior outcomes to treatment with the same therapy in a non-trial setting. The benefit of early chemotherapy seen in the CHAARTED study may therefore be a gross overestimate of benefit in the “real world.” Dr. Scher also discussed that there is no standard definition of “early” or “late” treatment with chemotherapy, which makes defining late versus early chemotherapy difficult to evaluate. The definition of “early” treatment with chemotherapy in clinical trials has typically been defined as the use of chemotherapy within 2-4 months of starting hormonal therapy. However, the use of “late” chemotherapy can occur at a variety of time points, including at the time of PSA progression, radiographic progression, clinical progression, etc. Ultimately this may lead to many men who could benefit from chemotherapy not receiving treatment as men and their physicians continue to put off chemotherapy due to concerns about toxicity.
Finally, Dr. Scher discussed that differences in outcomes between GETUG-AFU 15 and CHAARTED may be related to therapy availability during the study period. Very few options for treatment, other than docetaxel, were available to patients during the study period for patients in GETUG-AFU 15. However, men in the CHAARTED study had the opportunity to receive treatment with all of the newer agents that have been approved since 2009. This may result in an apparent survival benefit in CHAARTED that is driven more strongly by subsequent therapies than by up-front docetaxel itself, particularly if androgen receptor targeted agents were used for longer periods of time, or sooner, among patients who were in the docetaxel arm of CHAARTED. Ultimately Dr. Scher suggested that patients on the docetaxel arm of CHAARTED and GETUG-AFU 15 received 1.8-3 times more exposure to life-prolonging therapy than patients on the ADT-alone arms of those studies.
Ultimately Dr. Scher argued that a conservative approach and later incorporation of docetaxel into the treatment algorithm for men with advanced prostate cancer is prudent and preferred based on the currently available data. He urged us to consider both the CHAARTED and GETUG-AFU 15 data when making treatment decisions. Docetaxel appeared in the clinical trials to be well-tolerated, but in the “real world” patients are sicker and have more comorbidities than the ones in a clinical trial. Toxicity may be augmented in this population. Finally, therapy used after treatment with early docetaxel likely has a profound effect on survival outcomes, and consideration of that as we move forward with sequencing algorithms is imperative.
Read related content:
Bottom line: Timing of treatment with docetaxel for men with advanced prostate cancer
Presented by Howard I. Scher, MD at the American Society of Clinical Oncology (ASCO) Annual Meeting - Illumination & Innovation: Transforming Data into Learning - May 29 - June 2, 2015 - Chicago, Illinois USA
Memorial Sloan Kettering Cancer Center, New York, NY USA
Reported by Alicia K. Morgans, MD, assistant professor of medicine and medical oncologist at Vanderbilt-Ingram Cancer Center, and medical writer for UroToday.com