Curing More Prostate Cancer: Thinking Through the Options
Mené sur 961 patients atteints d'un cancer de la prostate à haut risque, cet essai de phase III évalue l'efficacité, du point de vue de la survie globale, de l'ajout de mitoxantrone et de prednisone à une thérapie anti-androgénique adjuvante, après une prostatectomie radicale (durée médiane de suivi : 11,2 ans)
Phase III clinical trials should generally be simple affairs. The rule of thumb is that the standard of care should be compared with a promising intervention among reasonably well-defined patients and the proposed outcome should be readily measurable, generalizable, and clinically meaningful. Ideally, the results, if positive, should change practice and be implemented widely. As a generality, one (and only one) variable should be changed in the experimental group to facilitate understanding the intervention and its consequences.
Simplicity, though an oft-stated goal, is not always achieved. In prostate cancer trials, outcomes will always occur long after the trial was designed. Trial architects are forced to consider various future treatment approaches, and the potential future state of affairs is inherently uncertain. Speculating on future scenarios is interesting, but even well-informed investigators may have substantial discordance in their views.
Currently in nonmetastatic prostate cancer, the time to reach the most relevant clinical end points (metastases or overall survival) can take a decade or even more. Definitions of prognostic categories, biomarkers, and treatments are all subject to flux over time. How to anticipate these changes can determine the success or failure of a trial. Much is at stake because both research dollars and trial participants are limited.
In the article that accompanies this editorial, let us examine the Southwest Oncology Group (SWOG) S9921 trial and the patients considered to be at high risk of death after radical prostatectomy (RP).1 First, the investigators should be congratulated for seeing a trial through to completion, two decades after conception. In SWOG S9921, patients were randomly assigned to 2 years of androgen-deprivation therapy (ADT) or 2 years of ADT plus mitoxantrone. Accrual to the trial was halted prematurely as a result of higher leukemia risk in the mitoxantrone-treated patients; however, the early stopping occurred after 961 patients were randomly assigned, thus providing a valuable and sizable data set with long-term follow-up.
In 1999, the standard of care for most of these patients was observation because no treatment had level I evidence showing clear clinical benefit. In 2009, standards changed for many high-risk patients as adjuvant radiation therapy (in SWOG 8794) was shown to prolong overall survival (OS).2 Since that time, no new trials in the adjuvant setting after RP have reported clear clinical benefit, but the truth is that post-RP patients with high-risk features rarely receive adjuvant radiation.3 Low use of adjuvant radiation is in part a result of the availability of prostate-specific antigen (PSA)–driven salvage treatments.4 Salvage approaches avoid radiation overuse in patients never destined to experience relapse, but whether clinical outcomes are similar is not yet clear. The Radiotherapy and Androgen Deprivation in Combination After Local Surgery (RADICALS) trial (ClinicalTrials.gov identifier: NCT00541047) will help answer the important question regarding the relative merits of adjuvant radiation versus PSA-driven salvage radiation.
The investigators in SWOG S9921 assessed adjuvant chemotherapy for patients deemed to be at high risk for death after RP. Controversially, they chose 2 years of ADT as the control arm despite the fact that no prior study supported the use of 2 years of ADT for these patients. The best supportive data for adjuvant ADT after RP come from the 1999 study by Messing et al5 performed in node-positive men. That small study (n = 100) used lifelong ADT and enrolled patients beginning in 1988 (the pre-PSA era). OS benefit was seen for adjuvant versus delayed ADT. Today, lifelong ADT is rarely used in such patients. Multiple studies of radiation plus ADT demonstrate positive benefit,6 but ADT plus radiation is not the same as ADT after RP. The combination of ADT and radiation seems to be synergistic, whereas data to support synergy between ADT and RP is sparse. Perhaps newer neoadjuvant studies can result in change (ClinicalTrials.gov identifier: NCT00430183).7
What do the authors of SWOG S9921 conclude? First, mitoxantrone provided no benefit. Second, the observed OS was improved relative to pretrial estimates. Third, only approximately 20% of the deaths were attributable to prostate cancer. Whether these better than expected observations were a result of patient selection, 2 years of ADT, stage migration, or various postprotocol therapies cannot be ascertained.
Journal of Clinical Oncology , éditorial en libre accès, 2017