High-risk prostate cancer: treat the prostate.

Comment High-risk prostate cancer: treat the prostate Published Online November 3, 2011 DOI:10.1016/S0140- Science Photo Library See Articles page 2104 Hundreds of thousands of men are diagnosed with clinically localised prostate cancer every year, and each faces a complex treatment decision with little high-quality evidence to help choose among treatments. Successfully completed, randomised trials of active treatments for localised prostate cancer are, unfortunately, scarce; a large systematic review com- missioned by the US Agency for Healthcare Research and Quality noted that insuﬃ cient evidence exists to make conclusions about the relative beneﬁ ts and harms of treatments. 1 The US Institute of Medicine has identiﬁ ed prostate cancer as among the USA’s top 25 priorities for future comparative eﬀ ectiveness research. 2 In The Lancet, Padraig Warde and colleagues 3 report a successfully accrued randomised trial comparing andro- gen deprivation therapy alone with androgen deprivation therapy plus radiation therapy. In a planned interim analysis of more than 1200 men with locally advanced or otherwise high-risk disease, combination treatment improved survival by an amount both statistically signiﬁ cant and clinically meaningful. After a median follow-up of 6 years, in the radiation plus androgen deprivation therapy group, cancer-speciﬁ c survival improved by 10% in absolute terms and by 46% (hazard ratio [HR] 0·54 [95% CI 0·22–0·73, p=0·0001]) in relative terms, compared with androgen deprivation therapy alone. For overall survival, the primary endpoint, the corresponding improvements were 8% and 23% (HR 0·77 [95% CI 0·61–0·98], p=0·033), respectively. Almost 10% of the androgen deprivation therapy only group received delayed radiation for local progression, so these results underestimate, if anything, the beneﬁ t of radiation. Other-cause mortality did not diﬀ er between treatment groups. Warde and colleagues’ assertion, however, that the beneﬁ t of radiation comes at no expense to long-term urinary or bowel eﬀ ects challenges clinical experience and many other studies. 4 The ﬁ ndings are probably aﬀ ected by the relative insensitivity to the eﬀ ects of radiation of the Functional Assessment of Cancer Therapy—Prostate and the European Organisation for Research and Treatment of Cancer QLQ-C30 quality-of- life instruments used in this trial, compared with newer measures. 5 Furthermore, the Functional Assessment of Cancer Therapy—Prostate instrument, completed by the large majority of patients in the trial, does not capture bowel symptoms. Only 120 patients—about 10% of the overall cohort—completed the European Organisation for Research and Treatment of Cancer questions about bowel symptoms during follow-up. This study improves on the SPCG-7 study, 6 which had a similar design and recorded an even larger treatment eﬀ ect. The SPCG-7 study, however, used antiandrogens—which would not be considered ade- quate androgen deprivation therapy by contem porary standards—rather than medical or surgical castration. 6 These trials are both commendable, although the results are not particularly surprising. Androgen deprivation therapy alone does not constitute curative therapy, and is not endorsed by clinical practice guidelines as a standard option for localised prostate cancer, high-risk or otherwise. 7,8 Indeed, only men with aggressive tumours receive the survival beneﬁ t from androgen deprivation therapy even compared with observation alone, and the eﬀ ect is small at best. 9 Androgen deprivation therapy is, however, frequently used in clinical practice, particularly for older men and those with high-risk disease, 10 who are most at risk for adverse eﬀ ects from androgen deprivation therapy and for cancer-speciﬁ c mortality, respectively. Indeed, overuse of androgen deprivation monotherapy might partly explain the notably high rates of cancer-speciﬁ c mortality among men diagnosed with high-risk prostate cancer even in their late 70s and 80s. 11 No randomised trial comparing surgery and radiation has yet been successfully completed. However, two www.thelancet.com Vol 378 December 17/24/31, 2011