The value of randomised trials for prostate cancer management

In The Lancet Oncology, David Dearnley and colleagues1Dearnaley DP Jovic G Syndikus I et al.Escalated-dose versus control-dose conformal radiotherapy for prostate cancer: long-term results from the MRC RT01 randomised controlled trial.Lancet Oncol. 2014; (published online Feb 26.)http://dx.doi.org/10.1016/S1470-2045(14)70040-3Google Scholar report the long-term outcomes of the Medical Research Council (MRC) RT01 study—a randomised study of 64 Gy versus 74 Gy of conformal radiotherapy given with 3–6 months of neoadjuvant or concomitant androgen deprivation therapy (ADT). The authors are to be commended for completing and successfully managing this high quality trial over the past 20 years. As they rightly point out, this is one of six randomised trials that have examined the possible benefits of dose escalation for external beam radiotherapy. In sum, an additional week of radiotherapy improves biochemical control by about 18%.2Viani GA Stefano EJ Afonso SL Higher-than-conventional radiation doses in localized prostate cancer treatment: a meta-analysis of randomized, controlled trials.Int J Radiat Oncol Biol Phys. 2009; 74: 1405-1418Summary Full Text Full Text PDF PubMed Scopus (382) Google Scholar In this trial with 843 participants, the 10-year absolute difference in biochemical progression-free survival was 12% (43% [95% CI 38–48] in the standard-dose group vs 55% [50–61]; hazard ratio [HR] 0·69 [95% CI 0·56–0·84]; p<0·0001) with no significant difference in overall survival (71% [95% CI 66–75] in both groups; HR 0·99 [95% CI 0·77–1·28]; p=0·96). Although overall survival is the gold-standard outcome to improve, it is exceptionally difficult to show in localised disease diagnosed in a screen-detected era when median overall survival approaches 20 years. This difficulty is particularly evident when technological advances introduce supposedly better techniques every 2–5 years. Notably, the SWOG 8794 study3Thompson Jr, IM Tangen CM Paradelo J et al.Adjuvant radiotherapy for pathologically advanced prostate cancer: a randomized clinical trial.JAMA. 2006; 296: 2329-2335Crossref PubMed Scopus (803) Google Scholar did not show an overall survival advantage when it reported its 10·6 year median follow-up results, despite having a high-risk postoperative population, and doing the trial early in the prostate-specific antigen (PSA) screening era. Although PSA recurrence is not a perfect surrogate for overall survival, clinical experience suggests that higher PSA control means that more patients feel good about their disease status, and are free of next-line treatment interventions with their attendant side-effects and costs. As the MRC RT01 study constitutes another piece of level 1 evidence, it is likely that dose-escalated radiotherapy with short-term ADT (at least compared with lower dose radiotherapy) will be listed as one of the options that should be offered to men with localised prostate cancer when guidelines about management of localised prostate cancer are updated. We can add this to the list of recommendations in localised prostate cancer: long-term versus short-term or no ADT for high-risk disease; radiotherapy plus ADT versus radiotherapy or ADT alone for high-risk disease; and adjuvant postoperative radiotherapy versus delayed or no postoperative radiotherapy for margin-positive or extracapsular disease. The problem is that much of what clinicians can offer is not based on level 1 evidence, despite many attempts to design appropriate trials—eg, early detection and screening; active surveillance; radical prostatectomy (in screened populations); robotic-assisted laparoscopic prostatectomy (in any population); low dose rate (LDR) brachytherapy; high dose rate (HDR) brachytherapy (compared with dose-escalated radiotherapy); intensity modulated radiotherapy; stereotactic ablative radiotherapy; cryotherapy; high intensity focused ultrasound; and focal ablative therapy. Each of these interventions will probably have sufficient evidence to warrant possible recommendation in a guideline. Although the purists will say that randomised trials are needed to inform every decision, the pragmatist knows that there are limits to this statement. First, there are limitations (eg, of funds, trial organisations, and personnel) to designing, doing, and analysing these trials. Second, and arguably more importantly, there has to be a balance of interests to do a randomised trial—the patient and supervising physician have to be uncertain as to the best treatment, unbiased (particularly financially) about which treatment might be better, and for the patient, be willing to enter into the study and subject themselves to random allocation of treatment. Random treatment allocation, although statistically the best way to balance for known and unknown prognostic and predictive factors, contradicts the patient empowerment movement. Third, are clinicians willing to stop innovating while they wait 20 years to design, enrol, and mature the results of each randomised controlled trial? The debate over LDR brachytherapy versus dose-escalated radiotherapy illustrates these points. In the MRC RT01 study, 46% of patients had biochemical failure by 10 years. Long-term results for LDR have shown 10-year failure ranging from 6% (LDR monotherapy for low and intermediate risk disease, N=1006)4Morris WJ Keyes M Spadinger I et al.Population-based 10-year oncologic outcomes after low-dose-rate brachytherapy for low-risk and intermediate-risk prostate cancer.Cancer. 2012; 119: 1537-1546Crossref PubMed Scopus (95) Google Scholar to 10% (LDR boost for high-risk disease, N=473).5Taira AV Merrick GS Butler WM et al.Long-term outcome for clinically localized prostate cancer treated with permanent interstitial brachytherapy.Intl Journal Radiat Oncol Biol Phys. 2011; 79: 1336-1342Summary Full Text Full Text PDF PubMed Scopus (130) Google Scholar With the same patient risk distribution as RT01, the expected occurrence of overall biochemical failure would be 7·7% with LDR. Since LDR is cheaper (at least in Canada), more convenient for patients, more efficient for the health-care system, and has equivalent or better quality of life,6Rodrigues G Yao X Loblaw AD Brundage M Chin JL Low-dose rate brachytherapy for patients with low- or intermediate-risk prostate cancer: a systematic review.Can Urol Assoc J. 2013; 7: 463-470PubMed Google Scholar is it ethical to do a randomised trial of these two options? We need more studies like the one reported by Dearnley and colleagues. However, for the sake of global health-care systems and economies, we also need to stop offering ineffective and resource-intensive treatments. Collectively, our greatest step forward might be to identify for each patient cohort the treatments that produce the highest incremental cost effectiveness ratios, and fund those. All other treatments would need to prove (through randomised trials) that they are of equal or better value than those to be publicly funded. I have received research support from Sanofi and Paladin and honoraria from AstraZeneca, Elekta, GE Healthcare, Sanofi, and Paladin. I have served on advisory boards for Astellas and Sanofi. I am an equity partner in TSRCC Radiation Oncology Associates. Escalated-dose versus control-dose conformal radiotherapy for prostate cancer: long-term results from the MRC RT01 randomised controlled trialAt a median follow-up of 10 years, escalated-dose conformal radiotherapy with neoadjuvant androgen deprivation therapy showed an advantage in biochemical progression-free survival, but this advantage did not translate into an improvement in overall survival. These efficacy data for escalated-dose treatment must be weighed against the increase in acute and late toxicities associated with the escalated dose and emphasise the importance of use of appropriate modern radiotherapy methods to reduce side-effects. Full-Text PDF Open Access

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