(UroToday.com) In the Society of Urologic Oncology plenary session held at the American Urologic Association Annual Meeting, Dr. Ronald Chen addressed the question of designing the ideal randomized controlled trial in high-risk localized prostate cancer.
Dr. Chen began by discussing the ProtecT trial, highlighting the incredible success of this effort to randomize patients with predominately low-risk prostate cancer to active monitoring, surgery, or radiotherapy. With 10 years of follow-up, in this study population, there is no evidence of prostate cancer-specific survival differences between the treatment approaches. However, there are notable differences in toxicity.
He further noted that a number of randomized controlled trials have demonstrated improvements in cancer-specific survival for surgically treated versus radiotherapy treated patients and in overall survival for those receiving treatment versus no treatment in similar risk patients. He suggested that comparing these results to those from ProtecT, these data are limited by significant unmeasured confounding. Further, the early splitting of survival curves identified in some of these studies almost certainly suggests a non-oncologic cause. He emphasized that the major biases and confounding in such analyses relate to standard clinical decision making and patient selection including age, comorbidity (including within group heterogeneity among Charlson scores), the extent and burden of disease (again, including heterogeneity within risk-groups), and other socioeconomic factors which may be difficult to capture.
Thus, he highlighted that a randomized trial is the “cleanest” study design. The SPCG-15 trial is ongoing comparing surgery and radiotherapy-based approaches in patients with locally advanced disease. However, it’s worth noting that the ProtecT trial enrolled from 2009 to 2009 and was subsequently published in 2016. He also suggested that there is a strong rationale to complement these randomized data with prospective comparative cohorts may represent a non-randomized alternative.
Dr. Chen emphasized the importance of a pragmatic approach to study design with emphasis on a multidisciplinary study team that is able to appropriately account for details of treatments being compared and considerations regarding adjuvant and salvage therapy. Additionally, these studies can be strengthened by detailed data on possible confounders, large sample size to allow for the identification of subgroups of patients between treatment modalities who are comparable, and the recruitment of a diverse patient population to increase the generalizability.
However, equally important is the identification of study endpoints. Overall survival and patient-reported quality of life are arguably the two most important outcomes. However, there is always interest in examining shorter-term endpoints for practical reasons. In terms of biochemical recurrence, he highlighted issues with differing definitions between surgery and radiotherapy which will always serve to lengthen the apparent time to recurrence among patients treated with radiotherapy. Further, concomitant ADT given with radiotherapy may delay recurrence without changing the natural history. Thus, he concluded that it is not a viable comparative endpoint for the two treatment modalities. Metastasis-free survival is an FDA-approved endpoint in nmCRPC and a surrogate for overall survival and may be relevant here. However, Dr. Chen raised the question of whether MFS defined based on PSMA PET-CT, rather than conventional imaging, would be equally valid.
TO highlight the importance of these issues, he highlighted the data from a number of recent trials examining postoperative radiotherapy. He emphasized that patients in two of these trials (RADICALS-RT and GETUG-AFU-15) could receive ADT with either adjuvant or salvage radiotherapy. Thus, as ADT may be given later for patients receiving salvage therapy, it may confound the assessment of the primary outcome of biochemical recurrence-free survival at 5-years.
Dr. Chen concluded by emphasizing the need for high-quality data comparing radical prostate and radiotherapy in high-risk prostate cancer. Carefully designed randomized controlled trials and non-randomized prospective studies can provide important high-quality evidence.
Presented by: Ronald Chen, MD, MPH, the Joe and Jean Brandmeyer Endowed Chair, Department of Radiation Oncology; Professor, Department of Radiation Oncology; Clinical Service Chief, Department of Radiation Oncology; Associate Director of Health Equity, University of Kansas Cancer CenterWritten by: Christopher J.D. Wallis, University of Toronto Twitter: @WallisCJD during the 2021 American Urological Association, (AUA) Annual Meeting, Fri, Sep 10, 2021 – Mon, Sep 13, 2021.