Radiation Therapy in the Treatment of Prostate Cancer
Background and Problem
In recent years, intensity modulated radiation therapy (IMRT) and proton beam radiation therapy (PBRT) have emerged as increasingly popular options for the treatment of prostate cancer. However, to date there have been no prospective studies comparing the impact on health outcomes of PBRT or IMRT in low and intermediate risk prostate cancer patients, which comprise about 80 percent of all patients diagnosed with this disease in the USA, and few high quality studies comparing these newer therapies to existing, widely available options such as brachytherapy.
This is an opportune time for a study comparing IMRT and PBRT for prostate cancer as there are only a few proton centers established, and payers are not yet providing routine coverage and reimbursement for this technology. If PBRT and IMRT are not evaluated before proton therapy facilities become widespread, PBRT may become the standard of care for radiation therapy of prostate cancer without ever having been rigorously and comparatively evaluated despite the fact that this treatment is about twice as expensive as IMRT. The window of opportunity to conduct such an evaluation will therefore have passed, which occurred with IMRT and the other established treatments for this condition.
Developing a Study Protocol
In 2006, CMTP convened a multi-stakeholder workgroup to identify evidence gaps in the scientific literature on the use of IMRT for the treatment of early stage prostate cancer. The workgroup concluded that the available evidence of the effectiveness of this therapy compared to alternative interventions was weak. However, due to broad adoption and strong enthusiasm from the clinical community, the potential interest from patients and clinicians in controlled comparative studies was felt to be limited.
In a parallel effort in February 2007, the California Technology Assessment Forum (CTAF), sponsored by the Blue Shield of California Foundation, convened a Roundtable of national experts, specialty societies, CMTP, and a representative from the National Cancer Institute to review and discuss a systematic review it commissioned on the use of IMRT in the treatment of prostate cancer. The Roundtable participants also noted the limited evidence associated with IMRT and PBRT, and therefore the group raised the possibility of CMTP helping to lead a collaborative effort to explore the feasibility of a comparative study of IMRT and PBRT. Thus, the CMTP workgroup reconvened in March 2007 to discuss a study question comparing the side effect and quality of life profiles of IMRT and PBRT. This group considered a wide range of study designs and outcome measures and decided to move forward with the development of a draft study protocol using a parallel cohort observational design, with 2 year patient reported bowel function as the primary endpoint.
When presented with the study protocol, the American Society for Therapeutic Radiology and Oncology’s (ASTRO) Emerging Technology Committee as well as other ASTRO leaders expressed support for the study question and for the inclusion of PBRT as one arm of the study. The draft protocol was further developed and refined though extensive consultation with clinical, methodological and policy experts, as well as public and private payers. A fully-developed protocol was presented and discussed on July 21, 2008 at a meeting convened by CMTP and co-hosted by AHRQ, which included payers, vendors, clinicians, researchers, and government representatives. At this meeting, there was broad agreement that producing comparative effectiveness data is an important goal to assist patients, physicians and payers with clinical decision making and coverage decisions. Payers strongly supported the proposed study, particularly the Centers for Medicare and Medicaid Services (CMS), who had recently listed PBRT for prostate cancer as a potential candidate for a national coverage determination (NCD) in part due to their awareness of the limited evidence currently available.
However, there were differences of opinion about the importance of conducting a randomized controlled trial (RCT) versus a prospective, observational registry study to address this research question. There are pros and cons to both approaches. Arguably, an RCT provides the strongest form of evidence about the relative efficacy and harms for many therapies. Nevertheless, the ability to adequately accrue patients is a major concern for this study. Difficulties in obtaining adequate patient recruitment in RCTs are not unique to those studying treatments for prostate cancer. For cancer trials in general, less than 5 percent of eligible patients enter clinical trials for cancer care. Slow recruitment delays the availability of research findings, and raises concerns about the generalizability of results to the pool of patients eligible for treatment.
Comparative effectiveness research aims to provide information on how therapies work in a broad population in actual practice. For this reason, a prospective, registry of prostate cancer patients is an appealing alternative to an RCT. Moreover, because proton beam facilities are constrained to a few geographic areas, these comparisons lend themselves to a natural experiment, somewhat mitigating concerns about selection bias. In response to these different views, there has been further exploration, collaboration, and consultation to further refine the proposed study and consider options to ensure that both camps are satisfied.
Collaboration
Undertaking a large effectiveness trial requires many different types of expertise. Therefore, in order to ensure that the resulting clinical trial is both scientifically robust, timely, and accounts for the perspectives of a wide range of stakeholders, CMTP has partnered with the researchers at the University of Pennsylvania, Massachusetts General Hospital, and Wayne State University and is currently working on developing a protocol for both a randomized controlled trial and a prospective registry.
