Comparative Effectiveness Research for Prostate Cancer Radiation Therapy

Current Status and Future Directions

Xinglei Shen; Nicholas G Zaorsky; Mark V Mishra; Kathleen A Foley; Terry Hyslop; Sarah Hegarty; Laura T Pizzi; Adam P Dicker; Timothy N Showalter


Future Oncol. 2012;8(1):37-54. 

In This Article

What is Comparative Effectiveness Research?

The contemporary concept of comparative effectiveness research (CER) seeks to use evidence to inform medical decision-making, based on measures of effectiveness of the various options in real-world scenarios.[1] This may differ from the traditional idea of evidence-based medicine, a system that has reigned supreme in medical education in the USA and which generally emphasizes evidence that focuses on efficacy of interventions in controlled or ideal conditions.[2] In evidence-based medicine, the scientific 'gold standard' is the randomized controlled trial (RCT), which evaluates efficacy and estimates treatment effect in a selected population of patients. RCTs are designed to eliminate confounding factors through randomization, and sometimes stratification, to provide causal evidence regarding efficacy of the intervention.

However, RCTs and other aspects of traditional evidence-based medicine have important limitations when applied to 'usual care' or 'real-life' settings.[2–4] First, efficacy trials are designed to balance the testing of treatment efficacy with minimal risk to the patient, and, therefore, typically exclude patients with a variety of comorbid conditions or potential inability to adhere to the treatment protocol. As a result, RCTs are often viewed as lacking generalizability to the broader patient population likely to receive the treatment. In addition, given the rigorous nature of RCTs, they are often conducted at major academic centers, which may have very different practice patterns compared with community-based care. For the practicing clinician who is caring for a patient with a poor performance status or multiple medical comorbidities that would have disqualified them from the pivotal RCT, how should the results of efficacy studies be applied? Efficacy trials often fall short of providing guidance to clinicians in everyday clinical practice. Second, efficacy trials often span many years, particularly in therapeutic trials of prostate cancer (PC) and results may be obsolete by the time they are published. An example of such a time delay-related limitation to RCTs is the Southwest Oncology Group (SWOG) 8794 trial of adjuvant radiation therapy (RT) versus observation for advanced PC. This RCT was 'positive' in the sense that adjuvant RT was associated with improvements in overall survival and distant metastasis-free survival, the study's primary end point.[5] However, the penetrance of the results into clinical practice has been limited, with less than 20% of qualifying PC patients receiving adjuvant RT,[6] since the availability of prostate-specific antigen (PSA) testing and the selective use of early salvage RT have changed the essential aspects of the 'observation' alternative to adjuvant RT.[7] Third, randomized clinical trial data do not exist for many clinically relevant comparisons because of the expense of conducting a RCT or challenges to accrual. These limitations call for complementary research, such as observational CER, to help clinicians make informed recommendations under real-world conditions.

CER complements efficacy studies by providing data on the effectiveness of medical interventions. In this case, effectiveness is distinguished from efficacy by measuring the effect of interventions under 'usual care', or 'real-world' conditions, within specific subpopulations.[2] Although no standardized definition exists for CER, it has commonly been acknowledged as an assessment of available options for treating specific medical conditions in selected groups of patients.[8–10] Federal agencies charged with CER investigations include the Patient-Centered Outcomes Research Institute (PCORI) and the Agency for Healthcare Research and Quality (AHRQ), and CER has been described by these organizations as research "designed to inform healthcare decisions by providing evidence on the effectiveness, benefits and harms of different treatment options. The evidence is generated from research studies that compare drugs, medical devices, tests, surgeries or ways to deliver healthcare".[201] Investigations in CER may include comparison of treatment effects in population studies, comparison between different efficacious treatment options, comparison within specific subpopulations to personalize treatment options, comparison of methods to reduce healthcare disparities and assessment of the benefit of newer technologies.[11,12] Rather than focus primarily on RCTs, a system focused on CER may, instead, evaluate strength of evidence using a framework such as the Grading of Recommendations Assessment, Development and Evaluation (GRADE) guidelines (Figures 1 & 2).[13,14]

Figure 1.

Grading of Recommendations Assessment, Development and Evaluation's process for developing recommendations.
Also labeled 'conditional' or 'discretionary'.
OC: Outcome; PICO: 'Patient, Population or Problem', 'Intervention or exposure', 'Comparison' and 'Outcome'; RCT: Randomized controlled trial; S: Study.
Reproduced with permission from [139].

Figure 2.

Quality assessment criteria for Grading of Recommendations Assessment, Development and Evaluation.
Reproduced with permission from [139].

The 2010 Patient Protection and Affordable Care Act (PPACA) established PCORI as a new leader in CER, and the legislation includes a detailed roadmap for the mission and activities of this new private–public entity.[15] In this act, Congress provided rules for the composition and governance of PCORI, a description of its duties and purposes, and a mechanism for ongoing funding as an independent, nonprofit organization. PCORI is led by a 21-member board of governors, which includes the directors of the NIH and the AHRQ. To date, PCORI has appointed 15 members to its Methodology Committee, held initial meetings, and has solicited public feedback regarding definition of patient-centered outcomes research and priority topics for the first round of competitive grant funding.[201] PCORI will be expected to set research priorities, carry out and fund research as the leading organization for CER in the USA.[15]

The concept of patient-centered outcomes research involves evidence that can assist in decision-making for individuals. The concurrent development of personalized medicine, which focuses on tailoring treatments based on molecular biology or other patient-specific considerations, provides one of the greatest challenges to conducting meaningful CER owing to the lack of established data sources that provide biomarker and genetic data for large patient populations.[9] Within radiation oncology, for example, it has been recognized that an individual's risk of normal-tissue toxicity due to RT is influenced by predictive factors; both biological, such as single-nucleotide polymorphisms; and physical, such as dose–volume factors.[16] The combination of CER, with large observational cohorts of patients who receive RT, with the specific biomarkers of personalized medicine will require the development of research-ready data sets to truly meet the call to action for patient-centered outcomes research.

Controversy persists regarding whether costs should be included as a component of CER. Language from the mandates of PCORI and the Centers for Medicare and Medicaid Services (CMS) bars consideration of cost in reimbursement or in investigations of CER, and legislation specifically prohibits PCORI from funding research that evaluates cost per quality-adjusted life-years (QALYs) or other similar measures.[202] However, in the current budget climate and owing to finite medical resources, costs have become an important consideration if not officially sanctioned. Unofficially, CER studies frequently include analyses of the economic impact of potential interventions, cost-effective analyses and cost–benefit analyses.[17–19] It is unclear whether this will change in the USA after the maturation and full implementation of PCORI. Given the federal government's large financial investment in CER,[3,20–23] it is expected to become increasingly important for practicing clinicians, patients, health systems and policymakers. Although the interest in CER covers all areas of medicine, CER is particularly relevant to PC care providers, since the Institute of Medicine included treatments for localized PC in the highest quartile of its 2009 list of the top 100 national priorities for CER.[1] The application of CER in oncology, however, has elicited concerns for a variety of reasons, including methodological challenges, choice of appropriate comparator, lack of biomarker data in large databases, lack of existing large-scale data inclusive of oncology-specific clinical characteristics and outcomes, and the challenge of producing research findings rapidly enough to keep pace with treatment innovation.


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