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Future Oncology
Review
Comparative effectiveness research for prostate cancer radiation therapy: current status and future directions Xinglei Shen1, Nicholas G Zaorsky1, Mark V Mishra1, Kathleen A Foley2, Terry Hyslop3, Sarah Hegarty3, Laura T Pizzi4, Adam P Dicker1 & Timothy N Showalter*1 Department of Radiation Oncology, Kimmel Cancer Center & Jefferson Medical College, Thomas Jefferson University, Philadelphia, PA, USA 2 Thomson Reuters Healthcare, Cambridge, MA, USA 3 Division of Biostatistics, Department of Pharmacology & Experimental Therapeutics, Thomas Jefferson University, Philadelphia, PA, USA 4 School of Pharmacy, Thomas Jefferson University, Philadelphia, PA, USA *Author for correspondence: Kimmel Cancer Center & Jefferson Medical College, Thomas Jefferson University, 111 S 11th Street, Bodine Center for Cancer Treatment, Philadelphia, PA 19107, USA n Tel.: +1 215 955 6702 n Fax: +1 215 955 0412 n
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Comparative effectiveness research aims to help clinicians, patients and policymakers make informed treatment decisions under real-world conditions. Prostate cancer patients have multiple treatment options, including active surveillance, androgen deprivation therapy, surgery and multiple modalities of radiation therapy. Technological innovations in radiation therapy for prostate cancer have been rapidly adopted into clinical practice despite relatively limited evidence for effectiveness showing the benefit for one modality over another. Comparative effectiveness research has become an essential component of prostate cancer research to help define the benefits, risks and effectiveness of the different radiation therapy modalities currently in use for prostate cancer treatment. 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 evidencebased 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 10.2217/FON.11.131 © 2012 Future Medicine Ltd
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 Future Oncol. (2012) 8(1), 37–54
Keywords American Recovery and Reinvestment Act n comparative effectiveness research n cost–effectiveness n patient-centered outcomes research n prostate cancer n radiation therapy n
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ISSN 1479-6694
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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 (GR ADE) guidelines (Figures 1 & 2) [13,14] . 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 38
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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 future science group
Comparative effectiveness research for prostate cancer radiation therapy
Review
Healthcare question (PICO) Systematic review S1
S2
S3
S4
OC1
OC2
OC3
OC4
Important outcomes
S5
Critical outcomes
Generate an estimate of effect for each outcome
Rate the quality of evidence for each outcome, across studies RCTs start with a high rating, observational studies with a low rating Rating is modified downward: – Study limitations – Imprecision – Inconsistency of results – Indirectness of evidence – Publication bias likely
Rating is modified upward: – Large magnitude of effect – Dose response – Confounders likely minimize the effect
Final rating of quality for each outcome: high, moderate, low or very low
Rate overall quality of evidence (lowest quality among critical outcomes)
Decide on the direction (for/against) and grade strength (strong/weak†) of the recommendation considering: Quality of the evidence Balance of desirable/undesirable outcomes Values and preferences Decide if any revision of direction or strength is necessary considering: resource use
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] .
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. future science group
CER for prostate cancer RT
PC treatment is a high-impact topic for CER within oncology. PC is the most commonly diagnosed cancer among men in the USA with 217,000 new cases in 2010 and is the secondleading cause of cancer mortality, with 28,660 deaths in 2008 [23,24] . The estimated direct cost of PC treatment in 2010 was US$11.9 billion and is projected to increase 38% by 2020 [25] . PC patients have multiple options at each stage of disease, including active surveillance (AS), androgen deprivation therapy, surgery with radical prostatectomy (RP) and multiple forms of RT. In most instances, there are no data to demonstrate clear differences in efficacy or in quality-of-life (QoL) outcomes [26] among the treatment options. Treatment decisions are often www.futuremedicine.com
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Study design Randomized trial
Observational study
Quality of evidence
Lower if
Higher if
High
Risk of bias – 1 Serious – 2 Very serious
Large effect +1 Large +2 Very large
Moderate
Inconsistency – 1 Serious – 2 Very serious
Dose response +1 Evidence of a gradient
Low
Indirectness – 1 Serious – 2 Very serious
Very low
Imprecision – 1 Serious – 2 Very serious
All plausible confounding +1 Would reduce a demonstrated effect or +1 Would suggest a spurious effect when results show no effect
Publication bias – 1 Likely – 2 Very likely
Figure 2. Quality assessment criteria for Grading of Recommendations Assessment, Development and Evaluation. Reproduced with permission from [139] .
based on subjective considerations, such as the preferences or biases of patients and physicians. For example, the long duration of externalbeam RT (EBRT) for PC has been cited as a primary reason for patients deciding against RT for definitive treatment [27] . Current data demonstrate both overtreatment of low-risk disease and under-treatment of high-risk disease, with wide difference in patterns of care across the USA [28] , suggesting that decisions are often based on physician and patient biases rather than evidence of comparative effectiveness. A better understanding of the effectiveness of each therapeutic alternative in a usual-care setting may improve decision-making. Comparing the pros and cons of each modality for an individual patient lies at the heart of CER. This article reviews recent efforts in CER regarding RT for PC. We focus on comparison between RT modalities as well as comparison of outcomes between RT and RP. We also discuss examples of cost analyses in RT. Using example CER studies, we highlight the complementary role of CER to traditional efficacy research, the limitations of the current tools for CER and areas of development for the future of CER. Comparisons between RT & other modalities RT versus RP
While RT and RP are considered to be equivalent in terms of biochemical control and longterm survival, this hypothesis has never been formally tested in a randomized setting. Multiple 40
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attempts at randomized comparisons have been abandoned owing to poor accrual, including the Surgical Prostatectomy Versus Interstitial Radiation Intervention Trial (SPIR IT), Medical Research Council (MRC) PR06 and SWOG 8890 trials. Relatively small older studies using suboptimal RT doses reported inferior outcomes with RT as compared with RP [29,30] . In the contemporary era of dose-escalated RT, single and multi-institutional studies have generally reported similar outcomes for all risk groups [31–33] . Population-based CER studies of outcomes following RT or RP have reported improved PC-specific survival with RP, but their results must be interpreted with caution owing to limitations in adjusting for confounding variables, both measured and unmeasured. Using the Cancer of the Prostate Strategic Urology Research Endeavor (CaPSURE) database, Cooperberg et al. reported that RT was associated with more than double the risk of PC-specific mortality compared with RP (hazard ratio [HR]: 2.21; 95% CI: 1.50–3.24) [34] . Concerns were raised regarding the study in subsequent letters to the editor that highlighted deficiencies in adjustment for confounders, which would lead to overestimation of the effectiveness of RP compared with RT [35,36] . A study of a cohort of older men in the Surveillance, Epidemiology and End Results (SEER)-Medicare linked database, which included patients with localized PC diagnosed in 1992 and treated with RT or RP future science group
Comparative effectiveness research for prostate cancer radiation therapy
showed similar findings: an estimated 10‑year PC-specific survival of 93.8 versus 98.1% (p
