WASHINGTON—To highlight the value of comparative effectiveness research (CER) in making health care decisions, the American Medical Association held a news briefing at the National Press Club here. The briefing featured CER studies on lung cancer and prostate cancer—among others—published in a theme issue of the Journal of the American Medical Association devoted to comparative effectiveness research (4/18/12 issue).
In opening remarks, moderator Phil B. Fontanarosa, MD, MBA—JAMA Executive Editor—noted that CER results have been brought to the forefront of U.S. health care discussions since more than $1 billion was allocated to CER in 2009. In addition, the new Patient-Centered Outcomes Research Institute (PCORI)—established by the Patient Protection and Affordable Care Act of 2010—has also focused attention on the topic. CER is needed, Fontanarosa said, because it can shed light on the value of different treatment options, and these options have important clinical implications and can sometimes have financial consequences.
Adding Bevacizumab to Carboplatin & Paclitaxel Did Not Increase Survival in Older Patients with NSCLC
In the first comparative study discussed at the briefing, adding bevacizumab to the standard regimen of carboplatin and paclitaxel did not improve the survival rate for Medicare patients age 65 and older with advanced non-small cell lung cancer (NSCLC) when compared with use of carboplatin and paclitaxel without bevacizumab ( Zhu et al: JAMA 2012;307:1593–1601).
The addition of bevacizumab to carboplatin and paclitaxel was approved by the Food and Drug Administration in 2006 for NSCLC. “We did not find evidence that adding bevacizumab provides a significant survival advantage,” said the study's senior author, Deborah Schrag, MD, MPH, Associate Professor of Medicine at Harvard Medical School and Deputy Associate Director of Population Sciences at Dana-Farber/Harvard Cancer Center. As a result, bevacizumab should not be considered standard of care in this patient population, she said, adding that in fact, physicians have not universally adopted the addition of bevacizumab to chemotherapy for this elderly population with advanced NSCLC.
Using Surveillance, Epidemiology and End Results (SEER) data from the National Cancer Institute, the retrospective study examined 4,168 Medicare beneficiaries 65 or older with Stages IIIB or IV non-squamous cell NSCLC diagnosed between 2002 and 2007. The main outcome measure was overall survival—measured from the first date of chemotherapy treatment until death or the censoring date of Dec. 31, 2009.
Schrag, who is Chair of the Comparative Effectiveness Research Committee of the Alliance for Clinical Trials in Oncology, noted that FDA approval of bevacizumab for NSCLC was based on just a single study (ECOG 4599), which showed that NSCLC patients who received bevacizumab plus standard chemotherapy had a survival advantage over those who did not receive bevacizumab. Asked why the drug was approved on the basis of a single study, she said the FDA's strict approval criteria are not about CER, but about efficacy: “The FDA is all about ‘can it work?’” she said.
She and her coauthors note in the article that a recent meta-analysis of four randomized trials did not find a significant one-year overall survival advantage when bevacizumab was added to standard chemotherapy.
Genentech Disputes the Conclusions
A statement by bevacizumab's manufacturer, Genentech, disputes the JAMA study's conclusions on advanced NSCLC and bevacizumab in elderly Medicare patients. Citing ECOG 4599, the company said: “Patients in E4599 who received Avastin plus chemotherapy had a 20 percent improvement in overall survival compared to those who received chemotherapy alone (based on a hazard ratio of 0.80; median survival of 12.3 months compared to 10.3 months).”
The Genentech statement also cites favorable data on bevacizumab in treating NSCLC from a large Phase IV observational study, ARIES, data presented at the 2010 American Society of Clinical Oncology Annual Meeting.
Comparison of 3 Types of Radiation for Localized Prostate Cancer
The second comparative study (Sheets et al: JAMA 2012;307:1611–1620) compared three different types of radiation therapy used to treat localized prostate cancer: conformal radiation therapy; intensity-modulated radiation therapy (IMRT), which has become the standard for Medicare patients; and proton therapy, which the study authors termed “a high-profile, high-cost prostate cancer treatment.”
Overall, the results in the JAMA study “do not clearly demonstrate a clinical benefit to support the recent increase in proton therapy use for prostate cancer,” the researchers concluded. Senior author Ronald C. Chen, MD, MPH, Assistant Professor of Radiation Oncology at the University of North Carolina Lineberger Comprehensive Cancer Center, noted that there has been limited research on older versus newer prostate cancer treatments, and that various groups have called for CER studies on localized prostate cancer treatments.
He added that the rapid move over the last eight years from conformal radiation to use of IMRT for more than 95 percent of patients was done with very little CER data.
In the JAMA population-based study, the researchers used SEER Medicare-linked data from 2000 to 2009 to examine and compare outcomes for patients with localized prostate cancer. In a sample of 12,976 men who received IMRT vs. conformal radiation therapy, the IMRT patients were less likely to experience gastrointestinal morbidities (such as rectal bleeding or diarrhea) and hip fractures, but were more likely to have erectile dysfunction.
The IMRT group was nearly 20 percent less likely to undergo additional cancer therapy. When compared with 1,368 men receiving proton therapy, the IMRT group had a 34 percent lower risk of gastrointestinal adverse events than did the proton group.
Based on these data, Chen and his co-authors concluded that “comparative effectiveness research in localized prostate cancer treatments is needed because of the large number of men with this disease and the continued trend of a rapid increase in use of newer and costlier treatments with unproven clinical benefit.”
But, Chen noted, the JAMA study was an observational study and not a clinical trial, and CER studies on IMRT vs. proton therapy are ongoing. Asked if some men with localized prostate cancer might choose a nerve-sparing radical prostatectomy over IMRT if they knew of the increased risk of erectile dysfunction, he replied that for men with localized prostate cancer, “there are many different issues,” and that all have to be considered when men discuss their choices with their physicians and choose a treatment. Such issues include age, family history, co-morbidities, concern about specific side effects, and willingness to travel for treatments (unlike IMRT, proton therapy is not available everywhere).
Dispute about Proton Therapy Conclusions
In a statement reacting to the JAMA study on localized prostate cancer, Eugen Hug, MD, Medical Director and Chief Medical Officer of ProCure Treatment Centers, (which provide proton therapy) disputed the conclusion that proton therapy causes more GIl side effects than IMRT does. He said a number of well-regarded, peer-reviewed studies have found that “protons reduce—not increase—gastrointestinal side effects.”
He added, “The UNC study runs counter to what we know from these studies, from research being carried out by ProCure and other proton centers and from our first-hand experience treating hundreds of patients with this important cancer therapy....The statements made by the UNC researchers about the merits and relative morbidity of the radiation modalities are at best questionable and at worst misleading.”
Need to Involve Both Clinicians and Patients in CER Research
While some results of CER studies will no doubt provoke controversy (as the cancer studies in JAMA did), PCORI Chief Operating Officer Anne C. Beal, MD, MPH, said the need for CER is clear, as is the need to involve patients and clinicians in CER research. “We are very committed to getting both clinicians and patients engaged in the work that we're doing,” said Beal, who also participated in the news briefing. She noted that PCORI's first project announcement—which solicited projects focused on methods for engaging patients and other stakeholders in all aspects of the research process—drew more than 800 responses.
“Patients have different priorities, and we need to respect that,” she said, noting that CER can help patients choose treatments that honor their priorities. She cited as an example her 83-year-old aunt, who—upon receiving a diagnosis of lung cancer—said she had two priorities: she didn't want to feel pain, and she didn't want to lose her hair. While another patient might have had different priorities, her aunt's wishes were valid, individual reasons for making treatment choices for herself, Beal said.