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Harold J. Burstein

One of the treasures of oncology practice is a vast and accessible clinical literature to draw on to guide clinical treatment. Truly, oncology is a field dominated by science and evidence. Some great resources in oncology are comprehensive treatment guidelines, such as those from NCCN, that review, interpret and instill the literature, and infuse it with clinical expertise to create a road map for effective treatment. Given my thoughts on these, it was sobering to read a recent paper that investigated the levels of evidence underlying NCCN recommendations for 10 common cancers.1 The authors reviewed NCCN Guidelines levels of evidence and consensus (1, high evidence, uniform consensus; 2A, lower evidence, uniform consensus; 2B, lower evidence without uniform consensus but no major disagreement; 3, any level of evidence but major disagreement), identified all treatment recommendations in the Guidelines, and tallied the level of evidence behind those recommendations. The major findings were that only 6% of recommendations were level 1; the vast majority (83%) were level 2A—consensus, but less evidence. Among diagnostic workup and cancer surveillance, 0% of recommendations were level 1, and in many major cancer types (lung, prostate, colorectal, melanoma, pancreas, lymphoma, bladder, uterus), fewer than 10% of all recommendations were level 1. The most level 1 recommendations were in initial therapy; beyond that, the rate drops substantially. These observations point to a large gap in evidence for many oncology practices, and though these observations are not necessarily new, it is time for all of us in oncology to mind...
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Harold J. Burstein

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Harold J. Burstein

In April, the National Academy of Science published its report, “A National Cancer Clinical Trials System for the 21st Century: Reinvigorating the NCI Cooperative Group Program” (available at: www.nap.edu). The document is required reading for those interested in clinical trials in oncology, but the findings will not surprise those who have participated in cooperative groups trials. The groups deserve great credit for important clinical advances, conducting phase III trials that often define standards of care. At the same time, the processes that govern current development and administration of studies are too complicated and too slow, as well as highly inefficient and woefully underfunded. Some sobering statistics: • Only 60% of NCI-funded cooperative group trials reach their accrual goal; • The accrual of 25,000 patients per year requires the involvement of 3100 treating institutions, suggesting an average accrual of 8 patients per site per year; • The vast majority of patients at all cancer clinics are not treated on studies; • Funding for the cooperative groups in general has been stagnant for the past decade; • Per capita funding for cooperative group trials both lags industry-supported trials and is considered sufficient to cover only one third to one half of the costs of participating in a clinical study; • The slow development and accrual to studies limits the scientific value of many trials. The report calls for both intellectual and administrative changes to the cooperative groups process. It identifies goals of enhancing the speed and efficiency of trial development; identifying innovative science and trial designs; improving the...
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Harold J. Burstein

Although the calendar said “summer” and baseball season was in high gear, July seemed to be an early fall for Avastin in breast cancer. The Oncology Drugs Advisory Committee (ODAC) of the FDA voted 12 to 1 that the AVADO and RIBBON1 trials did not provide confirmatory evidence supporting the original ECOG 2100 study that had led to accelerated approval of bevacizumab in combination with paclitaxel for advanced breast cancer. The FDA will decide in September whether to withdraw the label for the agent. A previous ODAC vote, in 2007, was 5 to 4 against approval, a recommendation not honored in the subsequent FDA decision. To date, there have been no fewer than 5 randomized clinical trials of chemotherapy with or without bevacizumab. Of these, the first (capecitabine ± bevacizumab) showed no difference in progression-free survival (PFS). The second (ECOG 2100; paclitaxel ± bevacizumab) showed major improvement in PFS. The next 3 trials—all placebo-controlled—showed changes in PFS that were, though all statistically significant, arguably not clinically compelling, with improvements in PFS of 2 to 3 months. None of these studies, nor a meta-analysis, suggests a survival advantage for adding bevacizumab in advanced breast cancer. These results leave more questions than answers. The second most common, after the question of bevacizumab itself, is, “what should be the end points for oncology drug approval?” The FDA has offered guidance for clinical trial end points and approval of cancer drugs (available at: http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ucm071590.pdf). A variety of end points can lead to approval, including...
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Harold J. Burstein

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Harold J. Burstein