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BackgroundA previous analysis of 113 National Comprehensive Cancer Network® (NCCN®) recommendations reported that NCCN frequently recommends beyond Food and Drug Administration (FDA)-approved indications (44 off-label recommendations) and claimed that the evidence for these recommendations was weak.MethodsIn order to determine the strength of the evidence, we carried out an in-depth re-analysis of the 44 off-label recommendations listed in the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®).ResultsOf the 44 off-label recommendations, 14 were later approved by the FDA and/or are supported by randomized controlled trial (RCT) data. In addition, 13 recommendations were either very minor extrapolations from the FDA label (n = 8) or were actually on-label (n = 5). Of the 17 remaining extrapolations, 8 were for mechanism-based agents applied in rare cancers or subsets with few available treatment options (median response rate = 43%), 7 were based on non-RCT data showing significant efficacy (>50% response rates), and 2 were later removed from the NCCN Guidelines because newer therapies with better activity and/or safety became available.ConclusionOff-label drug use is a frequent component of care for patients with cancer in the United States. Our findings indicate that when the NCCN recommends beyond the FDA-approved indications, the strength of the evidence supporting such recommendations is robust, with a significant subset of these drugs later becoming FDA approved or supported by RCT. Recommendations without RCT data are often for mechanism-based drugs with high response rates in rare cancers or subsets without effective therapies.

The use of a selected group of biological markers in breast cancer patients who are disease free but at risk of relapse after mastectomy has potential for detecting recurrent tumor before there is clinical evidence. In this preliminary study, multiple materials were serially analyzed in the body fluids of patients without overt tumor but receiving adjuvant chemotherapy because of positive axillary nodes at surgery. The total frequency of elevated levels was determined and compared for those patients who remained disease free, for those who subsequently relapsed, and for a third group of patients with proven metastases. Frequency of elevation was directly proportional to increasing disease. Although differences in the relative frequency of individual materials was observed, the same trends with increasing tumor burden were found. The results suggest that the serial measurement of biological markers has potential for indicating the presence of occult disease. A nucleus of biological markers to be considered should include carcinoembryonic antigen, urinary hydroxyproline/creatinine ratio for bone lesions, and gamma-glutamyltranspeptidase for liver involvement.