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Fighting Fire with Fire: Rekindling the Bevacizumab Debate

Alberto J. Montero, M.D., and Charles Vogel, M.D.

N Engl J Med 2012; 366:374-375January 26, 2012

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The results of the National Surgical Adjuvant Breast and Bowel Project (NSABP) B-40 trial1 and the GeparQuinto (GBG44) trial,2 both of which are reported in this issue of the Journal, are particularly timely given the definitive announcement by the Food and Drug Administration (FDA) on November 18, 2011, revoking approval of bevacizumab in combination with paclitaxel for the treatment of metastatic breast cancer (see www.fda.gov/downloads/NewsEvents/Newsroom/UCM280546.pdf). Bevacizumab, a monoclonal antibody against circulating vascular endothelial growth factor A, was granted accelerated FDA approval in 2008 for the first-line treatment of human epidermal growth factor receptor 2 (HER2)–negative metastatic breast cancer. Initial approval was given on the basis of evidence showing a significant improvement in progression-free survival, but not overall survival, with weekly treatment with paclitaxel and bevacizumab, as compared with paclitaxel alone.3,4 This approval led to a large number of clinical trials of bevacizumab with other chemotherapeutic agents; the NSABP B-40 and GBG44 studies are among the first trials of neoadjuvant therapy to report preliminary data. Both trials were designed on the basis of the plausible assumption that a surrogate clinical end point, such as progression-free survival, should be used in cases of metastatic breast cancer, since patients live far longer than the duration of a trial and typically receive many other systemic therapies that can confound the end point of overall survival.5 The unresolved issue is whether significant improvements in a surrogate end point like progression-free survival, in the absence of a benefit for overall survival, are potentially predictive of curative benefits in patients with earlier-stage breast cancer. Only data on recurrence and survival from ongoing trials of adjuvant and neoadjuvant therapy with bevacizumab can definitively resolve this issue.

The ongoing controversy surrounding bevacizumab therapy for breast cancer goes beyond the science of tumor angiogenesis and involves broader questions about the use of surrogate end points in clinical trials, as well as economic arguments over the ever-increasing cost of new medicines for the treatment of cancer.5,6 It is through this lens that the NSABP B-40 and GBG44 trials should be viewed, since each of these trials reports a significant improvement with bevacizumab in another putative surrogate clinical end point: pathological complete response. The primary objective of both the GBG44 and NSABP B-40 trials was to determine whether combining bevacizumab with various chemotherapy regimens would significantly improve the rate of pathological complete response in women with nonmetastatic HER2-negative breast cancer. Both studies showed significant improvements in the rate of pathological complete response. The two studies used different definitions of the primary end point; in the GBG44 trial, pathological complete response was defined as the absence of residual tumor in the breast and nodes, whereas in the NSABP B-40 trial, the less stringent definition of the absence of residual tumor in the breast only was used. In the GBG44 study, the overall rate of pathological complete response with the addition of bevacizumab was 3.5 percentage points higher than the rate without bevacizumab (P=0.04), whereas in the NSABP B-40 study, the rate with bevacizumab was 6.3 percentage points higher than the rate without bevacizumab (P=0.02). However, when the more stringent definition of pathological complete response was used, the differences noted in the NSABP B-40 were no longer significant. An analysis of survival is still premature in both trials.

The GBG44 and NSABP B-40 trials used docetaxel-based chemotherapy regimens, rather than the weekly paclitaxel regimen that was used in the trial that led to the initial approval of bevacizumab.4 The weekly paclitaxel–bevacizumab regimen has led to a median progression-free survival of approximately 1 year in three separate trials,4,7,8 which is arguably better than the progression-free survival that has been reported with all other bevacizumab-based chemotherapy regimens in patients with metastatic breast cancer. One possible explanation that has been posited for this discrepancy is that the benefit of bevacizumab is chemotherapy-specific, and when it is combined with weekly paclitaxel, it has a more synergistic antiangiogenic effect than when it is combined with other chemotherapies.9

Subgroup analyses in the NSABP B-40 and GBG44 trials revealed contradictory results. In the GBG44 trial, the rates of pathological complete response were significantly increased with bevacizumab therapy in patients with hormone-receptor–negative (“triple negative”) breast cancer, whereas in the NSABP B-40 trial, there was only a trend favoring bevacizumab in that population. In contrast, the NSABP B-40 trial showed a significant increase in the rate of pathological complete response in patients with hormone-receptor–positive cancer, whereas in the GBG44 trial, no differences were noted in that population. Some potential explanations for these discrepancies are well summarized in one of the articles2 and are likely to be due to differences between the two trials in eligibility criteria and study design. Although the benefits (in the case of the GBG44 trial) and trends (in the NSABP B-40 trial) with respect to triple-negative breast cancer are consistent with those in other trials,10 the specific benefit of bevacizumab in patients with hormone-receptor–positive cancer is unexpected and should be considered as hypothesis-generating. The cooperative groups from both trials are analyzing several biomarkers, and it is hoped that these analyses will elucidate robust predictive biomarkers for response to bevacizumab, which would increase the overall clinical benefit of this drug for patients with breast cancer by allowing more refined patient selection.

These two well-performed trials do not resolve existing controversies surrounding bevacizumab therapy. If surrogate end points like progression-free survival in patients with metastatic breast cancer and pathological complete response in the neoadjuvant setting are ultimately predictive of survival benefits in earlier-stage disease, then the use of these surrogates in clinical research will be vindicated, and the FDA’s decision to withdraw the indication of bevacizumab for metastatic breast cancer will be further called into question. However, in the context of unsustainable expenditures for cancer care in the United States,6 any survival benefit of bevacizumab, or other molecularly targeted drugs, will be balanced against the considerable development costs of modern molecularly targeted oncology drugs.