Bevacizumab Beyond Progression: Does This Make Sense?
Authors: Lee M. Ellis, Daniel G. Haller
Journal: Journal of Clinical Oncology (2008)

For almost five decades after fluorouracil was patented, little changed in the management of patients with colorectal cancer (CRC). Without competition, it was the one-eyed man in a land of the blind. Perseverance and optimism led to the finding nearly two decades ago that a cytotoxic with modest effects in advanced disease had significant efficacy in adjuvant therapy. Over the last 10 years, we have witnessed a radical change in the use of systemic therapy for metastatic CRC, with the introduction of three cytotoxics and three monoclonal antibodies (MoABs). New treatment paradigms have evolved that include the use of multiple chemotherapeutic agents in several lines of therapy, the ability to convert unresectable patients with liver metastases to resectable status, and the incorporation of MoABs targeting vascular endothelial growth factor (VEGF) and the epidermal growth factor receptor (EGFR) into everyday practice. With this relative abundance of treatment options, it comes as no great surprise that both clinical researchers and clinicians have experienced increased difficulty defining a standard of care for patients with metastatic CRC, if indeed a single standard is either expected or desired. Traditional lines of therapy have become blurred—particularly with the use of biologics—and the availability of sequential therapy has created new challenges in determining an actual overall survival benefit for any new agents or regimens. The relative wealth and availability of drugs, the complexities of combination therapy, and the use of breaks in therapy have called into question the likelihood that any new intervention will allow for firm, data-driven recommendations supporting the use any particular regimen as the gold standard of success leading to improvement in overall survival. Exciting new data showing that KRAS mutational status predicts for resistance to anti-EGFR MoAB therapy are likely to further modify treatment algorithms and to challenge conventional methods of assessing optimal use of anticancer agents. Although we all recognize that there is an art in caring for our patients, the regulatory and reimbursement agencies may not allow the use of artistic license. Thus, we must provide both clinical and biologic arguments for the use of particular agents or regimens in the care of our patients. In this issue of Journal of Clinical Oncology, Grothey et al report results from a large observational study (Bevacizumab Regimens Investigation of Treatment Effects and Safety [BRiTE]) suggesting that the continuation of bevacizumab, despite changing the chemotherapeutic regimen after progression on a bevacizumab/chemotherapy regimen (bevacizumab beyond progression), led to an overall survival of approximately 32 months. This contrasted with patients who received further therapy but without bevacizumab, in whom overall survival was approximately 20 months. The latter survival duration is consistent with findings in recent first-line phase III trials with chemotherapy and bevacizumab. There was a third group of patients with a poorer performance status who did not receive therapy beyond first progression, and they will not be discussed further in this editorial. We now must evaluate these data to determine the impact of these findings on day-to-day practice and to hypothesize why continuation of bevacizumab as a component of multidrug regimens may improve overall survival. The study by Grothey et al provides a glimpse into the everyday practice of oncology in the United States. Surprisingly, perhaps, only approximately 60% of patients received all three active chemotherapeutic agents during their course of treatment. In a prior publication, Grothey et al showed that patients who received all three active chemotherapeutic drugs (fluorouracil, oxaliplatin, and irinotecan) had a better overall survival than patients who did not. Thus, it is unclear why less than two thirds of patients in this observational study received all three active drugs during the prolonged course of therapy. Furthermore, only 51% of patients who did not receive bevacizumab beyond progression were treated with EGFR inhibitors. On the basis of National Comprehensive Cancer Network guidelines, patients who experience progression on first-line bevacizumab-containing regimens should receive an anti-EGFR antibody in subsequent lines of therapy. Although there are occasional contraindications for such therapy, it seems highly unlikely that half of these patients would be ineligible for therapy. Although one may be critical of the practices of the physicians who contributed patients to this study, a recently reported randomized trial of oxaliplatin-based chemotherapy, with either placebo or bevacizumab, also showed that, despite participation in a predefined protocol, treatment with either chemotherapy or bevacizumab was frequently discontinued before disease progression. The authors noted that, “while discontinuation of oxaliplatin with continuation of fluoropyrimidine and bevacizumab was permitted, our analysis shows that this course of action was rarely taken.” This randomized, controlled trial also suggested that “the duration of bevacizumab therapy is likely to be important, and that treatment until PD [progressive disease] may be necessary to maximize the clinical benefit derived from bevacizumab therapy.” The data did not, however, permit any conclusion about treatment with bevacizumab beyond progression. JOURNAL OF CLINICAL ONCOLOGY E D I T O R I A L VOLUME 26 NUMBER 33 NOVEMBER 2