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Originally published as JCO Early Release 10.1200/JCO.2009.23.1050 on August 31 2009 © 2009 American Society of Clinical Oncology.
Progression-Free Survival in Bevacizumab-Based First-Line Treatment for Patients With Metastatic Colorectal Cancer: Is It a Really Good End Point?Department of Oncology, San Giuseppe Hospital, Empoli, Florence, Italy
"Giorgio Segre" Department of Pharmacology, University of Siena, Siena, Italy
Department of Oncology, San Giuseppe Hospital, Empoli, Florence, Italy To the Editor: The treatment of metastatic colorectal carcinoma has always relied on systemic administration of cytotoxic drugs. Fluorouracil (FU) was the first drug to show efficacy and fluoropyrimidines are still the backbone of chemotherapeutic combinations. Oxaliplatin and irinotecan demonstrated to add a little but significant improvement. A recent analysis showed that median survival was longer for patients receiving concomitant or sequential FU, oxaliplatin, and irinotecan compared with patients missing one or two of these drugs. Recently monoclonal antibodies (MoAbs) bevacizumab (BV), cetuximab, and panitumumab have showed efficacy in the treatment of this pathology when combined with chemotherapy or, in the case of cetuximab, even when used alone. MoAbs demonstrated to improve chemotherapy results in terms of overall response rate (ORR), median progression-free survival (PFS), and median overall survival (OS). BV is a powerful inhibitor of all vascular endothelial growth factor (VEGF) A isoforms, able to reduce angiogenesis both in vitro and in vivo considerably. Its administration is followed by drastic changes in cancer vascularization, namely disappearance of many blood vessels and normalization of the remainings. These effects are also seen when using different antiangiogenic drugs targeting VEGF receptors, such as sorafenib, sunitinib, and other tyrosine kinase inhibitors. However, after their suspension, blood vessels regrow in few days.1 It is not clear if BV treatment can alter cancer behavior after its suspension, but there are concerns that tumors would grow at increased rate with faster progression. During BV administration, tumors may upregulate VEGF or exploit VEGF-independent angiogenesis, overexpressing other proangiogenic molecules like basic fibroblast growth factor or interleukin-8. It is reasonable that once VEGF is available again, angiogenesis will occur at a higher rate. Another concern is that BV can increase ischemic areas as a result of reduction in blood vessels. It is well known that low oxygen tension and poor nutrients facilitate the appearance of more aggressive and more resistant neoplastic clones. Warnings of a possible more aggressive behavior BV-treated cancer can also be deduced from clinical observation. Cacheux et al2 found evidence of tumor growth acceleration in patients with metastatic colorectal cancer after interruption of BV. Although limited by the small sample size, this is the first clinical report about a rapid regrowth after BV discontinuation.
Median OS is a universally accepted end point for the evaluation of treatment efficacy in cancer patients. Recently Tang et al3 performed an analysis of 39 randomized trials of first-line cytotoxic FU-based chemotherapy in patients metastatic colorectal cancer. They found a statistically significant association between median PFS and median OS. They also established PFS offers many advantages over OS as a primary end point. The use of PFS instead of OS as a primary end point allows studies of shorter duration with consequent earlier results and lower costs. Given the large number of studies included in the analysis, it could seem reasonable to extend Tang et al's conclusions to other first-line treatment of this pathology. The analysis, however, did not include any study comparing MoAbs to standard cytotoxic drugs. The inclusion of MoAbs in the chemotherapy regimen could change the biologic behavior of tumor and alter the relations between surrogate end points and survival. To verify this hypothesis, we looked up in literature controlled or randomized studies of first-line, BV-based treatments of patients with metastatic colorectal cancer, with at least 100 patients enrolled reporting both median PFS and median OS. MEDLINE and the Cochrane Register were used to search for controlled trials containing "bevacizumab" and "avastin," and abstracts of the American Society of Clinical Oncology and European Society of Medical Oncology annual meetings were searched manually. Five studies comparing nine arms of different chemotherapeutic regimens with or without BV were found (Table 1).4–9
The nonparametric Spearman rank correlation test (  ) was used to search for relations between PFS and OS in arms with and without BV. Also  PFS and OS were calculated (Table 1). SPSS software, version 14, (SPSS Inc, Chicago, IL) was used for the analysis.
Although the limited sample size does not allow definitive conclusions, a significant correlation between PFS and OS was found in first-line cytotoxic chemotherapy, in confirming the results reported by Tang et al. In contrast, we were not able to demonstrate any significant association between PFS and OS when BV was added to chemotherapy. Surrogate end points of survival have been hypothosized and validated for patients with metastatic colorectal cancer treated with first-line FU-based cytotoxic chemotherapy. Outside this specific situation, their utility is not clear. In particular, they could be useless when considering newer drugs like BV and other antiangiogenic drugs.
In conclusion, the correlation between PFS and OS and between AUTHORS' DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST The author(s) indicated no potential conflicts of interest. ACKNOWLEDGMENT We thank dott Lidia Lamoglie for her help in the development of this manuscript. REFERENCES 1. Mancuso MR, Davis R, Norberg SM, et al: Rapid vascular regrowth in tumors after reversal of VEGF inhibition. J Clin Invest 116:2610–2621, 2006.[CrossRef][Medline] 2. Cacheux W, Boisserie T, Goldwasser F, et al: Reversible tumor growth acceleration following bevacizumab interruption in metastatic colorectal cancer patients scheduled for surgery. Ann Oncol 19:1659–1661, 2008. 3. Tang PA, Bentzen SM, Siu LL, et al: Surrogate end points for median overall survival in metastatic colorectal cancer: Literature-based analysis from 39 randomized controlled trials of first-line chemotherapy. J Clin Oncol 25:4562–4568, 2007. 4. Saltz LB, Clarke S, Cassidy J, et al: Bevacizumab in combination with oxaliplatin-based chemotherapy as first-line therapy in metastatic colorectal cancer: A randomized phase III study. J Clin Oncol 26:2013–2019, 2008. 5. Cassidy J, Clarke S, Salts L, et al. XELOX-1/NO16966, a randomized phase III trial of first-line XELOX compared with FOLFOX4 for patients with metastatic colorectal cancer (MCRC): Updated survival and tolerability results. San Francisco, CA: American Society of Clinical Oncology Gastrointestinal Symposium, January 15-17, 2009 (abstr 389). 6. Fuchs CS, Marshall J, Barrueco J, et al: Randomized controlled trial of irinotecan plus infusional, bolus, or oral, fluoropyrimidines in first-line treatment of metastatic colorectal cancer: Results from the BICC-C study. J Clin Oncol 25:4779–4786, 2007. 7. Hochster HS, Hart LL, Hedrick E, et al: Safety and efficacy of oxaliplatin and fluoropyrimidine regimens with or without bevacizumab as first-line treatment of metastatic colorectal cancer: Results of the TREE study. J Clin Oncol 26:3523–4697, 2008. 8. Kabbinavar FF, Schulz J, Novotny WF, et al: Addition of bevacizumab to bolus fluorouracil and leucovorin in first-line metastatic colorectal cancer: Results of a randomized phase II trial. J Clin Oncol 23:3697–3705, 2005. 9. Hurwitz H, Fehrenbacher L, Kabbinavar F, et al: Bevacizumab plus irinotecan, fluorouracil, and leucovorin for metastatic colorectal cancer. N Engl J Med 325:2335–2342, 2004.
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Copyright © 2009 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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