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Originally published as JCO Early Release 10.1200/JCO.2008.17.4540 on October 14 2008 © 2008 American Society of Clinical Oncology.
Bevacizumab Beyond Progression: Does This Make Sense?
The University of Texas M. D. Anderson Cancer Center, Houston, TX
University of Pennsylvania, Philadelphia, PA 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.1-3 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 al4 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.5 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 al4 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 al6 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.5 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."5 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. Studies must investigate the driving force behind preferences (or lack thereof) for certain drugs in specific indications. Does cost play a role? Marketing? Toxicity? Patient preference? The observations from the BRiTE study4 and the study by Saltz et al5 suggest particular preferences or biases by individual oncologists (or patients) participating in these trials, and thus, we should refrain from overinterpreting the data until confirmed in prospective, randomized studies. Regardless of the nuances and limitations of observational studies (see the editorial on this topic by Levine and Julian in this issue of Journal of Clinical Oncology), the most interesting aspect of the report by Grothey et al4 of the BRiTE study is the apparent added benefit of continuing bevacizumab (and in most cases, fluorouracil) while changing the chemotherapeutic variable (ie, oxaliplatin or irinotecan). How can this drug be effective through multiple lines of therapy? The mechanisms of action (MOAs) of bevacizumab are diverse and complex. Proposed MOAs of bevacizumab (and other anti-VEGF therapies) include the following: antiangiogenic activity (including inhibition of new blood vessel growth and vascular regression); vascular constriction; vascular normalization; direct effects on tumor cell function; offsetting of effects of chemotherapy induction of VEGF levels; and inhibition of VEGF repression of dendritic cell function.7 Admittedly, it is difficult to determine the exact MOA in metastatic CRC because no study in humans can adequately address or interrogate all of the possibilities. However, insights into the MOAs of anti-VEGF therapy can sometimes be obtained from clinical trial results. For example, data on response rates (RRs) would have been informative. A high RR would have suggested that bevacizumab is a chemotherapy-sensitizing agent through multiple lines of chemotherapy. In contrast, no increase in RR accompanied by a prolonged overall survival may inform us that this agent is cytostatic in this setting. If the latter is the case, then one could question whether bevacizumab could be used as single-agent maintenance therapy. However, there is no evidence that bevacizumab as a single agent has activity in patients with metastatic CRC, especially refractory patients, as demonstrated in the Eastern Cooperative Oncology Group 3200 trial.8 Unfortunately, without RR data in the current study, we can only speculate on the MOA of bevacizumab in refractory patients, in whom it may be different from that in chemotherapy-naive patients. It is of note that, in the trial reported by Saltz et al5 in first-line patients, a statistically significant improvement in progression-free survival (the primary end point) was achieved by the addition of bevacizumab, without any improvement in RR. Recent studies presented at the annual meeting of the American Association for Cancer Research provided some insight into the mechanisms by which bevacizumab increases the effectiveness of chemotherapy. In contrast to the normalization hypothesis, whereby bevacizumab leads to a redistribution of tumor blood flow, resulting in increased delivery of chemotherapy to the tumor, Kasman et al9 did not find any increase in drug uptake in mice bearing human cancer xenografts. Instead, these investigators showed that an antibody to VEGF led to increased vascular damage when combined with chemotherapy. VEGF activates a number of survival pathways in endothelial cells, and Klement et al10 have shown that blockade of VEGF signaling could sensitize endothelial cells, rather than tumor cells, to the effects of chemotherapy. Although we typically consider sensitivity or resistance as emanating from tumor cells, we now must consider the possibility that endothelial cells may also be sensitive or resistant to chemotherapy. It is possible that changing cytotoxic chemotherapy may expose endothelial cells to a different genotoxic stress and that the addition of anti-VEGF therapy may serve as a chemotherapy sensitizer to the tumor vasculature through multiple lines of therapy. Of course, the same argument could be made for tumor cells, where VEGF receptors have been shown to mediate numerous tumor cell functions, including survival.11 The BRiTE study, among others, raises interesting questions. For example, what should we use in second-line therapy for metastatic CRC in patients who have experienced progression on a bevacizumab-containing regimen? For the sake of discussion, let us assume that a patient has experienced progression on infusional fluorouracil, leucovorin, and oxaliplatin plus bevacizumab (approximately 60% to 70% of patients in the United States will receive a similar first-line regimen). On the basis of National Comprehensive Cancer Network guidelines, it would be reasonable to consider an irinotecan-based regimen ± cetuximab for such a patient. However, since these guidelines were developed, we have learned that patients with tumors with mutated KRAS are unlikely to benefit from anti-EGFR MoAB therapy. If this holds true, then cetuximab (or panitumumab) should not be considered for patients whose tumors express mutated KRAS. This limits our options in second- and third-line therapy yet provides an opportunity to study other biologics in this setting. It would have been informative if Grothey et al4 had analyzed tumors from the BRiTE study to determine whether bevacizumab beyond progression is effective in the group of patients with KRAS mutations (thus poor candidates for anti-EGFR MoABs). Although KRAS mutational status has not been shown to affect outcome in patients receiving first-line bevacizumab,12 it is possible that KRAS may have an impact on outcome in refractory patients. Therefore, it is essential to study new approaches for patients who have a mutated KRAS tumor who have experienced progression on bevacizumab. For example, should we study the effects of continued anti-VEGF therapy by tweaking the anti-VEGF approach and using another VEGF-targeted agent, such as sorafenib (an agent designed to target VEGF receptors and Raf, a downstream mediator of Ras signaling)? There are emerging data on the use of VEGF inhibitors in patients with renal cell carcinoma, in whom patients refractory to one VEGFR tyrosine kinase inhibitor may respond to a different tyrosine kinase inhibitor.13 Although the 32-month overall survival time of patients receiving bevacizumab beyond progression in this registry is suggestive of a possible benefit for continued bevacizumab beyond first progression, we must keep in mind that this is an observational study and not a prospective randomized trial. There is always a component of investigator bias and selection in observational studies. For example, as shown in Table 1 of the article by Grothey et al,4 the percentage of patients with an Eastern Cooperative Oncology Group performance status of 0 is 50% in the bevacizumab beyond progression group compared with 40% in the group who did not receive bevacizumab beyond progression. A prospective randomized trial (Intergroup Bevacizumab Continuation Trial/Southwest Oncology Group 0600) is ongoing in an attempt to answer the question of whether or not to continue bevacizumab (in combination with chemotherapy and cetuximab) after progression on first-line therapy. However, this trial is being modified as a result of the recent data on KRAS mutations and resistance to anti-EGFR therapy, again demonstrating the rapidly evolving field of therapy for metastatic CRC. Observational studies such as the BRiTE registry are important tools that allow us to develop new hypotheses, setting the stage for testing these hypotheses in prospective randomized trials. Oncologists should continue to individualize patient care and adjust their therapies based on data obtained from clinical trials results and US Food and Drug Administration approvals. However, there will be circumstances where there are no clinical trial data to answer a specific question, and educated oncologists must fully grasp and interpret available clinical data to support the use of drugs to maximize patient benefit, while considering the associated expense and toxicity. AUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST Although all authors completed the disclosure declaration, the following author(s) indicated a financial or other interest that is relevant to the subject matter under consideration in this article. Certain relationships marked with a "U" are those for which no compensation was received; those relationships marked with a "C" were compensated. For a detailed description of the disclosure categories, or for more information about ASCO's conflict of interest policy, please refer to the Author Disclosure Declaration and the Disclosures of Potential Conflicts of Interest section in Information for Contributors. Employment or Leadership Position: None Consultant or Advisory Role: Lee M. Ellis, ImClone Systems (C); Daniel G. Haller, Genentech (C), Sanofi-Aventis (C) Stock Ownership: None Honoraria: Lee M. Ellis, Genentech; Daniel G. Haller, Roche Research Funding: Lee M. Ellis, Amgen, ImClone Systems, Sanofi-Aventis; Daniel G. Haller, Roche, Bristol-Myers Squibb Co Expert Testimony: None Other Remuneration: None AUTHOR CONTRIBUTIONS Conception and design: Lee M. Ellis, Daniel G. Haller Data analysis and interpretation: Lee M. Ellis, Daniel G. Haller Manuscript writing: Lee M. Ellis, Daniel G. Haller Final approval of manuscript: Lee M. Ellis, Daniel G. Haller NOTES published online ahead of print at www.jco.org on October 13, 2008 REFERENCES
1. Amado RG, Wolf M, Peeters M, et al: Wild-type kras is required for panitumumab efficacy in patients with metastatic colorectal cancer. J Clin Oncol 26:1626-1634, 2008 2. Khambata-Ford S, Garrett CR, Meropol NJ, et al: Expression of epiregulin and amphiregulin and k-ras mutation status predict disease control in metastatic colorectal cancer patients treated with cetuximab. J Clin Oncol 25:3230-3237, 2007 3. Lievre A, Bachet JB, Boige V, et al: Kras mutations as an independent prognostic factor in patients with advanced colorectal cancer treated with cetuximab. J Clin Oncol 26:374-379, 2008 4. Grothey A, Sugrue MM, Purdie DM, et al: Bevacizumab beyond first progression is associated with prolonged overall survival in metastatic colorectal cancer: Results from a large observational cohort study (BRiTE). J Clin Oncol doi:10.1200/JCO.2008.16.3212 5. Saltz LB, Clarke S, Diaz-Rubio E, 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 6. Grothey A, Sargent D, Goldberg RM, et al: Survival of patients with advanced colorectal cancer improves with the availability of fluorouracil-leucovorin, irinotecan, and oxaliplatin in the course of treatment. J Clin Oncol 22:1209-1214, 2004 7. Ellis LM, Hicklin DJ: VEGF-targeted therapy: Mechanisms of anti-tumour activity. Nat Rev Cancer 8:579-591, 2008[Medline] 8. Giantonio BJ, Catalano PJ, Meropol NJ, et al: Bevacizumab in combination with oxaliplatin, fluorouracil, and leucovorin (FOLFOX4) for previously treated metastatic colorectal cancer: Results from the Eastern Cooperative Oncology Group study E3200. J Clin Oncol 25:1539-1544, 2007 9. Kasman I, Bagri A, Mak J, et al: Mechanistic evaluation of the combination effect of anti-VEGF and chemotherapy. Proceedings of the 100th Annual Meeting of the American Association for Cancer Research, San Diego, CA, April 12-16, 2008 (abstr A2494) 10. Klement G, Baruchel S, Rak J, et al: Continuous low-dose therapy with vinblastine and VEGF receptor-2 antibody induces sustained tumor regression without overt toxicity. J Clin Invest 105:R15-R24, 2000[Medline] 11. Dallas NA, Fan F, Gray MJ, et al: Functional significance of vascular endothelial growth factor receptors on gastrointestinal cancer cells. Cancer Metastasis Rev 26:433-441, 2007[CrossRef][Medline] 12. Ince WL, Jubb AM, Holden SN, et al: Association of k-ras, b-raf, and p53 status with the treatment effect of bevacizumab. J Natl Cancer Inst 97:981-989, 2005 13. Tamaskar I, Garcia JA, Elson P, et al: Antitumor effects of sunitinib or sorafenib in patients with metastatic renal cell carcinoma who received prior antiangiogenic therapy. J Urol 179:81-86, 2008[Medline] Related Articles
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Copyright © 2008 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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