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Journal of Clinical Oncology, Vol 24, No 21 (July 20), 2006: pp. 3325-3327 © 2006 American Society of Clinical Oncology. DOI: 10.1200/JCO.2006.06.2067
Progress With Biological Agents in Metastatic Colorectal Cancer Leads to Many ChallengesDigestive Oncology Unit, University Hospital Gasthuisberg, Leuven, Belgium The management of patients with metastatic colorectal cancer (CRC) has changed dramatically over the last 5 years, with increased chances of prolonged survival. Many factors have certainly contributed to this progress. Among these factors is the development of new drugs. Until the mid-1990s the only available drug, with limited activity in metastatic CRC, was fluorouracil (FU). The development of the cytotoxic agents irinotecan, oxaliplatin, and capecitabine, and of the biologic agents cetuximab and bevacizumab, has clearly increased therapeutic options. It has been shown that capecitabine is at least as active FU.1 The combination of oxaliplatin with FU/leucovorin (FU/LV) and of irinotecan with FU/LV (FOLFIRI) is more active in the first-line management of metastatic CRC than FU/LV.2-4 Oxaliplatin plus FU/LV (FOLFOX) and irinotecan ± FU/LV are also active options in the second-line treatment of CRC.5-7 Recently, it has been shown in randomized phase III trials that bevacizumab, when combined with irinotecan plus bolus FU/LV in the first-line treatment of metastatic CRC and with FOLFOX in second-line treatment leads to an increased median survival, progression-free survival (PFS), and response rate (RR) compared with the cytotoxic chemotherapy alone.8,9 Moreover, it has been demonstrated in a few randomized phase II studies and in a combined analysis of these phase II studies that bevacizumab increases the activity of FU/LV in the first-line setting.10-12 The mechanism of action of bevacizumab and the data from phase II studies indicating a high activity of bevacizumab in combination with several oxaliplatin-based combinations support the expectations that bevacizumab will also significantly increase the activity of oxaliplatin-based combinations in the first-line treatment of metastatic CRC and support its use in the first-line treatment of metastatic CRC.13 The results of the randomized phase III study of FOLFOX compared with capecitabine plus oxaliplatin ± bevacizumab in the first-line treatment are expected to be reported in late 2006. Cetuximab is active in epidermal growth factor receptor (EGFR) -expressing irinotecan refractory metastatic CRC.14,15 The combination of cetuximab with irinotecan was more active in this setting.16 Panitumumab, a human monoclonal antibody against EGFR, has also shown to be active in irinotecan- and oxaliplatin-refractory metastatic CRC.17 The response rate of the anti-EGFR antibodies in chemorefractory CRC is consistently around 10%. The combination of cetuximab plus irinotecan leads to an increased RR (23% v 11%) and time to tumor progression (TTP; 4.1% v 1.5%) compared with cetuximab alone in irinotecan-refractory CRC.16 With this information in mind, bevacizumab is often used in clinical practice in combination with an active cytotoxic regimen in the first-line treatment of metastatic CRC (FOLFIRI or FOLFOX) and cetuximab plus irinotecan in chemorefractory CRC, at least if patients are fit and if there are no contraindications for these therapeutic options. Many open questions and challenges remain in relation to the use of the anti-vascular endothelial growth factor (VEGF) and anti-EGFR antibodies in metastatic CRC. Answers are needed to optimize the outcome for patients and to develop more optimal use of resources. A crucial challenge is to demonstrate which patients are more likely to respond to bevacizumab-containing regimens and to the anti-EGFR antibodies cetuximab and panitumumab. Until now, large studies validating molecular markers that are useful in the prediction of response to anti-EGFR antibodies are not yet available in metastatic CRC.18 The clinical studies evaluating the activity of cetuximab and panitumumab have been carried out in EGFR-expressing tumors, as determined by immunohistochemistry. The intensity of EGFR immunostaining is not related to antitumor activity, and clinical benefit is also seen in patients whose tumors had no EGFR immunostaining. EGFR gene mutations have not been demonstrated to play a role in the response prediction in CRC. Although it has been reported in a small study that EGFR gene copy number, as assessed by fluorescence in situ hybridization, correlates with the propensity of CRC to respond to EGFR-directed antibodies, this finding is at the moment controversial.19 Studies looking at clinical, biochemical, and molecular markers for higher activity after treatment with bevacizumab failed also to show the usefulness of these markers in the discrimination of patients that will benefit more or less from bevacizumab-containing regimens. An analysis of predictive markers showed indeed that bevacizumab increased the activity of irinotecan plus FU/LV regardless of the level of VEGF expression, thrombospondin expression, and microvessel density.20 Mutations of k-ras, b-raf, and p53 could not predict for a prolonged survival on bevacizumab plus irinotecan plus bolus FU/LV.21 Molecular markers for response prediction are under intensive investigation, but it is unlikely that they will influence our daily clinical practice in the short term. Therefore, the data so far mainly suggest that the selection of patients that will benefit most from a bevacizumab-containing regimen should rely on the likelihood for an individual patient of developing toxicity and on efficacy as demonstrated in the larger studies. Therefore, tumor, serum, and plasma from patients with CRC have to be collected in prospective trials to look for markers for efficacy of the cytotoxics and of the biologics. A second important challenge is the strategic questions on the best combination, on the best sequence, and on the most optimal use of the different cytotoxic agents in combination with the biological agents in CRC. The study by Chen et al22 contributes to our knowledge, but leaves us with some unanswered questions. This large nonrandomized study shows that the combination of bevacizumab and a bolus regimen of FU/LV is not active enough in heavily pretreated, bevacizumab-naive patients to support the use of bevacizumab with bolus FU/LV in chemorefractory metastatic CRC. The question raised in this trial was certainly a legitimate question in view of the mechanism of action of the angiogenesis inhibitor bevacizumab and of the potentiation of the activity of the studied regimens in first- and second-line treatment of metastatic CRC by bevacizumab. However, in the studies in metastatic CRC in which the activity of bevacizumab was demonstrated, bevacizumab was combined with an active chemotherapy regimen. In the study by Chen et al bolus FU/LV is used in combination with bevacizumab. Bolus FU/LV is inactive in the setting of chemorefractory CRC. Moreover, bevacizumab monotherapy is not active in second-line CRC either. The reasons why bevacizumab increases the activity of a marginally active regimen of bolus FU/LV in the first-line treatment of metastatic CRC, and not of this same regimen in chemorefractory metastatic CRC, are not understood. It is clear that bevacizumab increases the activity of an active regimen in the first- and second-line treatment of CRC, but not of an inactive regimen in chemorefractory CRC and thus appears not to measurably reverse resistance to FU/LV. However, the anti-EGFR monoclonal antibody cetuximab reverses resistance when combined with irinotecan in irinotecan-refractory CRC and has also a single agent activity in this setting.16 Other recent promising data from a small randomized phase II trial have shown that bevacizumab when added to cetuximab or to cetuximab plus irinotecan has a high activity in chemorefractory CRC.23 Indeed, response rates were 37% and 20% and time to progression was 7.9 months and 5.6 months in irinotecan-refractory CRC for the combination of bevacizumab, cetuximab, and irinotecan and bevacizumab plus cetuximab, respectively.23 These appealing data for the doublets of biological agents in chemorefractory CRC have to be confirmed in larger studies. Data from several small phase II trials have shown a high RR, a long TTP, and a long median survival in the first-line treatment of metastatic CRC when cetuximab is combined with FU/LV plus irinotecan or FU/LV plus oxaliplatin.24,25 These clinical data, as well the preclinical data suggesting an at least additive effect of anti-VEGF and anti-EGFR antibodies, have led to the design of trials looking at the activity of bevacizumab plus cetuximab or panitumumab in combination with cytotoxic regimens, with the hope of further increasing the survival of patients with metastatic CRC. In the Cancer and Leukemia Group B trial 80405, the working hypothesis is to increase the median survival to 27.5 months with the combination of bevacizumab plus cetuximab and the cytotoxic regimen. Therefore, it will certainly be more important to look for the population or group of patients who benefit most from the combination of a doublet of biological agents, so that health resources can be used as rationally as possible. Another important clinical question in relation to the strategy of the biological agents that is not answered by the study of Chen et al,22 but that is under evaluation, is: should bevacizumab be continued following failure of a first-line combination, in combination with subsequent cytotoxic regimens? An important challenge is understanding the reason that tumors that initially respond to a combination of cytotoxics and biological agents may become resistant to this combination. In order to unravel the underlying causes, sequential tumor biopsies, serum, and plasma before, during, and after treatment have to be collected to look for molecular markers that can explain the cause of acquired resistance to the treatment. The only option to cure patients with metastatic CRC is the possibility of resection of metastatic disease. Resection of liver-only metastases has become a standard of care, with long-term survival in 25% to 35% of selected patients.26 Patients with initially unresectable metastases that are downsized to resectable metastases by systemic treatment have a similar chance of long-term survival after resection.27 It is important to determine in this setting the combination of cytotoxics and biological agents (single agent or doublets) with the highest likelihood of regression that may lead to resection of the metastases.28 Indeed, several new studies focus on the proportion of patients that will undergo resection after downsizing of initially unresectable liver metastases while being treated with one or two biological agents. Safety evaluation is important in this setting because it is actually unclear what the impact of angiogenesis inhibitors will be on postoperative complications, wound healing, and liver regeneration. New drugs interfering with the EGFR and with angiogenesis via VEGF or via other targets are under development. Many new agents acting on novel targets are under preclinical or early clinical development. Among the new promising classes of targeted agents in CRC are the insulin-like growth factor (IGF) inhibitors, the Src inhibitors, the mTOR inhibitors, and the histone deacetylase inhibitors. The systematic evaluation of these new classes of agents in CRC is important if we want to increase the survival of our patients with metastatic CRC. The hurdles for the demonstration of the activity of these new agents are increasing. This can probably only be solved through the precise understanding of the mechanisms of action and resistance of these drugs and especially through the selection of the patients with predictive molecular markers, who will be more likely to benefit from these new agents. A final challenge the society and the patient have to cope with is the rapidly increasing costs of the treatment of metastatic CRC. Here, also, a better selection of patients benefiting from the different treatment options is crucial. In conclusion, the biological agents have clearly increased the therapeutic armamentarium of patients with metastatic CRC and offer also prospects for an increased chance of a longer survival. Now the major challenge is to implement strategies in which patients can be selected based on molecular characteristics and/or pharmacogenomic profiles so that the new drugs and the resources can be used optimally for our patients with metastatic CRC. Author's Disclosures of Potential Conflicts of Interest
The author or immediate family members indicated a financial interest. No conflict exists for drugs or devices used in a study if they are not being evaluated as part of the investigation. 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.
Dollar Amount Codes (A) < $10,000 (B) $10,000-99,999 (C)
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Rothenberg M, Oza A, Bigelow R, et al: Superiority of oxaliplatin and fluorouracil-leucovorin compared with either therapy alone in patients with progressive colorectal cancer after irinotecan and fluorouracil-leucovorin: Interim results of a phase III trial. J Clin Oncol 21:2059-2069, 2003 6. Cunningham D, Pyrhonen S, James RD, et al: Randomised trial of irinotecan plus supportive care versus supportive care alone after fluorouracil failure for patients with metastatic colorectal cancer. Lancet 352:1413-1418, 1998[CrossRef][Medline] 7. Rougier P, Van Cutsem E, Bajetta E, et al: Randomised trial of irinotecan versus fluorouracil by continuous infusion after fluorouracil failure in patients with metastatic colorectal cancer. Lancet 352:1407-1412, 1998[CrossRef][Medline] 8. Hurwitz H, Fehrenbacher L, Novotny, et al: Bevacizumab plus irinotecan, fluorouracil, and leucovorin for metastatic colorectal cancer. N Engl J Med 350:2335-2342, 2004 9. Giantonio BJ, Catalano P, Meropol N, et al: High-dose bevacizumab improves survival when combined with FOLFOX4 in previously treated advanced colorectal cancer: Results from the Eastern Cooperative Oncology Group (ECOG) study E3200. J Clin Oncol 23: 1s, 2005 (abstr 2) 10. Kabbinavar F, Schulz J, McLeod, et al: Addition of bevacizumab to bolus flourouracil and leucovorin in first-line metastatic colorectal cancer: Results of a randomized phase II trial. J Clin Oncol 23:3697-3705, 2005 11. Hurwitz H, Fehrenbacher L, Hainsworth J, et al: Bevacizumab in combinatie with flourouracil and leucovorin: An active regimen for first-line metastatic colorectal cancer. J Clin Oncol 23:3502-3508, 2005 12. Kabbinavar F, Hambleton J, Mass R, et al: Combined analysis of efficacy: The addition of bevacizumab to fluorouracil/leucovorin improves survival for patients with metastatic colorectal cancer. J Clin Oncol 23:3706-3712, 2005 13. Hochster H, Hart R, Ramanathan J, et al: Results of the tree-2 cohort: Safety, tolerability, and efficacy of bevacizumab added to three oxaliplatin/fluoropyrimidine regimens as first-line treatment of metastatic colorectal cancer. American Society of Clinical Oncology Gastrointestinal Cancer Symposium, 2006 (abstr 244) 14. Saltz L, Meropol N, Loehrer P, et al: Phase II trial of cetuximab in patients with refractory colorectal cancer that expresses the epidermal growth factor receptor. J Clin Oncol 22:1201-1208, 2004 15. Lenz HJ, Mayer RJ, Gold PJ, et al: Activity of cetuximab in patients with colorectal cancer refractory to both irinotecan and oxaliplatin. J Clin Oncol 22:247s, 2004 (abstr 3510) 16. Cunningham D, Humblet Y, Siena S, et al: Cetuximab monotherapy and cetuximab plus irinotecan in irinotecan-refractory metastatic colorectal cancer. N Engl J Med 351:337-345, 2004 17. Malik I, Hecht J, Patnaik A, et al: Safety and efficacy of panitumumab monotherapy in patients with metastatic colorectal cancer. J Clin Oncol 23:251s, 2005 (abstr 3520) 18. Vallbohmer D, Zhang W, Gordon M, et al: Molecular determinants of cetuximab efficacy. J Clin Oncol 23:3536-3544, 2005 19. Moroni M, Veronese S, Benvenuti S, et al: Gene copy number for epidermal growth factor receptor (EGFR) and clinical response to antiEGFR treatment in colorectal cancer: A cohort study. Lancet Oncol 6:279-286, 2005[CrossRef][Medline] 20. Jubb A, Hurwitz H, Bai W, et al: Impact of vascular endothelial growth factor-A expression, thrombospondin-2 expression, and microvessel density on the treatment effect of bevacizumab in metastatic colorectal cancer. J Clin Oncol 24:217-227, 2006 21. Ince W, Jubb A, 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 22. Chen H, Mooney M, Boron M, et al: Multicenter phase II trial of bevacizumab plus fluorouracil and leucovorin in patients with advanced colorectal cancer that progressed after standard chemotherapy: NCI treatment referral center trial TRC-0301. J Clin Oncol 24:3354-3360, 2006 23. Saltz L, Lenz H, Hochster H, et al: Randomized phase II trial of cetuximab/bevacizumab/irinotecan (CBI) versus cetuximab/bevacizumab (CB) in irinotecan-refractory colorectal cancer. J Clin Oncol 23:248s, 2005 (abstr 3508) 24. Folprecht G, Lutz M, Schoffski P, et al: Cetuximab and irinotecan/5-fluorouracil/folinic acid is a safe combination for the first-line treatment of patients with epidermal growth factor receptor expressing metastatic colorectal carcinoma. Ann Oncol 17:450-456, 2006 25. Diaz-Rubio E, Tabernero J, Van Cutsem E, et al: Cetuximab in combination with oxaliplatin/5-fluorouracil (5-FU)/folinic acid (FA) (FOLFOX-4) in the first-line treatment of patients with epidermal growth factor receptor (EGFR)-expressing metastatic colorectal cancer: An international phase II study. J Clin Oncol 23:254s, 2005 (abstr 3535) 26. Fong Y, Cohen A, Fortner J, et al: Liver resection for colorectal metastases. J Clin Oncol 15:938-946, 1997 27. Adam R, Avisar E, Ariche A, et al: Five-year survival following hepatic resection after neoadjuvant therapy for nonresectable colorectal. Ann Surg Oncol 8:347-353, 2001 28. Folprecht G, Grothey A, Alberts S, et al: Neoadjuvant treatment of unresectable colorectal liver metastases: Correlation between tumour response and resection rates. Ann Oncol 16:1311-1319, 2005
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Copyright © 2006 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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