Progress With Biological Agents in Metastatic Colorectal Cancer Leads to Many Challenges
Authors: Eric Van Cutsem
Journal: Journal of Clinical Oncology (2006)

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. 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. Oxaliplatin plus FU/LV (FOLFOX) and irinotecan FU/LV are also active options in the second-line treatment of CRC. 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. 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. 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 firstline treatment of metastatic CRC and support its use in the firstline treatment of metastatic CRC. 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. The combination of cetuximab with irinotecan was more active in this setting. Panitumumab, a human monoclonal antibody against EGFR, has also shown to be active in irinotecanand oxaliplatin-refractory metastatic CRC. 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 irinotecanrefractory CRC. 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. 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. 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 bevacizumabcontaining 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. Mutations of k-ras, b-raf, and p53 could not predict for a prolonged survival on bevacizumab plus irinotecan plus bolus FU/LV. 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 bevacizumabcontaining 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 JOURNAL OF CLINICAL ONCOLOGY E D I T O R I A L VOLUME 24 NUMBER 21 JULY 2