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Recent Developments on the Integration of Biologic Agents with Cytotoxic Chemotherapy in the Treatment of Advanced Colorectal Cancer
Introduction Edward Chu, MD Yale University School of Medicine New Haven, CT
Clinical Colorectal Cancer, Vol. 7, Suppl, 2, S46, 2008 DOI: 10.3816/CCC.2008.s.006
Recent Developments on the Integration of Biologic Agents with Cytotoxic Chemotherapy in the Treatment of Advanced Colorectal Cancer Colorectal cancer (CRC) is a worldwide public health problem, with nearly 800,000 new cases diagnosed each year, resulting in approximately 500,000 deaths. In the United States, it is the second leading cause of cancer mortality, and nearly 60,000 deaths will be attributed to this disease in 2008. When diagnosed as advanced/metastatic disease, CRC is traditionally associated with a poor prognosis, with 5-year survival rates in the range of 5%-8%. This survival rate has remained unchanged over the past 35-40 years. However, during the past 5 years, significant advances have been made in treatment options so that improvements in 2-year survival are now being reported, with median survival rates in the 21-24 month range in patients with metastatic disease. Chemotherapy has been the mainstay approach for patients with metastatic CRC (mCRC). For nearly 40 years, the main drug used for this disease was the fluoropyrimidine 5-fluorouracil (5-FU). Since the late 1990s, there has been a marked increase in the number of agents that have been approved for CRC. The anticancer agents that have been approved by the US Food and Drug Administration (FDA) include the topoisomerase I inhibitor irinotecan, the third-generation platinum analogue oxaliplatin, and the oral fluoropyrimidine capecitabine. Since February 2004, 3 biologic agents have been approved by the US FDA, and they include the anti–vascular endothelial growth factor bevacizumab and the anti–epidermal growth factor receptor (EGFR) antibodies cetuximab and panitumumab. In this supplement issue of Clinical Colorectal Cancer, Andrea Cercek and Leonard Saltz present a timely overview on the recent advances in the first-line treatment of metastatic disease, with a focus on the integration of biologic, targeted agents with cytotoxic chemotherapy regimens. Specifically, the respective roles of bevacizumab and cetuximab in combination with oxaliplatin- and irinotecan-based regimens are discussed. The availability of several first-line combination regimens now makes it possible to consider tailoring therapies for individual patients based on patient preferences relating to oral versus intravenous medication, and toxicity profiles, as well as on results from pharmacogenomic analyses. John Marshall provides a nice review on the key issues involved in integrating surgical resection of metastatic disease with chemotherapy. He outlines the general principles that should guide clinicians as to when it would be appropriate to consider patients for surgery who initially present with metastatic disease. Clearly, the development of effective cytotoxic regimens along with the integration of biologic tar-
geted agents, namely bevacizumab and cetuximab, have helped advance this therapeutic strategy. Perhaps the area in which such a combinedmodality approach has received the greatest attention is in liver-limited metastatic disease. Steve Alberts reviews the growing body of literature which has helped to define the role of chemotherapy plus biologic agents for potentially resectable liver metastases as well as for initially unresectable liver metastases. The goal of such a neoadjuvant or conversion therapy is to begin to effect real, substantive cure of patients with mCRC because treatment of patients with liver-limited disease who undergo combined-modality treatment with chemotherapy plus biologic agents and surgical resection, followed by additional chemotherapy is now yielding 30%-50% 5-year survival rates. Finally, Ramos and colleagues review the predictive role of K-ras status for EGFR-targeted therapies in the treatment of mCRC. Although cetuximab was originally approved for use in EGFR-expressing mCRC, it has now been well established that EGFR expression, at least as determined by immunohistochemistry, cannot reliably predict which patients will or will not respond to anti-EGFR antibody therapy. So why has the K-ras pathway generated such a great deal of interest as it relates to anti-EGFR antibody therapy? This pathway functions downstream of the EGFR and, as such, it mediates EGFR signaling. If K-ras is constitutively turned on as it would be with mutations, then this would lead to dysregulated growth of the tumor and also to resistance to therapies that target the EGFR receptor, whether it be antibodies or small molecules. Based on the studies discussed by Ramos et al, it is clear that patients whose tumors express mutant K-ras derive virtually little to no benefit from anti-EGFR antibody therapy, whether it be cetuximab or panitumumab. The benefit of either one of these antibodies, alone or when used in combination with cytotoxic chemotherapy, is limited to patients with wild-type K-ras. Moreover, in the case of cetuximab, the benefit is observed across all lines of treatment. What’s exciting for those of us in the field is that K-ras is the first molecular biomarker for CRC that can help identify which patients will derive benefit from antiEGFR therapy to be used either alone or in combination with standard chemotherapeutic regimens and is a terrific first step in helping us to develop individualized, personalized medicine.
Edward Chu, MD Supplement Editor
Dr Chu has received research support from Amgen, Inc.; Bristol-Myers Squibb Company; ImClone Systems Incorporated; Pfizer Inc.; and Roche Pharmaceuticals, and has served as a Paid Consultant or been on the Advisory Board of Amgen, Inc.; Bristol-Myers Squibb Company; ImClone Systems Incorporated; Pfizer Inc.; Roche Pharmaceuticals; and sanofi-aventis U.S.
S46
• Clinical Colorectal Cancer December 2008
Clinical Colorectal Cancer, Vol. 7, Suppl, 2, S46, 2008 DOI: 10.3816/CCC.2008.s.006
Recent Developments on the Integration of Biologic Agents with Cytotoxic Chemotherapy in the Treatment of Advanced Colorectal Cancer Colorectal cancer (CRC) is a worldwide public health problem, with nearly 800,000 new cases diagnosed each year, resulting in approximately 500,000 deaths. In the United States, it is the second leading cause of cancer mortality, and nearly 60,000 deaths will be attributed to this disease in 2008. When diagnosed as advanced/metastatic disease, CRC is traditionally associated with a poor prognosis, with 5-year survival rates in the range of 5%-8%. This survival rate has remained unchanged over the past 35-40 years. However, during the past 5 years, significant advances have been made in treatment options so that improvements in 2-year survival are now being reported, with median survival rates in the 21-24 month range in patients with metastatic disease. Chemotherapy has been the mainstay approach for patients with metastatic CRC (mCRC). For nearly 40 years, the main drug used for this disease was the fluoropyrimidine 5-fluorouracil (5-FU). Since the late 1990s, there has been a marked increase in the number of agents that have been approved for CRC. The anticancer agents that have been approved by the US Food and Drug Administration (FDA) include the topoisomerase I inhibitor irinotecan, the third-generation platinum analogue oxaliplatin, and the oral fluoropyrimidine capecitabine. Since February 2004, 3 biologic agents have been approved by the US FDA, and they include the anti–vascular endothelial growth factor bevacizumab and the anti–epidermal growth factor receptor (EGFR) antibodies cetuximab and panitumumab. In this supplement issue of Clinical Colorectal Cancer, Andrea Cercek and Leonard Saltz present a timely overview on the recent advances in the first-line treatment of metastatic disease, with a focus on the integration of biologic, targeted agents with cytotoxic chemotherapy regimens. Specifically, the respective roles of bevacizumab and cetuximab in combination with oxaliplatin- and irinotecan-based regimens are discussed. The availability of several first-line combination regimens now makes it possible to consider tailoring therapies for individual patients based on patient preferences relating to oral versus intravenous medication, and toxicity profiles, as well as on results from pharmacogenomic analyses. John Marshall provides a nice review on the key issues involved in integrating surgical resection of metastatic disease with chemotherapy. He outlines the general principles that should guide clinicians as to when it would be appropriate to consider patients for surgery who initially present with metastatic disease. Clearly, the development of effective cytotoxic regimens along with the integration of biologic tar-
geted agents, namely bevacizumab and cetuximab, have helped advance this therapeutic strategy. Perhaps the area in which such a combinedmodality approach has received the greatest attention is in liver-limited metastatic disease. Steve Alberts reviews the growing body of literature which has helped to define the role of chemotherapy plus biologic agents for potentially resectable liver metastases as well as for initially unresectable liver metastases. The goal of such a neoadjuvant or conversion therapy is to begin to effect real, substantive cure of patients with mCRC because treatment of patients with liver-limited disease who undergo combined-modality treatment with chemotherapy plus biologic agents and surgical resection, followed by additional chemotherapy is now yielding 30%-50% 5-year survival rates. Finally, Ramos and colleagues review the predictive role of K-ras status for EGFR-targeted therapies in the treatment of mCRC. Although cetuximab was originally approved for use in EGFR-expressing mCRC, it has now been well established that EGFR expression, at least as determined by immunohistochemistry, cannot reliably predict which patients will or will not respond to anti-EGFR antibody therapy. So why has the K-ras pathway generated such a great deal of interest as it relates to anti-EGFR antibody therapy? This pathway functions downstream of the EGFR and, as such, it mediates EGFR signaling. If K-ras is constitutively turned on as it would be with mutations, then this would lead to dysregulated growth of the tumor and also to resistance to therapies that target the EGFR receptor, whether it be antibodies or small molecules. Based on the studies discussed by Ramos et al, it is clear that patients whose tumors express mutant K-ras derive virtually little to no benefit from anti-EGFR antibody therapy, whether it be cetuximab or panitumumab. The benefit of either one of these antibodies, alone or when used in combination with cytotoxic chemotherapy, is limited to patients with wild-type K-ras. Moreover, in the case of cetuximab, the benefit is observed across all lines of treatment. What’s exciting for those of us in the field is that K-ras is the first molecular biomarker for CRC that can help identify which patients will derive benefit from antiEGFR therapy to be used either alone or in combination with standard chemotherapeutic regimens and is a terrific first step in helping us to develop individualized, personalized medicine.
Edward Chu, MD Supplement Editor
Dr Chu has received research support from Amgen, Inc.; Bristol-Myers Squibb Company; ImClone Systems Incorporated; Pfizer Inc.; and Roche Pharmaceuticals, and has served as a Paid Consultant or been on the Advisory Board of Amgen, Inc.; Bristol-Myers Squibb Company; ImClone Systems Incorporated; Pfizer Inc.; Roche Pharmaceuticals; and sanofi-aventis U.S.
S46
• Clinical Colorectal Cancer December 2008