New Treatment Options for Colorectal Cancer
http://www.100md.com
《新英格兰医药杂志》
Epidermal growth factor receptor (EGFR) is a member of the HER family of tyrosine kinase cell-surface receptors that are dysregulated in many types of tumor; its expression has been associated with a poor prognosis in colon cancer.1 There are at least two opportunities to interfere with EGFR signaling that are being exploited clinically.2 In one approach, the extracellular receptor domain is bound by antibodies, such as cetuximab, that block ligand-mediated dimerization and subsequent activation of the receptor. In the second, the tyrosine kinase domain is bound by drugs that inhibit phosphorylation, such as gefitinib and erlotinib.
Irinotecan is a topoisomerase I inhibitor that has been approved for the treatment of metastatic colorectal cancer when given either alone or in combination with fluorouracil and leucovorin. Studies have shown that the addition of irinotecan to fluorouracil and leucovorin increases the objective response rate, the time to tumor progression, and overall survival.3,4
Cetuximab has been shown to enhance the antitumor activity of irinotecan in preclinical studies.5 The mechanism underlying this enhancement is unclear, but it may involve an antiapoptotic effect or the independent antiangiogenic effect of the inhibition of EGFR signaling. The experimental paradigm of combining agents that interfere with signaling pathways that make cells resistant to chemotherapy or agents that target a mechanism that independently influences tumor growth, such as angiogenesis, has been gaining traction in the clinical setting.6 In this issue of the Journal, Cunningham and colleagues7 report the results of a randomized trial of cetuximab monotherapy as compared with cetuximab and irinotecan in combination in a population of patients with advanced, irinotecan-refractory colorectal cancer. It is difficult to achieve a meaningful treatment benefit in such patients. Those in the study by Cunningham et al. were carefully selected, and their disease was independently confirmed as refractory to irinotecan. Thus, a meaningful interpretation of the results could be expected.
Although the trial was designed to assess the efficacy of cetuximab monotherapy and of cetuximab and irinotecan in combination, it implicitly addressed the question of whether adding cetuximab to irinotecan resensitizes tumors that are refractory to irinotecan. In that sense, the trial was a success, and the findings clearly support the notion that interfering with EGFR signaling can overcome the resistance to irinotecan. Nevertheless, the appropriateness of the authors' reporting methods warrants discussion. The primary end point of the trial was a tumor response, and the planned sample size was based not on a comparison of groups but on an estimation of the response rate to a specified level of precision. Thus, the trial could be best labeled as a randomized, phase 2 trial. However, the authors present multiple comparative analyses, including an analysis of overall survival, which was underpowered to detect a clinically meaningful difference (having less than 60 percent power to detect a two-month improvement in median survival).
In addition, two of Cunningham and colleagues' conclusions are perhaps overstated. First, they suggest single-agent cetuximab for those patients who may not be able to tolerate the combination. The toxicity profile of the single agent is sufficiently favorable to justify such a statement, but the response rate — 10.8 percent, with a median time to progression of 1.5 months — raises the question of the magnitude of the benefit. Furthermore, the population for whom the authors suggest single-agent therapy should be considered was not specifically studied in this trial. Second, the authors state, "Cetuximab compares favorably with oxaliplatin-based therapy in patients with irinotecan-refractory disease." The efficacy of oxaliplatin-based therapy in this setting has been established in a large, randomized, phase 3 trial8; cetuximab has not yet been subjected to such rigorous validation.
This trial raises several additional questions. The authors attempt to address the critical issue of whether EGFR expression is a predictive marker of a response. Although the investigators performed this analysis in a central laboratory and in a standardized manner, several caveats should be noted. The specimens examined may not have been representative of the tumor at the time of treatment, since they were obtained from primary tumors or at least one metastasis at some point but not necessarily at the time of the study treatment. The processing and handling of the original specimens were not standardized. If the specimens were not fixed within a short interval after collection, then catalytic degradation of cell-surface receptors may have altered protein expression. The antibody used to determine the expression of EGFR may recognize an epitope that differs from the one to which cetuximab binds. In such cases, a positive tumor may be negative in terms of cetuximab binding; conversely, cetuximab may not bind to a positively staining tumor. In the current trial, the sample for the analysis of whether a correlation existed was small, and no patients without EGFR expression were tested. Whether a post hoc analysis of EGFR mutations in the extracellular domain will identify a subgroup of patients who are more likely than others to have a response to cetuximab, as recently reported for gefitinib in patients with lung cancer,9 is an open question.
Finally, the authors present intriguing data suggesting that the response to cetuximab is associated with a rash. Among patients in whom a rash occurred, it developed within the first three weeks after the start of therapy in 89 percent of the patients, but in 23 percent a rash never developed, and thus the analysis becomes subject to bias. Patients must have been treated sufficiently long for the toxic effect to develop; rapid failures were likely to occur in the group of patients without a rash, biasing the results toward poor response rates in this group. Prolongation of the time to progression and moderate improvements in the rate of response to cetuximab therapy come at a price, as discussed by Schrag10 in a Perspective article, also in this issue of the Journal.
In essence, the current trial seems to validate the previously reported single-group studies of cetuximab alone and cetuximab plus irinotecan.11,12 For these reasons and others that have been well chronicled,13 the past three years have provided no mature data on cetuximab and irinotecan as first-line treatment or in combination with fluorouracil or fluorouracil-and-oxaliplatin regimens. Nonetheless, trials of cetuximab as a component of first-line treatment are ongoing, and the agent is about to be added to an ongoing trial of adjuvant therapy for colon cancer.
For patients with metastatic colorectal cancer, the past year has seen multiple new and promising treatment options. The addition of cetuximab in the armamentarium of treatment options for this group of patients must be tempered by the small advances that it offers in terms of the time to progression and the response rate and its uncertain effect on survival in patients with irinotecan-refractory cancer. The development of fully humanized antibodies to EGFR, such as EMD72000and ABX-EGF, holds the potential for further refinement of EGFR-targeted therapy. Finally, the addition of cetuximab to the initial treatment of metastatic colorectal cancer or in the adjuvant setting may increase its usefulness. The results of the trial by Cunningham et al. are only a first step toward defining the role of targeted therapy with the use of an antibody directed against EGFR in patients with colorectal cancer.
Source Information
From the Mayo Clinic, Rochester, Minn.
References
Grunwald V, Hidalgo M. Developing inhibitors of the epidermal growth factor receptor for cancer treatment. J Natl Cancer Inst 2003;95:851-867.
Thomas SM, Grandis JR. Pharmacokinetic and pharmacodynamic properties of EGFR inhibitors under clinical investigation. Cancer Treat Rev 2004;30:255-268.
Saltz LB, Cox JV, Blanke C, et al. Irinotecan plus fluorouracil and leucovorin for metastatic colorectal cancer. N Engl J Med 2000;343:905-914.
Douillard JY, Cunningham D, Roth AD, et al. Irinotecan combined with fluorouracil compared with fluorouracil alone as first-line treatment for metastatic colorectal cancer: a multicentre randomised trial. Lancet 2000;355:1041-1047.
Prewett MC, Hooper AT, Bassi R, Ellis LM, Waksal HW, Hicklin DJ. Enhanced antitumor activity of anti-epidermal growth factor receptor monoclonal antibody IMC-C225 in combination with irinotecan (CPT-11) against human colorectal tumor xenografts. Clin Cancer Res 2002;8:994-1003.
Hurwitz H, Fehrenbacher L, Novotny W, et al. Bevacizumab plus irinotecan, fluorouracil, and leucovorin for metastatic colorectal cancer. N Engl J Med 2004;350:2335-2342.
Cunningham D, Humblet Y, Siena S, et al. A randomised comparison of cetuximab monotherapy and cetuximab plus irinotecan in irinotecan-refractory metastatic colorectal cancer. N Engl J Med 2004;351:337-345.
Rothenberg ML, Oza AM, Bigelow RH, 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 2003;21:2059-2069.
Lynch TJ, Bell DW, Sordella R, et al. Activating mutations in the epidermal growth factor receptor underlying responsiveness of non-small-cell lung cancer to gefitinib. N Engl J Med 2004;350:2129-2139.
Schrag D. The price tag on progress -- chemotherapy for colorectal cancer. N Engl J Med 2004;351:317-319.
Saltz L, Rubin M, Hochster H, et al. Cetuximab (IMC-C225) plus irinotecan (CPT-11) is active in CPT-11-refractory colorectal cancer (CRC) that expresses epidermal growth factor receptor (EGFR). Prog Proc Am Soc Clin Oncol 2001;20:3a. abstract.
Saltz LB, Meropol NJ, Loehrer PJ Sr, Needle MN, Kopit J, Mayer RJ. Phase II trial of cetuximab in patients with refractory colorectal cancer that expresses the epidermal growth factor receptor. J Clin Oncol 2004;22:1201-1208.
Randal J. Erbitux trial flawed from the beginning, committee finds. J Natl Cancer Inst 2002;94:1824-1825.(Charles Erlichman, M.D., )
Irinotecan is a topoisomerase I inhibitor that has been approved for the treatment of metastatic colorectal cancer when given either alone or in combination with fluorouracil and leucovorin. Studies have shown that the addition of irinotecan to fluorouracil and leucovorin increases the objective response rate, the time to tumor progression, and overall survival.3,4
Cetuximab has been shown to enhance the antitumor activity of irinotecan in preclinical studies.5 The mechanism underlying this enhancement is unclear, but it may involve an antiapoptotic effect or the independent antiangiogenic effect of the inhibition of EGFR signaling. The experimental paradigm of combining agents that interfere with signaling pathways that make cells resistant to chemotherapy or agents that target a mechanism that independently influences tumor growth, such as angiogenesis, has been gaining traction in the clinical setting.6 In this issue of the Journal, Cunningham and colleagues7 report the results of a randomized trial of cetuximab monotherapy as compared with cetuximab and irinotecan in combination in a population of patients with advanced, irinotecan-refractory colorectal cancer. It is difficult to achieve a meaningful treatment benefit in such patients. Those in the study by Cunningham et al. were carefully selected, and their disease was independently confirmed as refractory to irinotecan. Thus, a meaningful interpretation of the results could be expected.
Although the trial was designed to assess the efficacy of cetuximab monotherapy and of cetuximab and irinotecan in combination, it implicitly addressed the question of whether adding cetuximab to irinotecan resensitizes tumors that are refractory to irinotecan. In that sense, the trial was a success, and the findings clearly support the notion that interfering with EGFR signaling can overcome the resistance to irinotecan. Nevertheless, the appropriateness of the authors' reporting methods warrants discussion. The primary end point of the trial was a tumor response, and the planned sample size was based not on a comparison of groups but on an estimation of the response rate to a specified level of precision. Thus, the trial could be best labeled as a randomized, phase 2 trial. However, the authors present multiple comparative analyses, including an analysis of overall survival, which was underpowered to detect a clinically meaningful difference (having less than 60 percent power to detect a two-month improvement in median survival).
In addition, two of Cunningham and colleagues' conclusions are perhaps overstated. First, they suggest single-agent cetuximab for those patients who may not be able to tolerate the combination. The toxicity profile of the single agent is sufficiently favorable to justify such a statement, but the response rate — 10.8 percent, with a median time to progression of 1.5 months — raises the question of the magnitude of the benefit. Furthermore, the population for whom the authors suggest single-agent therapy should be considered was not specifically studied in this trial. Second, the authors state, "Cetuximab compares favorably with oxaliplatin-based therapy in patients with irinotecan-refractory disease." The efficacy of oxaliplatin-based therapy in this setting has been established in a large, randomized, phase 3 trial8; cetuximab has not yet been subjected to such rigorous validation.
This trial raises several additional questions. The authors attempt to address the critical issue of whether EGFR expression is a predictive marker of a response. Although the investigators performed this analysis in a central laboratory and in a standardized manner, several caveats should be noted. The specimens examined may not have been representative of the tumor at the time of treatment, since they were obtained from primary tumors or at least one metastasis at some point but not necessarily at the time of the study treatment. The processing and handling of the original specimens were not standardized. If the specimens were not fixed within a short interval after collection, then catalytic degradation of cell-surface receptors may have altered protein expression. The antibody used to determine the expression of EGFR may recognize an epitope that differs from the one to which cetuximab binds. In such cases, a positive tumor may be negative in terms of cetuximab binding; conversely, cetuximab may not bind to a positively staining tumor. In the current trial, the sample for the analysis of whether a correlation existed was small, and no patients without EGFR expression were tested. Whether a post hoc analysis of EGFR mutations in the extracellular domain will identify a subgroup of patients who are more likely than others to have a response to cetuximab, as recently reported for gefitinib in patients with lung cancer,9 is an open question.
Finally, the authors present intriguing data suggesting that the response to cetuximab is associated with a rash. Among patients in whom a rash occurred, it developed within the first three weeks after the start of therapy in 89 percent of the patients, but in 23 percent a rash never developed, and thus the analysis becomes subject to bias. Patients must have been treated sufficiently long for the toxic effect to develop; rapid failures were likely to occur in the group of patients without a rash, biasing the results toward poor response rates in this group. Prolongation of the time to progression and moderate improvements in the rate of response to cetuximab therapy come at a price, as discussed by Schrag10 in a Perspective article, also in this issue of the Journal.
In essence, the current trial seems to validate the previously reported single-group studies of cetuximab alone and cetuximab plus irinotecan.11,12 For these reasons and others that have been well chronicled,13 the past three years have provided no mature data on cetuximab and irinotecan as first-line treatment or in combination with fluorouracil or fluorouracil-and-oxaliplatin regimens. Nonetheless, trials of cetuximab as a component of first-line treatment are ongoing, and the agent is about to be added to an ongoing trial of adjuvant therapy for colon cancer.
For patients with metastatic colorectal cancer, the past year has seen multiple new and promising treatment options. The addition of cetuximab in the armamentarium of treatment options for this group of patients must be tempered by the small advances that it offers in terms of the time to progression and the response rate and its uncertain effect on survival in patients with irinotecan-refractory cancer. The development of fully humanized antibodies to EGFR, such as EMD72000and ABX-EGF, holds the potential for further refinement of EGFR-targeted therapy. Finally, the addition of cetuximab to the initial treatment of metastatic colorectal cancer or in the adjuvant setting may increase its usefulness. The results of the trial by Cunningham et al. are only a first step toward defining the role of targeted therapy with the use of an antibody directed against EGFR in patients with colorectal cancer.
Source Information
From the Mayo Clinic, Rochester, Minn.
References
Grunwald V, Hidalgo M. Developing inhibitors of the epidermal growth factor receptor for cancer treatment. J Natl Cancer Inst 2003;95:851-867.
Thomas SM, Grandis JR. Pharmacokinetic and pharmacodynamic properties of EGFR inhibitors under clinical investigation. Cancer Treat Rev 2004;30:255-268.
Saltz LB, Cox JV, Blanke C, et al. Irinotecan plus fluorouracil and leucovorin for metastatic colorectal cancer. N Engl J Med 2000;343:905-914.
Douillard JY, Cunningham D, Roth AD, et al. Irinotecan combined with fluorouracil compared with fluorouracil alone as first-line treatment for metastatic colorectal cancer: a multicentre randomised trial. Lancet 2000;355:1041-1047.
Prewett MC, Hooper AT, Bassi R, Ellis LM, Waksal HW, Hicklin DJ. Enhanced antitumor activity of anti-epidermal growth factor receptor monoclonal antibody IMC-C225 in combination with irinotecan (CPT-11) against human colorectal tumor xenografts. Clin Cancer Res 2002;8:994-1003.
Hurwitz H, Fehrenbacher L, Novotny W, et al. Bevacizumab plus irinotecan, fluorouracil, and leucovorin for metastatic colorectal cancer. N Engl J Med 2004;350:2335-2342.
Cunningham D, Humblet Y, Siena S, et al. A randomised comparison of cetuximab monotherapy and cetuximab plus irinotecan in irinotecan-refractory metastatic colorectal cancer. N Engl J Med 2004;351:337-345.
Rothenberg ML, Oza AM, Bigelow RH, 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 2003;21:2059-2069.
Lynch TJ, Bell DW, Sordella R, et al. Activating mutations in the epidermal growth factor receptor underlying responsiveness of non-small-cell lung cancer to gefitinib. N Engl J Med 2004;350:2129-2139.
Schrag D. The price tag on progress -- chemotherapy for colorectal cancer. N Engl J Med 2004;351:317-319.
Saltz L, Rubin M, Hochster H, et al. Cetuximab (IMC-C225) plus irinotecan (CPT-11) is active in CPT-11-refractory colorectal cancer (CRC) that expresses epidermal growth factor receptor (EGFR). Prog Proc Am Soc Clin Oncol 2001;20:3a. abstract.
Saltz LB, Meropol NJ, Loehrer PJ Sr, Needle MN, Kopit J, Mayer RJ. Phase II trial of cetuximab in patients with refractory colorectal cancer that expresses the epidermal growth factor receptor. J Clin Oncol 2004;22:1201-1208.
Randal J. Erbitux trial flawed from the beginning, committee finds. J Natl Cancer Inst 2002;94:1824-1825.(Charles Erlichman, M.D., )