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Irinotecan in 5-Fluorouracil—Refractory Colorectal Cancer
Commentary Irinotecan in 5-Fluorouracil–Refractory Colorectal Cancer Romano Danesi Antonello Di Paolo Division of Pharmacology and Chemotherapy Department of Oncology University of Pisa, Italy
Over the past few years, it has become widely accepted that palliative chemotherapy can improve survival and quality of life for patients with metastatic colorectal cancer, a leading cause of cancer morbidity and mortality. In particular, the early use of chemotherapy in asymptomatic patients prolongs both symptom-free survival and overall survival.1 Chemotherapy is also being used in symptomatic patients, and in this issue of Clinical Colorectal Cancer, Michael and colleagues provide evidence that, when administered to patients with advanced colorectal cancer refractory to 5-fluorouracil (5-FU), irinotecan provides substantial palliative benefit at a higher rate than expected from the radiological response, mainly by improving pain score and reducing analgesic consumption.2 Optimal Treatment Approaches for Colorectal Cancer The first issue that is raised by this study relates to defining the optimal agent and/or treatment approach in patients with 5-FU–resistant colorectal cancer. Previous studies have addressed this point. Patients with advanced colorectal cancer with proven 5-FU resistance were treated every 4 weeks with folinic acid 200 mg/m2 followed by a 5-FU 400-mg/m2 bolus injection, then 5-FU 600 mg/m2 by continuous infusion on days 1 and 2 every 2 weeks administered alternately with 180 mg/m2 irinotecan on day 1 and 85 mg/m2 oxaliplatin on day 15 versus oxaliplatin 85 mg/m2 and irinotecan 200 mg/m2 every 3 weeks. Two partial responses, lasting 10.7 and 16 months, were observed with the first regimen, and 7 partial responses (median duration, 11 months) were observed with the second regimen. Median overall survival times
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were 9.8 and 12.3 months, respectively, in the first versus the second regimen, and severe toxicities were, respectively, neutropenia (53% and 47%), febrile neutropenia (13% and 3%), diarrhea (19% and 10%), vomiting (6% and 13%), and neurosensory (3% in each arm).3 Additional schedules of treatment were examined in patients affected by colorectal cancer with documented progression ≤ 6 months following chemotherapy with 5-FU or other thymidylate synthase inhibitors. The administration of oxaliplatin 100 mg/m2 every 2 weeks and a protracted venous infusion of 5-FU 300 mg/ m2/day produced an objective tumor response rate of 29% and disease stabilization in 52.6% (20 patients). The median duration of response was 3.9 months, and patients who had previously received both 5-FU and irinotecan experienced a partial response (27.3%) with oxaliplatin and 5-FU. Most patients were symptomatic (pain, anorexia, and lethargy) on entry into the study; a symptomatic improvement after treatment was observed in most cases. Grade 3/4 toxicities were anemia (10.6%), neutropenia (2.6%), thrombocytopenia (5.2%), diarrhea (18.9%), nausea and vomiting (2.7%), infection (5.4%), and lethargy (37.8%). Median survival was 9.1 months.4 The clinical benefit of irinotecan 350 mg/m2 once every 3 weeks was also assessed in patients with 5-FU–resistant metastatic colorectal cancer; the response rate was 13.7%, lasting a median of 8.5 months, and stable disease was observed in 44.2% with a median duration of 4.8 months. Most importantly, there was weight stabilization or weight gain in 81% of patients, an improvement in performance status in 91%, and pain relief in 54%. Neutropenia was short-lasting and noncumulative; severe diarrhea occurred in 7% of cycles and in 26% of patients.5 Finally, protracted infusion of 5-FU 300 mg/m2/24 hours plus bolus mitomycin 7 mg/m2 every 6 weeks adminis-
tered to patients with metastatic colorectal cancer resistant to 5-FU resulted in a 12.5% partial response rate; minor response or stable disease was observed in 42% patients, with a median overall survival of 9.0 months and no severe drug-related toxicity, although 33% of patients required a dose reduction and/or interruption for persistent grade 2 toxicity.6 Various treatment regimens have been shown to have clinical benefit in the palliative setting. Since cytotoxic chemotherapy has clinical activity after 5-FU failure, the most significant predictive parameters for tumor response, progression-free survival and toxicity, were investigated in patients with 5FU–resistant metastatic colorectal carcinoma in order to select patients who were likely to benefit from this approach. Normal baseline hemoglobin level, time since diagnosis of colorectal carcinoma, grade 3/4 neutropenia or diarrhea at first cycle, and a low number of organs involved were the most predictive factors for tumor growth control. Significant prognostic variables for progression-free survival were performance status, liver and lymph node involvement, time since diagnosis, age, and carcinoembryonic antigen. In addition to this, baseline bilirubin, hemoglobin level, number of organs involved, and time from diagnosis were predictive factors for neutropenia while performance status, serum creatinine, leukocyte count, time from 5-FU progression, and prior abdominopelvic irradiation were predictive factors for delayed diarrhea.7 At the molecular level, alterations that were associated with resistance to 5-FU, including high activity/expression of thymidylate synthase,8 dihydropyrimidine dehydrogenase, and nuclear dUTP hydrolase, did not influence the molecular markers of irinotecan activity, including the expression/ activity of topoisomerase I and that of the carboxylesterase-converting enzyme.9 Although there is a general agreement on the potential clinical efficacy
of administering irinotecan-based chemotherapy in patients with 5FU–resistant disease, the percentage of patients who experience benefit from this potentially toxic treatment may be variable, and drug-induced toxicity may be significant. Therefore, the following question remains: What is the next class of agents for the treatment of these critically ill patients? Whether classical cytotoxic agents are the drugs of choice for the treatment of symptomatic subjects with poor performance status and advanced, drug-resistant disease is still a matter of discussion. In this setting, novel agents with well-defined molecular targets and a low toxicity profile would be ideal. The development of cyclooxygenase-2 (COX-2) inhibitors and small molecules and antibodies directed against the epidermal growth factor receptor (EGFR) signaling pathway represent promising avenues of research. Early evidence suggests that the COX2 isoform is critical in the pathogenesis of colorectal cancer because it is undetectable in a normal colon but is significantly upregulated in the majority of colon carcinomas.10 COX-2 inhibitors such as celecoxib have fewer side effects than traditional nonsteroidal antiinflammatory drugs but retain the ability to induce cell cycle arrest and apoptosis in tumor cell lines and inhibit the processes of angiogenesis and metasta-
sis.11 Finally, inhibition of the EGFR signaling pathway may represent a powerful strategy for treating colorectal cancer because there is increased expression of EGFR in 70%-80% of all colorectal tumors. Both antibodies directed against the EGFR and small molecules targeting the EGFR-associated tyrosine kinase are being developed as single agents and in combination with standard cytotoxic agents.12 Conclusion The present data underscore the importance of relieving disease-associated symptoms and improving qualityof-life parameters in patients in the palliative setting. Unfortunately, symptomatic patients with advanced disease are potentially more likely to experience the adverse side-effects associated with chemotherapy, and in this setting, the risks may outweigh any benefits of treatment. These are clinically relevant issues that the practicing physician must address, and the development and investigation of novel therapeutic strategies is strongly encouraged to provide optimal palliative relief to our patients with advanced colorectal cancer. 01. Tebbutt NC, Cattell E, Midgley R, et al. Systemic treatment of colorectal cancer. Eur J Cancer 2002; 38:1000-1015. 02. Michael M, Moore MJ, Hedley D, et al. The palliative benefit of irinotecan in 5-FU–refractory colorectal cancer: its prospective evaluation by a multi-
center Canadian trial. Clin Colorectal Cancer 2002; 2:93-101. 03. Becouarn Y, Gamelin E, Coudert B, et al. Randomized multicenter phase II study comparing a combination of fluorouracil and folinic acid and alternating irinotecan and oxaliplatin with oxaliplatin and irinotecan in fluorouracil-pretreated metastatic colorectal cancer patients. J Clin Oncol 2001; 19:41954201. 04. Chau I, Webb A, Cunningham D, et al. Oxaliplatin and protracted venous infusion of 5-fluorouracil in patients with advanced or relapsed 5-fluorouracil pretreated colorectal cancer. Br J Cancer 2001; 85:1258-1264. 05. Van Cutsem E, Cunningham D, Ten Bokkel Huinink WW, et al. Clinical activity and benefit of irinotecan (CPT-11) in patients with colorectal cancer truly resistant to 5-fluorouracil (5-FU). Eur J Cancer 1999; 35:54-59. 06. Chester JD, Dent JT, Wilson G, et al. Protracted infusional 5-fluorouracil (5-FU) with bolus mitomycin in 5-FU-resistant colorectal cancer. Ann Oncol 2000; 11:235-237. 07. Freyer G, Rougier P, Bugat R, et al. Prognostic factors for tumour response, progression-free survival and toxicity in metastatic colorectal cancer patients given irinotecan (CPT-11) as second-line chemotherapy after 5FU failure. CPT-11 F205, F220, F221 and V222 study groups. Br J Cancer 2000; 83:431437. 08. Shirota Y, Stoehlmacher J, Brabender J, et al. ERCC1 and thymidylate synthase mRNA levels predict survival for colorectal cancer patients receiving combination oxaliplatin and fluorouracil chemotherapy. J Clin Oncol 2001; 19:4298-4304. 09. Danesi R, De Braud F, Fogli S, et al. Pharmacogenetic determinants of anti-cancer drug activity and toxicity. Trends Pharmacol Sci 2001; 22:420-426. 10. Soslow RA, Dannenberg AJ, Rush D, et al. COX-2 is expressed in human pulmonary, colonic, and mammary tumors. Cancer 2000; 89:2637-2645. 11. Elder DJ, Halton DE, Crew TE, et al. Apoptosis induction and cyclooxygenase-2 regulation in human colorectal adenoma and carcinoma cell lines by the cyclooxygenase-2-selective non-steroidal anti-inflammatory drug NS-398. Int J Cancer 2000; 86:553-560. 12. Sirotnak FM, Zakowski MF, Miller VA, et al. Efficacy of cytotoxic agents against human tumor xenografts is markedly enhanced by coadministration of ZD1839 (Iressa), an inhibitor of EGFR tyrosine kinase. Clin Cancer Res 2000; 6:4885-4892.
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Over the past few years, it has become widely accepted that palliative chemotherapy can improve survival and quality of life for patients with metastatic colorectal cancer, a leading cause of cancer morbidity and mortality. In particular, the early use of chemotherapy in asymptomatic patients prolongs both symptom-free survival and overall survival.1 Chemotherapy is also being used in symptomatic patients, and in this issue of Clinical Colorectal Cancer, Michael and colleagues provide evidence that, when administered to patients with advanced colorectal cancer refractory to 5-fluorouracil (5-FU), irinotecan provides substantial palliative benefit at a higher rate than expected from the radiological response, mainly by improving pain score and reducing analgesic consumption.2 Optimal Treatment Approaches for Colorectal Cancer The first issue that is raised by this study relates to defining the optimal agent and/or treatment approach in patients with 5-FU–resistant colorectal cancer. Previous studies have addressed this point. Patients with advanced colorectal cancer with proven 5-FU resistance were treated every 4 weeks with folinic acid 200 mg/m2 followed by a 5-FU 400-mg/m2 bolus injection, then 5-FU 600 mg/m2 by continuous infusion on days 1 and 2 every 2 weeks administered alternately with 180 mg/m2 irinotecan on day 1 and 85 mg/m2 oxaliplatin on day 15 versus oxaliplatin 85 mg/m2 and irinotecan 200 mg/m2 every 3 weeks. Two partial responses, lasting 10.7 and 16 months, were observed with the first regimen, and 7 partial responses (median duration, 11 months) were observed with the second regimen. Median overall survival times
102 • Clinical Colorectal Cancer August 2002
were 9.8 and 12.3 months, respectively, in the first versus the second regimen, and severe toxicities were, respectively, neutropenia (53% and 47%), febrile neutropenia (13% and 3%), diarrhea (19% and 10%), vomiting (6% and 13%), and neurosensory (3% in each arm).3 Additional schedules of treatment were examined in patients affected by colorectal cancer with documented progression ≤ 6 months following chemotherapy with 5-FU or other thymidylate synthase inhibitors. The administration of oxaliplatin 100 mg/m2 every 2 weeks and a protracted venous infusion of 5-FU 300 mg/ m2/day produced an objective tumor response rate of 29% and disease stabilization in 52.6% (20 patients). The median duration of response was 3.9 months, and patients who had previously received both 5-FU and irinotecan experienced a partial response (27.3%) with oxaliplatin and 5-FU. Most patients were symptomatic (pain, anorexia, and lethargy) on entry into the study; a symptomatic improvement after treatment was observed in most cases. Grade 3/4 toxicities were anemia (10.6%), neutropenia (2.6%), thrombocytopenia (5.2%), diarrhea (18.9%), nausea and vomiting (2.7%), infection (5.4%), and lethargy (37.8%). Median survival was 9.1 months.4 The clinical benefit of irinotecan 350 mg/m2 once every 3 weeks was also assessed in patients with 5-FU–resistant metastatic colorectal cancer; the response rate was 13.7%, lasting a median of 8.5 months, and stable disease was observed in 44.2% with a median duration of 4.8 months. Most importantly, there was weight stabilization or weight gain in 81% of patients, an improvement in performance status in 91%, and pain relief in 54%. Neutropenia was short-lasting and noncumulative; severe diarrhea occurred in 7% of cycles and in 26% of patients.5 Finally, protracted infusion of 5-FU 300 mg/m2/24 hours plus bolus mitomycin 7 mg/m2 every 6 weeks adminis-
tered to patients with metastatic colorectal cancer resistant to 5-FU resulted in a 12.5% partial response rate; minor response or stable disease was observed in 42% patients, with a median overall survival of 9.0 months and no severe drug-related toxicity, although 33% of patients required a dose reduction and/or interruption for persistent grade 2 toxicity.6 Various treatment regimens have been shown to have clinical benefit in the palliative setting. Since cytotoxic chemotherapy has clinical activity after 5-FU failure, the most significant predictive parameters for tumor response, progression-free survival and toxicity, were investigated in patients with 5FU–resistant metastatic colorectal carcinoma in order to select patients who were likely to benefit from this approach. Normal baseline hemoglobin level, time since diagnosis of colorectal carcinoma, grade 3/4 neutropenia or diarrhea at first cycle, and a low number of organs involved were the most predictive factors for tumor growth control. Significant prognostic variables for progression-free survival were performance status, liver and lymph node involvement, time since diagnosis, age, and carcinoembryonic antigen. In addition to this, baseline bilirubin, hemoglobin level, number of organs involved, and time from diagnosis were predictive factors for neutropenia while performance status, serum creatinine, leukocyte count, time from 5-FU progression, and prior abdominopelvic irradiation were predictive factors for delayed diarrhea.7 At the molecular level, alterations that were associated with resistance to 5-FU, including high activity/expression of thymidylate synthase,8 dihydropyrimidine dehydrogenase, and nuclear dUTP hydrolase, did not influence the molecular markers of irinotecan activity, including the expression/ activity of topoisomerase I and that of the carboxylesterase-converting enzyme.9 Although there is a general agreement on the potential clinical efficacy
of administering irinotecan-based chemotherapy in patients with 5FU–resistant disease, the percentage of patients who experience benefit from this potentially toxic treatment may be variable, and drug-induced toxicity may be significant. Therefore, the following question remains: What is the next class of agents for the treatment of these critically ill patients? Whether classical cytotoxic agents are the drugs of choice for the treatment of symptomatic subjects with poor performance status and advanced, drug-resistant disease is still a matter of discussion. In this setting, novel agents with well-defined molecular targets and a low toxicity profile would be ideal. The development of cyclooxygenase-2 (COX-2) inhibitors and small molecules and antibodies directed against the epidermal growth factor receptor (EGFR) signaling pathway represent promising avenues of research. Early evidence suggests that the COX2 isoform is critical in the pathogenesis of colorectal cancer because it is undetectable in a normal colon but is significantly upregulated in the majority of colon carcinomas.10 COX-2 inhibitors such as celecoxib have fewer side effects than traditional nonsteroidal antiinflammatory drugs but retain the ability to induce cell cycle arrest and apoptosis in tumor cell lines and inhibit the processes of angiogenesis and metasta-
sis.11 Finally, inhibition of the EGFR signaling pathway may represent a powerful strategy for treating colorectal cancer because there is increased expression of EGFR in 70%-80% of all colorectal tumors. Both antibodies directed against the EGFR and small molecules targeting the EGFR-associated tyrosine kinase are being developed as single agents and in combination with standard cytotoxic agents.12 Conclusion The present data underscore the importance of relieving disease-associated symptoms and improving qualityof-life parameters in patients in the palliative setting. Unfortunately, symptomatic patients with advanced disease are potentially more likely to experience the adverse side-effects associated with chemotherapy, and in this setting, the risks may outweigh any benefits of treatment. These are clinically relevant issues that the practicing physician must address, and the development and investigation of novel therapeutic strategies is strongly encouraged to provide optimal palliative relief to our patients with advanced colorectal cancer. 01. Tebbutt NC, Cattell E, Midgley R, et al. Systemic treatment of colorectal cancer. Eur J Cancer 2002; 38:1000-1015. 02. Michael M, Moore MJ, Hedley D, et al. The palliative benefit of irinotecan in 5-FU–refractory colorectal cancer: its prospective evaluation by a multi-
center Canadian trial. Clin Colorectal Cancer 2002; 2:93-101. 03. Becouarn Y, Gamelin E, Coudert B, et al. Randomized multicenter phase II study comparing a combination of fluorouracil and folinic acid and alternating irinotecan and oxaliplatin with oxaliplatin and irinotecan in fluorouracil-pretreated metastatic colorectal cancer patients. J Clin Oncol 2001; 19:41954201. 04. Chau I, Webb A, Cunningham D, et al. Oxaliplatin and protracted venous infusion of 5-fluorouracil in patients with advanced or relapsed 5-fluorouracil pretreated colorectal cancer. Br J Cancer 2001; 85:1258-1264. 05. Van Cutsem E, Cunningham D, Ten Bokkel Huinink WW, et al. Clinical activity and benefit of irinotecan (CPT-11) in patients with colorectal cancer truly resistant to 5-fluorouracil (5-FU). Eur J Cancer 1999; 35:54-59. 06. Chester JD, Dent JT, Wilson G, et al. Protracted infusional 5-fluorouracil (5-FU) with bolus mitomycin in 5-FU-resistant colorectal cancer. Ann Oncol 2000; 11:235-237. 07. Freyer G, Rougier P, Bugat R, et al. Prognostic factors for tumour response, progression-free survival and toxicity in metastatic colorectal cancer patients given irinotecan (CPT-11) as second-line chemotherapy after 5FU failure. CPT-11 F205, F220, F221 and V222 study groups. Br J Cancer 2000; 83:431437. 08. Shirota Y, Stoehlmacher J, Brabender J, et al. ERCC1 and thymidylate synthase mRNA levels predict survival for colorectal cancer patients receiving combination oxaliplatin and fluorouracil chemotherapy. J Clin Oncol 2001; 19:4298-4304. 09. Danesi R, De Braud F, Fogli S, et al. Pharmacogenetic determinants of anti-cancer drug activity and toxicity. Trends Pharmacol Sci 2001; 22:420-426. 10. Soslow RA, Dannenberg AJ, Rush D, et al. COX-2 is expressed in human pulmonary, colonic, and mammary tumors. Cancer 2000; 89:2637-2645. 11. Elder DJ, Halton DE, Crew TE, et al. Apoptosis induction and cyclooxygenase-2 regulation in human colorectal adenoma and carcinoma cell lines by the cyclooxygenase-2-selective non-steroidal anti-inflammatory drug NS-398. Int J Cancer 2000; 86:553-560. 12. Sirotnak FM, Zakowski MF, Miller VA, et al. Efficacy of cytotoxic agents against human tumor xenografts is markedly enhanced by coadministration of ZD1839 (Iressa), an inhibitor of EGFR tyrosine kinase. Clin Cancer Res 2000; 6:4885-4892.
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