Adjuvant Therapy for Colon Cancer — The Pace Quickens
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《新英格兰医药杂志》
Every year in the United States, approximately 30,000 people receive the diagnosis of lymph-node–positive colon cancer (stage III); worldwide, the number approaches 200,000. The primary therapy for this condition is surgical resection, which cures 50 to 60 percent of patients with average-risk stage III disease.1,2 During the past 15 years, sequential advances in chemotherapy after surgical resection (adjuvant chemotherapy) have had an irrefutable and substantial benefit, with the 4-year rate of overall survival approaching 80 percent.3 In this issue of the Journal, Twelves and colleagues report on the Xeloda in Adjuvant Colon Cancer Therapy (X-ACT) trial, in which 1987 patients with stage III colon cancer were randomly assigned to adjuvant therapy with either bolus intravenous fluorouracil and leucovorin, given for 5 consecutive days every 28 days, or to oral capecitabine, given twice daily for 14 of every 21 days.4 Both regimens were given for a total of 24 weeks.
Capecitabine, an oral fluoropyrimidine, was approved in the United States in 2001 for the treatment of metastatic colorectal cancer. The direct comparison of bolus fluorouracil and leucovorin with capecitabine in two large randomized trials involving patients with metastatic colorectal cancer showed that the overall survival was equivalent with the two regimens.5 The convenience of oral administration, coupled with a favorable profile of toxic effects, formed a compelling basis for testing capecitabine in the adjuvant setting.
Fluorouracil has been the backbone of colorectal-cancer management for almost 50 years. Capecitabine, a prodrug, requires a multistep activation that culminates in its conversion to fluorouracil at the cellular level. Although the plasma half-life of fluorouracil is less than 10 minutes, the half-life of capecitabine is approximately 45 minutes; thus, twice-daily administration of capecitabine results in plasma levels that more closely resemble the levels achieved with protracted fluorouracil infusions than those obtained with daily or weekly bolus administration of fluorouracil. The small benefit of infusion over bolus administration of fluorouracil in advanced disease has not translated into an improved outcome in the adjuvant setting, where these two methods of fluorouracil delivery have similar efficacy.6,7
What about the efficacy of capecitabine in stage III colon cancer? On the basis of the similarity in efficacy of infusional and bolus therapy with fluorouracil in the adjuvant setting and the period of time in which the study was conducted, the choice of the control treatment, bolus fluorouracil and leucovorin, in the trial by Twelves and colleagues was appropriate. Despite the lack of central randomization, the demographic characteristics of the participants suggest that the two groups were well balanced. The rate of three-year disease-free survival in the control group (60.6 percent) is consistent with other reports of results with fluorouracil and leucovorin.3,6 The prospectively defined primary end point was disease-free survival, which is appropriate in the setting of adjuvant therapy for colon cancer; the upper limit of the hazard ratio of 1.20 for noninferiority was also appropriate.8 On the basis of these considerations, we can confidently conclude that capecitabine is at least equivalent to intravenous fluorouracil and leucovorin, with a P value excluding inferiority of P<0.001. Disease-free survival, relapse-free survival (as distinguished from disease-free survival by the exclusion of deaths from causes other than colon cancer), and overall survival all numerically favored capecitabine, with P values hovering close to 0.05. Although there is a suggestion that capecitabine may be superior to fluorouracil and leucovorin in stage III colon cancer, these data indicate that capecitabine is at least as efficacious as fluorouracil and leucovorin, as the authors have appropriately concluded.
Capecitabine had significantly less overall toxicity than bolus fluorouracil and leucovorin, with most of the difference attributable to a decrease in the incidence of neutropenia. A higher incidence of hyperbilirubinemia of uncertain clinical significance was noted with capecitabine, and as in previous trials in metastatic colorectal cancer, capecitabine was associated with an incidence of 17 percent of severe palmar–plantar erythrodysesthesia (hand–foot syndrome).
The starting dose of capecitabine (2500 mg per square meter of body-surface area given daily in two divided doses) in the study by Twelves et al. required a treatment modification in almost 60 percent of the patients. This dose of capecitabine, specified in the package insert, is generally felt to be poorly tolerated in the U.S. population, a situation that has led many oncologists in the United States to decrease the starting dose for most patients. The reason for the differential tolerance of capecitabine in the United States and other countries is unclear, but it may be related to the abundant supplementation of the U.S. diet with folic acid, a well-known enhancer of the toxicity of the fluoropyrimidines. The efficacy of capecitabine at doses typically given in the United States is critical, particularly in the adjuvant setting, where therapy is given with curative intent. Data in the present report should not be extrapolated to doses not tested, since efficacy at lower starting doses is unknown.
In the treatment of metastatic colorectal cancer, multiagent therapy has become the standard of care in the United States. This standard is based on studies that support the role of fluoropyrimidines and either oxaliplatin or irinotecan, an inhibitor of topoisomerase I, plus the antiangiogenic antibody bevacizumab.9,10 In the adjuvant setting, the recent Multicenter International Study of Oxaliplatin/5-Fluorouracil/Leucovorin in the Adjuvant Treatment of Colon Cancer (MOSAIC) trial and the National Surgical Adjuvant Breast and Bowel Project (NSABP) C-07 trial have demonstrated that adding oxaliplatin to a biweekly schedule of infused (MOSAIC) or weekly bolus (C-07) fluorouracil and leucovorin significantly prolongs disease-free survival in stage II and III colon cancer, as compared with leucovorin-modulated fluorouracil, with relative risk reductions of 23 percent and 21 percent, respectively.3,11 Table 1 shows the benefit for three-year disease-free survival of the addition of oxaliplatin to a fluoropyrimidine-based regimen among patients with phase III colon cancer. Randomized investigations comparing bolus or infusion schedules of fluorouracil, leucovorin, and irinotecan in patients with stage III colon cancer have not demonstrated the superiority over leucovorin-modulated fluorouracil.12,13
Table 1. Three-Year Disease-free Survival among Patients with Stage III Colon Cancer Treated with Adjuvant Chemotherapy.
Given the available data, where does capecitabine fit into the current management of locally advanced colon cancer? On the basis of convenience, efficacy, and favorable rates of toxic effects, capecitabine is an excellent choice when single-agent therapy is desired, provided that the treating physician is comfortable using the starting dose reported in the present investigation. The question of whether capecitabine should replace intravenous fluorouracil in multiagent adjuvant regimens, such as in combination with oxaliplatin, will not be answered until ongoing investigations have been completed. Meanwhile, current evidence favors combinations of oxaliplatin with intravenous fluorouracil and leucovorin as optimal adjuvant therapy.
Although chemotherapy in stage III colon cancer is a well-established standard, much controversy surrounds the use of chemotherapy in stage II disease. Given recent reports of a smaller but consistent therapeutic benefit seen with fluorouracil-based treatment in stage II disease,2,14 one could consider capecitabine as an option in patients with stage II disease. However, the present trial offers no guidance on this possibility, because it included only patients with stage III disease. A strategy of including patients with stage II or III disease in a clinical trial, as was done in the MOSAIC and NSABP trials, may be preferable in future investigations.
The prospects for a higher rate of cure in patients with locally advanced colon cancer are extremely promising, given the emerging evidence that supports therapeutic targeting of growth factors, growth-factor receptors, and downstream pathways. Both bevacizumab, a vascular endothelial growth factor antibody, and cetuximab, an endothelial growth factor–receptor antibody, have demonstrated benefit in advanced colorectal cancer.10,15 Their value in less advanced colon cancer is the subject of ongoing randomized investigations worldwide. Clearly, future investigations must identify specific patient populations that do not require postsurgical therapy as well as patients at high risk for relapse who may benefit from additional therapeutic intervention. The present state of generic therapy based on disease stage and histologic site of origin must give way to molecularly guided, personalized therapies, shifting the risk–benefit ratio of chemotherapeutic intervention toward an overwhelming individualized patient benefit — a goal clearly within our collective technological reach.
Source Information
From the Network for Medical Communication and Research, North Potomac, Md. (C.A.); and the Mayo Clinic Cancer Center, Rochester, Minn. (D.J.S.).
References
Moertel CG, Fleming TR, Macdonald JS, et al. Levamisole and fluorouracil for adjuvant therapy of resected colon carcinoma. N Engl J Med 1990;322:352-358.
Gill S, Loprinzi CL, Sargent DJ, et al. Pooled analysis of fluorouracil-based adjuvant therapy for stage II and III colon cancer: who benefits and by how much? J Clin Oncol 2004;22:1797-1806.
André T, Boni C, Mounedji-Boudiaf L, et al. Oxaliplatin, fluorouracil, and leucovorin as adjuvant treatment for colon cancer. N Engl J Med 2004;350:2343-2351.
Twelves C, Wong A, Nowacki MP, et al. Capecitabine as adjuvant treatment for stage III colon cancer. N Engl J Med 2005;352:2696-2704.
Van Cutsem E, Twelves C, Cassidy J, et al. Oral capecitabine compared with intravenous fluorouracil plus leucovorin in patients with metastatic colorectal cancer: results of a large phase III study. J Clin Oncol 2001;19:4097-4106.
Poplin EA, Benedetti JK, Estes NC, et al. Phase III Southwest Oncology Group 9415/Intergroup 0153 randomized trial of fluorouracil, leucovorin, and levamisole versus fluorouracil continuous infusion and levamisole for adjuvant treatment of stage III and high-risk stage II colon cancer. J Clin Oncol 2005;23:1819-1825.
André T, Colin P, Louvet C, et al. Semimonthly versus monthly regimen of fluorouracil and leucovorin administered for 24 or 36 weeks as adjuvant therapy in stage II and III colon cancer: results of a randomized trial. J Clin Oncol 2003;21:2896-2903.
Mayo Clinic. 3 Year DFS vs. 5 year OS as an endpoint for adjuvant colon cancer studies: data from randomized trials. (Accessed June 9, 2005, at http://www.fda.gov/cder/drug/cancer_endpoints/Sargent/index.htm.)
Goldberg RM, Sargent DJ, Morton RF, et al. A randomized controlled trial of fluorouracil plus leucovorin, irinotecan, and oxaliplatin combinations in patients with previously untreated metastatic colorectal cancer. J Clin Oncol 2004;22:23-30.
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.
Wolmark N, Wieand JP, Kuebler L, et al. A phase III trial comparing FULV to FULV + oxaliplatin in stage II or III carcinoma of the colon: results of NSABP protocol C-07. J Clin Oncol 2005;23:Suppl:252s-252s.(Carmen Allegra, M.D., and)
Capecitabine, an oral fluoropyrimidine, was approved in the United States in 2001 for the treatment of metastatic colorectal cancer. The direct comparison of bolus fluorouracil and leucovorin with capecitabine in two large randomized trials involving patients with metastatic colorectal cancer showed that the overall survival was equivalent with the two regimens.5 The convenience of oral administration, coupled with a favorable profile of toxic effects, formed a compelling basis for testing capecitabine in the adjuvant setting.
Fluorouracil has been the backbone of colorectal-cancer management for almost 50 years. Capecitabine, a prodrug, requires a multistep activation that culminates in its conversion to fluorouracil at the cellular level. Although the plasma half-life of fluorouracil is less than 10 minutes, the half-life of capecitabine is approximately 45 minutes; thus, twice-daily administration of capecitabine results in plasma levels that more closely resemble the levels achieved with protracted fluorouracil infusions than those obtained with daily or weekly bolus administration of fluorouracil. The small benefit of infusion over bolus administration of fluorouracil in advanced disease has not translated into an improved outcome in the adjuvant setting, where these two methods of fluorouracil delivery have similar efficacy.6,7
What about the efficacy of capecitabine in stage III colon cancer? On the basis of the similarity in efficacy of infusional and bolus therapy with fluorouracil in the adjuvant setting and the period of time in which the study was conducted, the choice of the control treatment, bolus fluorouracil and leucovorin, in the trial by Twelves and colleagues was appropriate. Despite the lack of central randomization, the demographic characteristics of the participants suggest that the two groups were well balanced. The rate of three-year disease-free survival in the control group (60.6 percent) is consistent with other reports of results with fluorouracil and leucovorin.3,6 The prospectively defined primary end point was disease-free survival, which is appropriate in the setting of adjuvant therapy for colon cancer; the upper limit of the hazard ratio of 1.20 for noninferiority was also appropriate.8 On the basis of these considerations, we can confidently conclude that capecitabine is at least equivalent to intravenous fluorouracil and leucovorin, with a P value excluding inferiority of P<0.001. Disease-free survival, relapse-free survival (as distinguished from disease-free survival by the exclusion of deaths from causes other than colon cancer), and overall survival all numerically favored capecitabine, with P values hovering close to 0.05. Although there is a suggestion that capecitabine may be superior to fluorouracil and leucovorin in stage III colon cancer, these data indicate that capecitabine is at least as efficacious as fluorouracil and leucovorin, as the authors have appropriately concluded.
Capecitabine had significantly less overall toxicity than bolus fluorouracil and leucovorin, with most of the difference attributable to a decrease in the incidence of neutropenia. A higher incidence of hyperbilirubinemia of uncertain clinical significance was noted with capecitabine, and as in previous trials in metastatic colorectal cancer, capecitabine was associated with an incidence of 17 percent of severe palmar–plantar erythrodysesthesia (hand–foot syndrome).
The starting dose of capecitabine (2500 mg per square meter of body-surface area given daily in two divided doses) in the study by Twelves et al. required a treatment modification in almost 60 percent of the patients. This dose of capecitabine, specified in the package insert, is generally felt to be poorly tolerated in the U.S. population, a situation that has led many oncologists in the United States to decrease the starting dose for most patients. The reason for the differential tolerance of capecitabine in the United States and other countries is unclear, but it may be related to the abundant supplementation of the U.S. diet with folic acid, a well-known enhancer of the toxicity of the fluoropyrimidines. The efficacy of capecitabine at doses typically given in the United States is critical, particularly in the adjuvant setting, where therapy is given with curative intent. Data in the present report should not be extrapolated to doses not tested, since efficacy at lower starting doses is unknown.
In the treatment of metastatic colorectal cancer, multiagent therapy has become the standard of care in the United States. This standard is based on studies that support the role of fluoropyrimidines and either oxaliplatin or irinotecan, an inhibitor of topoisomerase I, plus the antiangiogenic antibody bevacizumab.9,10 In the adjuvant setting, the recent Multicenter International Study of Oxaliplatin/5-Fluorouracil/Leucovorin in the Adjuvant Treatment of Colon Cancer (MOSAIC) trial and the National Surgical Adjuvant Breast and Bowel Project (NSABP) C-07 trial have demonstrated that adding oxaliplatin to a biweekly schedule of infused (MOSAIC) or weekly bolus (C-07) fluorouracil and leucovorin significantly prolongs disease-free survival in stage II and III colon cancer, as compared with leucovorin-modulated fluorouracil, with relative risk reductions of 23 percent and 21 percent, respectively.3,11 Table 1 shows the benefit for three-year disease-free survival of the addition of oxaliplatin to a fluoropyrimidine-based regimen among patients with phase III colon cancer. Randomized investigations comparing bolus or infusion schedules of fluorouracil, leucovorin, and irinotecan in patients with stage III colon cancer have not demonstrated the superiority over leucovorin-modulated fluorouracil.12,13
Table 1. Three-Year Disease-free Survival among Patients with Stage III Colon Cancer Treated with Adjuvant Chemotherapy.
Given the available data, where does capecitabine fit into the current management of locally advanced colon cancer? On the basis of convenience, efficacy, and favorable rates of toxic effects, capecitabine is an excellent choice when single-agent therapy is desired, provided that the treating physician is comfortable using the starting dose reported in the present investigation. The question of whether capecitabine should replace intravenous fluorouracil in multiagent adjuvant regimens, such as in combination with oxaliplatin, will not be answered until ongoing investigations have been completed. Meanwhile, current evidence favors combinations of oxaliplatin with intravenous fluorouracil and leucovorin as optimal adjuvant therapy.
Although chemotherapy in stage III colon cancer is a well-established standard, much controversy surrounds the use of chemotherapy in stage II disease. Given recent reports of a smaller but consistent therapeutic benefit seen with fluorouracil-based treatment in stage II disease,2,14 one could consider capecitabine as an option in patients with stage II disease. However, the present trial offers no guidance on this possibility, because it included only patients with stage III disease. A strategy of including patients with stage II or III disease in a clinical trial, as was done in the MOSAIC and NSABP trials, may be preferable in future investigations.
The prospects for a higher rate of cure in patients with locally advanced colon cancer are extremely promising, given the emerging evidence that supports therapeutic targeting of growth factors, growth-factor receptors, and downstream pathways. Both bevacizumab, a vascular endothelial growth factor antibody, and cetuximab, an endothelial growth factor–receptor antibody, have demonstrated benefit in advanced colorectal cancer.10,15 Their value in less advanced colon cancer is the subject of ongoing randomized investigations worldwide. Clearly, future investigations must identify specific patient populations that do not require postsurgical therapy as well as patients at high risk for relapse who may benefit from additional therapeutic intervention. The present state of generic therapy based on disease stage and histologic site of origin must give way to molecularly guided, personalized therapies, shifting the risk–benefit ratio of chemotherapeutic intervention toward an overwhelming individualized patient benefit — a goal clearly within our collective technological reach.
Source Information
From the Network for Medical Communication and Research, North Potomac, Md. (C.A.); and the Mayo Clinic Cancer Center, Rochester, Minn. (D.J.S.).
References
Moertel CG, Fleming TR, Macdonald JS, et al. Levamisole and fluorouracil for adjuvant therapy of resected colon carcinoma. N Engl J Med 1990;322:352-358.
Gill S, Loprinzi CL, Sargent DJ, et al. Pooled analysis of fluorouracil-based adjuvant therapy for stage II and III colon cancer: who benefits and by how much? J Clin Oncol 2004;22:1797-1806.
André T, Boni C, Mounedji-Boudiaf L, et al. Oxaliplatin, fluorouracil, and leucovorin as adjuvant treatment for colon cancer. N Engl J Med 2004;350:2343-2351.
Twelves C, Wong A, Nowacki MP, et al. Capecitabine as adjuvant treatment for stage III colon cancer. N Engl J Med 2005;352:2696-2704.
Van Cutsem E, Twelves C, Cassidy J, et al. Oral capecitabine compared with intravenous fluorouracil plus leucovorin in patients with metastatic colorectal cancer: results of a large phase III study. J Clin Oncol 2001;19:4097-4106.
Poplin EA, Benedetti JK, Estes NC, et al. Phase III Southwest Oncology Group 9415/Intergroup 0153 randomized trial of fluorouracil, leucovorin, and levamisole versus fluorouracil continuous infusion and levamisole for adjuvant treatment of stage III and high-risk stage II colon cancer. J Clin Oncol 2005;23:1819-1825.
André T, Colin P, Louvet C, et al. Semimonthly versus monthly regimen of fluorouracil and leucovorin administered for 24 or 36 weeks as adjuvant therapy in stage II and III colon cancer: results of a randomized trial. J Clin Oncol 2003;21:2896-2903.
Mayo Clinic. 3 Year DFS vs. 5 year OS as an endpoint for adjuvant colon cancer studies: data from randomized trials. (Accessed June 9, 2005, at http://www.fda.gov/cder/drug/cancer_endpoints/Sargent/index.htm.)
Goldberg RM, Sargent DJ, Morton RF, et al. A randomized controlled trial of fluorouracil plus leucovorin, irinotecan, and oxaliplatin combinations in patients with previously untreated metastatic colorectal cancer. J Clin Oncol 2004;22:23-30.
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.
Wolmark N, Wieand JP, Kuebler L, et al. A phase III trial comparing FULV to FULV + oxaliplatin in stage II or III carcinoma of the colon: results of NSABP protocol C-07. J Clin Oncol 2005;23:Suppl:252s-252s.(Carmen Allegra, M.D., and)