Two Steps Forward in the Treatment of Colorectal Cancer
http://www.100md.com
《新英格兰医药杂志》
Until recently, fluorouracil was the only effective systemic treatment for colorectal cancer. It acts primarily by inhibiting thymidylate synthase, a key enzyme in DNA synthesis, and because leucovorin (folinic acid) enhances this effect, fluorouracil and leucovorin (FL) are given together. FL has been given in various dose schedules, with a continuous infusion appearing slightly more effective than a bolus.1 FL reduces tumor size by 50 percent or more (objective response) in approximately 20 percent of patients with advanced colorectal cancer and prolongs median survival from approximately 6 months (without treatment) to about 11 months.2 When given as adjuvant therapy after the complete resection of a colon cancer that has spread to regional lymph nodes (stage III disease), FL increases the probability of remaining free of tumor (disease-free survival) at five years from approximately 42 percent to 58 percent and the likelihood of surviving for five years (overall five-year survival) from about 51 percent to 64 percent.3 The use of adjuvant FL in patients without involvement of regional lymph nodes (stage II disease) is controversial; for them, the probability of five-year disease-free survival increases from 72 percent to 76 percent after treatment, but the likelihood of overall survival is approximately 80 percent for treated and untreated patients alike.3
During the past five years, the Food and Drug Administration (FDA) has approved four new treatments for advanced colorectal cancer. Two of them (irinotecan [Camptosar] and oxaliplatin [Eloxatin]) are traditional cytotoxic drugs, whereas the other two (cetuximab [Erbitux] and bevacizumab [Avastin]) are monoclonal antibodies against molecular targets.
Irinotecan is an inhibitor of topoisomerase I, an enzyme involved in DNA repair. Oxaliplatin distorts DNA into adducts; its additional ability to reduce thymidylate synthase levels may explain its synergism with fluorouracil.4 Oxaliplatin frequently causes a sensory peripheral neuropathy, which is usually reversible. Studies involving patients with advanced colorectal cancer have shown that the addition of irinotecan to FL, given by bolus (IFL regimen)5 or infusion,6 or the addition of oxaliplatin to infusional FL7 increases the objective response rate from approximately 20 percent to about 40 percent and increases the time to tumor progression from four months to seven months. The benefits of these two approaches appear to be similar.8 Sequential exposure to various one- or two-drug combinations of fluorouracil, irinotecan, and oxaliplatin extends median overall survival to approximately 20 months.
Cetuximab is a monoclonal antibody against the epidermal growth factor receptor that, when activated, initiates intracellular signaling that evokes cellular proliferation. Cetuximab appears to be synergistic with irinotecan, even in irinotecan-resistant tumors. Experience with cetuximab in the treatment of colorectal cancer is presently limited to patients with advanced disease that is resistant to irinotecan. In this subgroup, the objective response rate with cetuximab alone is 10 percent, whereas the combination of cetuximab and irinotecan causes disease regression in approximately 22 percent of patients.9 Bevacizumab is a monoclonal antibody against vascular endothelial growth factor, a critical regulator of angiogenesis. A small clinical trial involving patients who had received no previous therapy for advanced colorectal cancer showed that the addition of bevacizumab to FL increased the response rate from 17 percent to 40 percent.10
This issue of the Journal contains reports of two large randomized trials, both designed by pharmaceutical-industry sponsors. One (the Multicenter International Study of Oxaliplatin/5-Fluorouracil/Leucovorin in the Adjuvant Treatment of Colon Cancer [MOSAIC]) deals with the benefit of adding oxaliplatin to FL as adjuvant therapy11; the other, by Hurwitz and colleagues, concerns the value of adding bevacizumab to IFL as initial treatment for metastatic disease.12 Both trials report positive results.
In the MOSAIC trial,11 André and colleagues enrolled 2246 patients — 40 percent of whom had stage II and 60 percent of whom had stage III disease — at 146 centers in 20 countries, stratified them according to surgical stage, and randomly assigned them to receive 12 fortnightly treatments (i.e., six months) of FL alone or combined with oxaliplatin. The last patient was enrolled in January 2001. Compliance with the protocol was excellent. Peripheral neuropathy was the main side effect of FL plus oxaliplatin, occurring in 92.1 percent of patients and classified as grade 3 in 12.4 percent of the patients receiving this treatment. The neurotoxic effects were generally reversible; 18 months after the completion of treatment with FL plus oxaliplatin, only 3.9 percent of patients had persistent grade 2 or 3 symptoms.
The authors emphasize that disease-free survival (rather than overall survival) was their primary objective. After 36 months, 78.2 percent of the patients given FL plus oxaliplatin were alive and free of disease, as compared with 72.9 percent of the FL group (P=0.002). This difference was far more evident among patients with stage III disease (72.2 percent vs. 65.3 percent) than among those with stage II tumors (87.0 percent vs. 84.3 percent). At the time of the analysis, there was no significant difference in estimated overall survival at three years between the group given FL plus oxaliplatin and the FL group (87.7 percent vs. 86.6 percent). The authors conclude that FL plus oxaliplatin is superior to FL alone.
The results of the MOSAIC study suggest a role for oxaliplatin in the adjuvant treatment of colorectal cancer. However, the data are preliminary, and the authors' conclusion is somewhat premature. It is disappointing that the cutoff date for the analysis was April 2003, more than 13 months ago. André et al. argue that disease-free survival rates after three years of follow-up accurately predict overall survival rates after five years and cite the results of a recent symposium to buttress their contention.13 Although this idea may turn out to be valid, until such time as it gains broader acceptance, there is simply no substitute for overall survival as the most convincing and meaningful end point in a trial of adjuvant therapy. With more than 40 months now having elapsed since the enrollment of the last patient, presumably definitive survival data should soon be available.
How might the data of André and coworkers now affect recommendations for the adjuvant treatment of colon cancer? In the absence of a relevant clinical trial, it seems reasonable to consider FL plus oxaliplatin strongly for high-risk patients with stage III cancers (e.g., more than three involved regional lymph nodes [N2] or tumor invasion beyond the serosa [T4 lesion]). The marginal and statistically nonsignificant difference between FL plus oxaliplatin and FL alone among patients with stage II disease argues against the use of oxaliplatin in this subgroup, especially in view of the drug's neurotoxicity; it remains unclear whether even FL should be offered to most of these patients. For patients with standard-risk stage III tumors (e.g., involvement of one to three regional lymph nodes), FL alone and FL with oxaliplatin are both reasonable choices.
In their trial assessing bevacizumab,12 Hurwitz and colleagues randomly assigned 813 patients who had received no previous therapy for metastatic colorectal cancer to receive IFL with either bevacizumab or a placebo. Overall survival was the primary end point. Compliance was also excellent in this study. The main side effect of bevacizumab was grade 3 hypertension (in 11.0 percent of patients). The study unequivocally demonstrated the superiority of IFL plus bevacizumab to IFL alone in terms of median overall survival (20.3 months vs. 15.6 months, P<0.001), the objective response rate (44.8 percent vs. 34.8 percent, P=0.004), and median progression-free survival (10.6 months vs. 6.2 months, P<0.001). The authors carefully conclude that the addition of bevacizumab increases the survival benefit afforded by IFL.
These impressive results appropriately led the FDA to approve the use of bevacizumab in patients with metastatic colorectal cancer. Yet, because this approval is based on a single clinical trial involving a single chemotherapy regimen, questions remain.
It is tempting to attribute the effect of bevacizumab to a direct antiangiogenic mechanism, which, in theory, would be similar when added to any form of chemotherapy. However, the validity of this assumption is presently uncertain. The benefit of adding bevacizumab to IFL as a treatment for metastatic colon cancer contrasts with its more limited value when added to FL for the initial treatment of colon cancer14 and its lack of benefit when added to an oral form of fluorouracil (capecitabine) as second-line therapy for breast cancer.15 The results of a large trial examining the impact of bevacizumab on FL plus oxaliplatin as second-line treatment for colorectal cancer have not yet been reported. Hurwitz et al. did not measure surrogate markers of antiangiogenesis,16 and they acknowledge that bevacizumab may have altered tumor vasculature and decreased elevated interstitial pressures in tumors,17 thereby enhancing the intracellular delivery of chemotherapy in general and — possibly — irinotecan in particular. How specific such a mechanism might be for irinotecan remains to be determined.
Much has been written about bevacizumab in the pages of financial and mass-media publications because of its perceived unique mechanism of activity. Such publicity has led to unrealistically high expectations. Patients need to be informed that bevacizumab does not cure metastatic colorectal cancer and that there is no evidence as yet that the antibody has antitumor activity when administered as a single agent for this disease. Rather, bevacizumab is an additional and welcome tool that can be incorporated into at least one combination of chemotherapy — IFL — resulting in a definite and encouraging extension of median survival by 4.7 months.
Such a prolongation of survival comes at a price. Treating a patient who weighs 80 kg with the dose of 5 mg per kilogram of body weight used by Hurwitz et al. for a median of 40.4 weeks (i.e., 20 doses) would add from $42,800 (given a cost of $2,140 per 400-mg vial of IFL) to $55,000 (given a cost of $2,750 per 400-mg vial) to the cost of noncurative care for advanced colorectal cancer, depending on the type of purchasing contract for the drug. Since the FDA granted a surprisingly broad indication for the use of bevacizumab (i.e., together with any fluorouracil-based combination, not just IFL, when given as first-line therapy), the antibody could be prescribed for most patients with advanced colorectal cancer. With approximately 30,000 to 40,000 such patients identified annually in the United States, the fiscal impact of the FDA's approval could exceed $1.5 billion each year.
Progress in the management of colorectal cancer has been rapid during the past five years. The development of novel treatments has drawn the attention of physicians and patients alike and has created a host of different management options from which to choose. The acceptance of these new options into standard care should be based on mature data and carefully defined indications. Clinical trials to address these important issues are under way.
Source Information
From the Dana–Farber Cancer Institute, Boston.
References
Efficacy of intravenous continuous infusion of fluorouracil compared with bolus administration in advanced colorectal cancer. J Clin Oncol 1998;16:301-308.
Palliative chemotherapy for advanced or metastatic colorectal cancer. Cochrane Database Syst Rev 2000;2:CD001545-CD001545.
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.
Raymond E, Faivre S, Chaney S, Woynarowski J, Cvitkovic E. Cellular and molecular pharmacology of oxaliplatin. Mol Cancer Ther 2002;1:227-235.
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.
de Gramont A, Figer A, Seymour M, et al. Leucovorin and fluorouracil with or without oxaliplatin as first-line treatment in advanced colorectal cancer. J Clin Oncol 2000;18:2938-2947.
Tournigand C, Andre T, Achille E, et al. FOLFIRI followed by FOLFOX6 or the reverse sequence in advanced colorectal cancer: a randomized GERCOR study. J Clin Oncol 2004;22:229-237.
Cunningham D, Humblet Y, Siena S, et al. Cetuximab (C225) alone or in combination with irinotecan (CPT-11) in patients with epidermal growth factor receptor (EGFR)-positive, irinotecan-refractory metastatic colorectal cancer (MCRC). Prog Proc Am Soc Clin Oncol 2003;22:252. abstract.
Kabbinavar F, Hurwitz HI, Fehrenbacher L, et al. Phase II, randomized trial comparing bevacizumab plus fluorouracil (FU)/leucovorin (LV) with FU/LV alone in patients with metastatic colorectal cancer. J Clin Oncol 2003;21:60-65.
André T, Boni C, Mounedji-Boudiaf L, et al. Oxaliplatin, 5-fluorouracil, and leucovorin as adjuvant treatment for colon cancer. N Engl J Med 2004;350:2343-2351.
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.
Mayo Clinic. 3 Year DFS vs. 5 year OS as an endpoint for adjuvant colon cancer studies: data from randomized trials. (Accessed May 13, 2004, at http://www.fda.gov/cder/drug/cancer_endpoints/Sargent/index.htm.)
Pollack A. Genentech's cancer drug falls short in a second round of tests. New York Times. November 26, 2003:C3.
Miller KD, Rugo HS, Cobleigh MA, et al. Phase III trial of capecitabine (Xeloda) plus bevacizumab (Avastin) versus capecitabine alone in women with metastatic breast cancer (MBC) previously treated with an anthracycline and a taxane. Breast Cancer Res Treat 2002;76:Suppl 1:S37-S37. abstract.
Davis DW, McConkey DJ, Abbruzzese JL, Herbst RS. Surrogate markers in antiangiogenesis clinical trials. Br J Cancer 2003;89:8-14.
Jain RK. Normalizing tumor vasculature with anti-angiogenic therapy: a new paradigm for combination therapy. Nat Med 2001;7:987-989.(Robert J. Mayer, M.D.)
During the past five years, the Food and Drug Administration (FDA) has approved four new treatments for advanced colorectal cancer. Two of them (irinotecan [Camptosar] and oxaliplatin [Eloxatin]) are traditional cytotoxic drugs, whereas the other two (cetuximab [Erbitux] and bevacizumab [Avastin]) are monoclonal antibodies against molecular targets.
Irinotecan is an inhibitor of topoisomerase I, an enzyme involved in DNA repair. Oxaliplatin distorts DNA into adducts; its additional ability to reduce thymidylate synthase levels may explain its synergism with fluorouracil.4 Oxaliplatin frequently causes a sensory peripheral neuropathy, which is usually reversible. Studies involving patients with advanced colorectal cancer have shown that the addition of irinotecan to FL, given by bolus (IFL regimen)5 or infusion,6 or the addition of oxaliplatin to infusional FL7 increases the objective response rate from approximately 20 percent to about 40 percent and increases the time to tumor progression from four months to seven months. The benefits of these two approaches appear to be similar.8 Sequential exposure to various one- or two-drug combinations of fluorouracil, irinotecan, and oxaliplatin extends median overall survival to approximately 20 months.
Cetuximab is a monoclonal antibody against the epidermal growth factor receptor that, when activated, initiates intracellular signaling that evokes cellular proliferation. Cetuximab appears to be synergistic with irinotecan, even in irinotecan-resistant tumors. Experience with cetuximab in the treatment of colorectal cancer is presently limited to patients with advanced disease that is resistant to irinotecan. In this subgroup, the objective response rate with cetuximab alone is 10 percent, whereas the combination of cetuximab and irinotecan causes disease regression in approximately 22 percent of patients.9 Bevacizumab is a monoclonal antibody against vascular endothelial growth factor, a critical regulator of angiogenesis. A small clinical trial involving patients who had received no previous therapy for advanced colorectal cancer showed that the addition of bevacizumab to FL increased the response rate from 17 percent to 40 percent.10
This issue of the Journal contains reports of two large randomized trials, both designed by pharmaceutical-industry sponsors. One (the Multicenter International Study of Oxaliplatin/5-Fluorouracil/Leucovorin in the Adjuvant Treatment of Colon Cancer [MOSAIC]) deals with the benefit of adding oxaliplatin to FL as adjuvant therapy11; the other, by Hurwitz and colleagues, concerns the value of adding bevacizumab to IFL as initial treatment for metastatic disease.12 Both trials report positive results.
In the MOSAIC trial,11 André and colleagues enrolled 2246 patients — 40 percent of whom had stage II and 60 percent of whom had stage III disease — at 146 centers in 20 countries, stratified them according to surgical stage, and randomly assigned them to receive 12 fortnightly treatments (i.e., six months) of FL alone or combined with oxaliplatin. The last patient was enrolled in January 2001. Compliance with the protocol was excellent. Peripheral neuropathy was the main side effect of FL plus oxaliplatin, occurring in 92.1 percent of patients and classified as grade 3 in 12.4 percent of the patients receiving this treatment. The neurotoxic effects were generally reversible; 18 months after the completion of treatment with FL plus oxaliplatin, only 3.9 percent of patients had persistent grade 2 or 3 symptoms.
The authors emphasize that disease-free survival (rather than overall survival) was their primary objective. After 36 months, 78.2 percent of the patients given FL plus oxaliplatin were alive and free of disease, as compared with 72.9 percent of the FL group (P=0.002). This difference was far more evident among patients with stage III disease (72.2 percent vs. 65.3 percent) than among those with stage II tumors (87.0 percent vs. 84.3 percent). At the time of the analysis, there was no significant difference in estimated overall survival at three years between the group given FL plus oxaliplatin and the FL group (87.7 percent vs. 86.6 percent). The authors conclude that FL plus oxaliplatin is superior to FL alone.
The results of the MOSAIC study suggest a role for oxaliplatin in the adjuvant treatment of colorectal cancer. However, the data are preliminary, and the authors' conclusion is somewhat premature. It is disappointing that the cutoff date for the analysis was April 2003, more than 13 months ago. André et al. argue that disease-free survival rates after three years of follow-up accurately predict overall survival rates after five years and cite the results of a recent symposium to buttress their contention.13 Although this idea may turn out to be valid, until such time as it gains broader acceptance, there is simply no substitute for overall survival as the most convincing and meaningful end point in a trial of adjuvant therapy. With more than 40 months now having elapsed since the enrollment of the last patient, presumably definitive survival data should soon be available.
How might the data of André and coworkers now affect recommendations for the adjuvant treatment of colon cancer? In the absence of a relevant clinical trial, it seems reasonable to consider FL plus oxaliplatin strongly for high-risk patients with stage III cancers (e.g., more than three involved regional lymph nodes [N2] or tumor invasion beyond the serosa [T4 lesion]). The marginal and statistically nonsignificant difference between FL plus oxaliplatin and FL alone among patients with stage II disease argues against the use of oxaliplatin in this subgroup, especially in view of the drug's neurotoxicity; it remains unclear whether even FL should be offered to most of these patients. For patients with standard-risk stage III tumors (e.g., involvement of one to three regional lymph nodes), FL alone and FL with oxaliplatin are both reasonable choices.
In their trial assessing bevacizumab,12 Hurwitz and colleagues randomly assigned 813 patients who had received no previous therapy for metastatic colorectal cancer to receive IFL with either bevacizumab or a placebo. Overall survival was the primary end point. Compliance was also excellent in this study. The main side effect of bevacizumab was grade 3 hypertension (in 11.0 percent of patients). The study unequivocally demonstrated the superiority of IFL plus bevacizumab to IFL alone in terms of median overall survival (20.3 months vs. 15.6 months, P<0.001), the objective response rate (44.8 percent vs. 34.8 percent, P=0.004), and median progression-free survival (10.6 months vs. 6.2 months, P<0.001). The authors carefully conclude that the addition of bevacizumab increases the survival benefit afforded by IFL.
These impressive results appropriately led the FDA to approve the use of bevacizumab in patients with metastatic colorectal cancer. Yet, because this approval is based on a single clinical trial involving a single chemotherapy regimen, questions remain.
It is tempting to attribute the effect of bevacizumab to a direct antiangiogenic mechanism, which, in theory, would be similar when added to any form of chemotherapy. However, the validity of this assumption is presently uncertain. The benefit of adding bevacizumab to IFL as a treatment for metastatic colon cancer contrasts with its more limited value when added to FL for the initial treatment of colon cancer14 and its lack of benefit when added to an oral form of fluorouracil (capecitabine) as second-line therapy for breast cancer.15 The results of a large trial examining the impact of bevacizumab on FL plus oxaliplatin as second-line treatment for colorectal cancer have not yet been reported. Hurwitz et al. did not measure surrogate markers of antiangiogenesis,16 and they acknowledge that bevacizumab may have altered tumor vasculature and decreased elevated interstitial pressures in tumors,17 thereby enhancing the intracellular delivery of chemotherapy in general and — possibly — irinotecan in particular. How specific such a mechanism might be for irinotecan remains to be determined.
Much has been written about bevacizumab in the pages of financial and mass-media publications because of its perceived unique mechanism of activity. Such publicity has led to unrealistically high expectations. Patients need to be informed that bevacizumab does not cure metastatic colorectal cancer and that there is no evidence as yet that the antibody has antitumor activity when administered as a single agent for this disease. Rather, bevacizumab is an additional and welcome tool that can be incorporated into at least one combination of chemotherapy — IFL — resulting in a definite and encouraging extension of median survival by 4.7 months.
Such a prolongation of survival comes at a price. Treating a patient who weighs 80 kg with the dose of 5 mg per kilogram of body weight used by Hurwitz et al. for a median of 40.4 weeks (i.e., 20 doses) would add from $42,800 (given a cost of $2,140 per 400-mg vial of IFL) to $55,000 (given a cost of $2,750 per 400-mg vial) to the cost of noncurative care for advanced colorectal cancer, depending on the type of purchasing contract for the drug. Since the FDA granted a surprisingly broad indication for the use of bevacizumab (i.e., together with any fluorouracil-based combination, not just IFL, when given as first-line therapy), the antibody could be prescribed for most patients with advanced colorectal cancer. With approximately 30,000 to 40,000 such patients identified annually in the United States, the fiscal impact of the FDA's approval could exceed $1.5 billion each year.
Progress in the management of colorectal cancer has been rapid during the past five years. The development of novel treatments has drawn the attention of physicians and patients alike and has created a host of different management options from which to choose. The acceptance of these new options into standard care should be based on mature data and carefully defined indications. Clinical trials to address these important issues are under way.
Source Information
From the Dana–Farber Cancer Institute, Boston.
References
Efficacy of intravenous continuous infusion of fluorouracil compared with bolus administration in advanced colorectal cancer. J Clin Oncol 1998;16:301-308.
Palliative chemotherapy for advanced or metastatic colorectal cancer. Cochrane Database Syst Rev 2000;2:CD001545-CD001545.
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.
Raymond E, Faivre S, Chaney S, Woynarowski J, Cvitkovic E. Cellular and molecular pharmacology of oxaliplatin. Mol Cancer Ther 2002;1:227-235.
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.
de Gramont A, Figer A, Seymour M, et al. Leucovorin and fluorouracil with or without oxaliplatin as first-line treatment in advanced colorectal cancer. J Clin Oncol 2000;18:2938-2947.
Tournigand C, Andre T, Achille E, et al. FOLFIRI followed by FOLFOX6 or the reverse sequence in advanced colorectal cancer: a randomized GERCOR study. J Clin Oncol 2004;22:229-237.
Cunningham D, Humblet Y, Siena S, et al. Cetuximab (C225) alone or in combination with irinotecan (CPT-11) in patients with epidermal growth factor receptor (EGFR)-positive, irinotecan-refractory metastatic colorectal cancer (MCRC). Prog Proc Am Soc Clin Oncol 2003;22:252. abstract.
Kabbinavar F, Hurwitz HI, Fehrenbacher L, et al. Phase II, randomized trial comparing bevacizumab plus fluorouracil (FU)/leucovorin (LV) with FU/LV alone in patients with metastatic colorectal cancer. J Clin Oncol 2003;21:60-65.
André T, Boni C, Mounedji-Boudiaf L, et al. Oxaliplatin, 5-fluorouracil, and leucovorin as adjuvant treatment for colon cancer. N Engl J Med 2004;350:2343-2351.
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.
Mayo Clinic. 3 Year DFS vs. 5 year OS as an endpoint for adjuvant colon cancer studies: data from randomized trials. (Accessed May 13, 2004, at http://www.fda.gov/cder/drug/cancer_endpoints/Sargent/index.htm.)
Pollack A. Genentech's cancer drug falls short in a second round of tests. New York Times. November 26, 2003:C3.
Miller KD, Rugo HS, Cobleigh MA, et al. Phase III trial of capecitabine (Xeloda) plus bevacizumab (Avastin) versus capecitabine alone in women with metastatic breast cancer (MBC) previously treated with an anthracycline and a taxane. Breast Cancer Res Treat 2002;76:Suppl 1:S37-S37. abstract.
Davis DW, McConkey DJ, Abbruzzese JL, Herbst RS. Surrogate markers in antiangiogenesis clinical trials. Br J Cancer 2003;89:8-14.
Jain RK. Normalizing tumor vasculature with anti-angiogenic therapy: a new paradigm for combination therapy. Nat Med 2001;7:987-989.(Robert J. Mayer, M.D.)