TAC — A New Standard in Adjuvant Therapy for Breast Cancer?
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《新英格兰医药杂志》
Chemotherapy, an integral component of adjuvant treatment for women with resected node-positive breast cancer, improves disease-free and overall survival in many patients. Older regimens include such combinations as cyclophosphamide, methotrexate, and fluorouracil; doxorubicin and cyclophosphamide; fluorouracil, doxorubicin, and cyclophosphamide given in various doses and according to various schedules; and fluorouracil, epirubicin, and cyclophosphamide, among others. Standards of care continue to evolve, owing to the availability of new drugs and data from innovative clinical trials that have tested different combinations of existing and new agents.
The taxanes (docetaxel and paclitaxel) have emerged as potent agents for the adjuvant treatment of early breast cancer; studies involving more than 20,000 patients have been reported or are ongoing. In this issue of the Journal, Martin and colleagues give an account of one such study, the Breast Cancer International Research Group 001 trial, which represents an advance in the treatment of breast cancer.1 The trial was a phase 3 randomized comparison of six cycles of docetaxel, doxorubicin, and cyclophosphamide (TAC) with six cycles of fluorouracil, doxorubicin, and cyclophosphamide (FAC). It is important to examine carefully whether the data from this study justify the consideration of TAC as a new standard — or even the new standard — of adjuvant therapy for resected node-positive breast cancer. Factors to consider include the clinical relevance of the differences in efficacy between TAC and FAC, the tolerability of the two regimens, the suitability of the control group in terms of the current standard of care, and the results of this trial in the context of other studies involving adjuvant taxane therapy.
The statistical and clinical relevance of the differences in disease-free and overall survival supports the use of TAC in place of the older FAC regimen.1 With a median follow-up period of 55 months, the disease-free survival rate was 75 percent among patients receiving TAC as compared with 68 percent for those receiving FAC, with a hazard ratio of 0.72 (P=0.001). The estimated overall survival rate at five years was 87 percent for TAC and 81 percent for FAC, with a hazard ratio of 0.70 (P=0.008). These results are clinically significant and in the same range as other recently reported results of randomized trials that compared older with newer regimens in the setting of adjuvant treatment.
Tolerability was worse with TAC than with FAC, with a 36.3 percent rate of severe nonhematologic toxic effects (including severe asthenia and stomatitis), as compared with the 26.6 percent rate with FAC.1 There were also more hematologic toxic effects with TAC: 24.7 percent of patients in the TAC group had febrile neutropenia (despite the prophylactic use of antibiotics and the introduction of growth-factor support after the first episode of febrile neutropenia or infection), as compared with 2.2 percent in the FAC group, and 4.6 percent of patients in the TAC group required blood transfusions, as compared with 1.5 percent in the FAC group. Among the patients in the two groups, 97 percent completed the six cycles of FAC, and 91 percent received the prespecified six cycles of TAC. Another critical point is that the Breast Cancer International Research Group 001 trial was restricted to women who were 70 years of age or younger, making it impossible to assess the benefit and tolerability in older patients. An additional issue is that the cardiac safety of TAC used concurrently with trastuzumab has not been evaluated; thus, its use may be limited in patients with HER2-positive breast cancer.
The validity of FAC as the control treatment is a more complex question. FAC was a reasonable choice during the treatment period of 1995 to 1998, but this may not be the case in 2005. The FAC regimen tested by Martin et al. delivered 30 percent less of the fluorouracil and cyclophosphamide doses per cycle (with a cumulative doxorubicin dose of 300 mg per square meter of body-surface area) than did another "standard" regimen involving the same agents (cyclophosphamide, doxorubicin, and fluorouracil, with a cumulative dose of doxorubicin of 360 mg per square meter). Cumulative doses of doxorubicin of 240 to 360 mg per square meter have, however, been accepted as appropriate for patients in the control groups of other trials involving adjuvant therapy.2,3,4 We can only speculate as to whether the FAC regimen used in this trial is inferior to that involving other doses and delivery schedules of cyclophosphamide, doxorubicin, and fluorouracil, since data from randomized studies comparing these regimens are lacking.
Since 1998, the standard of care for patients with node-positive breast cancer in the United States and other parts of the world has been treatment with doxorubicin and cyclophosphamide followed by the taxane paclitaxel. This treatment regimen was based on an intergroup study demonstrating that the addition of paclitaxel to doxorubicin and cyclophosphamide led to rates of disease-free survival of 70 percent and overall survival of 80 percent at five years, as compared with 65 percent and 77 percent, respectively, for doxorubicin and cyclophosphamide alone, with modest differences in the rate of toxic effects.2 This regimen was first administered on a schedule of once every three weeks and then, more recently, once every two weeks, after a comparative trial demonstrated improved efficacy (a 7 percent absolute improvement in disease-free survival and a 2 percent improvement in overall survival at three years) with the schedule involving more frequent administration (referred to as dose-dense therapy).4 Thus, investigators who would initiate a randomized trial of the adjuvant treatment of node-positive breast cancer in 2005 would choose not FAC but another taxane-containing regimen as the control.
Whether the ratio of efficacy to toxicity for TAC warrants the general use of this combination for the adjuvant treatment of breast cancer remains a compelling question. Some important facts must be kept in mind: there are many other studies to be considered, with important differences in numbers of patients enrolled, median ages, menopausal status, rates of estrogen-receptor positivity, and use or nonuse of hormonal treatments. All studies that have evaluated the addition of a taxane to an anthracycline-based regimen have demonstrated improvements in disease-free survival, overall survival, or both, except for the recently reported National Surgical Adjuvant Breast and Bowel Project trial B-27.5,6 This study showed that treatment with doxorubicin and cyclophosphamide followed by docetaxel did not improve rates of disease-free or overall survival among patients with early breast cancer, a surprising result in light of the positive results of other large trials involving taxanes. These exceptions and differences illustrate the difficulty inherent in cross-study comparisons and the problems encountered when large-scale studies that take years to complete are conducted in an area in which standards of care can change. Several other trials have been designed to optimize the role of taxanes in the adjuvant-therapy setting, including new schedules of the same agents, the addition of other chemotherapy drugs, the introduction of targeted biologic agents, and the integration of molecular predictors of response.7,8,9,10,11
In conclusion, on the basis of the available data, one can consider TAC to be a standard of care, as is the dose-dense regimen of doxorubicin and cyclophosphamide followed by paclitaxel, for patients with resected node-positive breast cancer. However, the exclusion of patients older than 70 years and the toxic effects associated with TAC in the Breast Cancer International Research Group trial cannot be minimized. With this regimen, prophylactic growth-factor support is necessary to ameliorate myelosuppression and febrile neutropenia. A recommendation for the selection of one regimen over the other must await completion of the prospective National Surgical Adjuvant Breast and Bowel Project trial B-38, for which the accrual of data is expected to be complete in the next few years.8 Although standards of care will continue to evolve as the results of these trials become available, we must offer our patients with node-positive breast cancer the therapies that have already been demonstrated to improve disease-free and overall survival, as compared with older regimens such as those involving cyclophosphamide, methotrexate, and fluorouracil; FAC in previously administered doses and delivery schedules; or doxorubicin and cyclophosphamide. This means adjuvant treatment with TAC or with a regimen of doxorubicin and cyclophosphamide followed by paclitaxel, or participation in a clinical trial.
Source Information
From the Mayo Clinic, Jacksonville, Fla.
References
Martin M, Pienkowski T, Mackey J, et al. Adjuvant docetaxel for node-positive breast cancer. N Engl J Med 2005;352:2302-2313.
Henderson IC, Berry DA, Demetri GD, et al. Improved outcomes from adding sequential paclitaxel but not from escalating doxorubicin dose in an adjuvant chemotherapy regimen for patients with node-positive primary breast cancer. J Clin Oncol 2003;21:976-983.
Mamounas EP, Bryant J, Lembersky C, et al. Paclitaxel (T) following doxorubicin/cyclophosphamide (AC) as adjuvant chemotherapy for node-positive breast cancer: results from NSABP B-28. Proc Am Soc Clin Oncol 2003;22:4. abstract.
Citron ML, Berry DA, Cirrincione C, et al. Randomized trial of dose-dense versus conventionally scheduled and sequential versus concurrent combination chemotherapy as postoperative adjuvant treatment of node-positive primary breast cancer: first report of Intergroup Trial C9741/Cancer and Leukemia Group B Trial 9741. J Clin Oncol 2003;21:1431-1439.
Perez E. Adjuvant therapy approaches to breast cancer: should taxanes be incorporated? Curr Oncol Rep 2003;5:66-71.
Bear HD, Anderson S, Smith RE, et al. A randomized trial comparing preoperative (preop) doxorubicin/cyclophosphamide (AC) to preop AC followed by preop docetaxel (T) and to preop AC followed by postoperative (postop) T in patients (pts) with operable carcinoma of the breast: results of NSABP B-27. Breast Cancer Res Treat 2004;88:Suppl 1:S16-S16.(Edith A. Perez, M.D.)
The taxanes (docetaxel and paclitaxel) have emerged as potent agents for the adjuvant treatment of early breast cancer; studies involving more than 20,000 patients have been reported or are ongoing. In this issue of the Journal, Martin and colleagues give an account of one such study, the Breast Cancer International Research Group 001 trial, which represents an advance in the treatment of breast cancer.1 The trial was a phase 3 randomized comparison of six cycles of docetaxel, doxorubicin, and cyclophosphamide (TAC) with six cycles of fluorouracil, doxorubicin, and cyclophosphamide (FAC). It is important to examine carefully whether the data from this study justify the consideration of TAC as a new standard — or even the new standard — of adjuvant therapy for resected node-positive breast cancer. Factors to consider include the clinical relevance of the differences in efficacy between TAC and FAC, the tolerability of the two regimens, the suitability of the control group in terms of the current standard of care, and the results of this trial in the context of other studies involving adjuvant taxane therapy.
The statistical and clinical relevance of the differences in disease-free and overall survival supports the use of TAC in place of the older FAC regimen.1 With a median follow-up period of 55 months, the disease-free survival rate was 75 percent among patients receiving TAC as compared with 68 percent for those receiving FAC, with a hazard ratio of 0.72 (P=0.001). The estimated overall survival rate at five years was 87 percent for TAC and 81 percent for FAC, with a hazard ratio of 0.70 (P=0.008). These results are clinically significant and in the same range as other recently reported results of randomized trials that compared older with newer regimens in the setting of adjuvant treatment.
Tolerability was worse with TAC than with FAC, with a 36.3 percent rate of severe nonhematologic toxic effects (including severe asthenia and stomatitis), as compared with the 26.6 percent rate with FAC.1 There were also more hematologic toxic effects with TAC: 24.7 percent of patients in the TAC group had febrile neutropenia (despite the prophylactic use of antibiotics and the introduction of growth-factor support after the first episode of febrile neutropenia or infection), as compared with 2.2 percent in the FAC group, and 4.6 percent of patients in the TAC group required blood transfusions, as compared with 1.5 percent in the FAC group. Among the patients in the two groups, 97 percent completed the six cycles of FAC, and 91 percent received the prespecified six cycles of TAC. Another critical point is that the Breast Cancer International Research Group 001 trial was restricted to women who were 70 years of age or younger, making it impossible to assess the benefit and tolerability in older patients. An additional issue is that the cardiac safety of TAC used concurrently with trastuzumab has not been evaluated; thus, its use may be limited in patients with HER2-positive breast cancer.
The validity of FAC as the control treatment is a more complex question. FAC was a reasonable choice during the treatment period of 1995 to 1998, but this may not be the case in 2005. The FAC regimen tested by Martin et al. delivered 30 percent less of the fluorouracil and cyclophosphamide doses per cycle (with a cumulative doxorubicin dose of 300 mg per square meter of body-surface area) than did another "standard" regimen involving the same agents (cyclophosphamide, doxorubicin, and fluorouracil, with a cumulative dose of doxorubicin of 360 mg per square meter). Cumulative doses of doxorubicin of 240 to 360 mg per square meter have, however, been accepted as appropriate for patients in the control groups of other trials involving adjuvant therapy.2,3,4 We can only speculate as to whether the FAC regimen used in this trial is inferior to that involving other doses and delivery schedules of cyclophosphamide, doxorubicin, and fluorouracil, since data from randomized studies comparing these regimens are lacking.
Since 1998, the standard of care for patients with node-positive breast cancer in the United States and other parts of the world has been treatment with doxorubicin and cyclophosphamide followed by the taxane paclitaxel. This treatment regimen was based on an intergroup study demonstrating that the addition of paclitaxel to doxorubicin and cyclophosphamide led to rates of disease-free survival of 70 percent and overall survival of 80 percent at five years, as compared with 65 percent and 77 percent, respectively, for doxorubicin and cyclophosphamide alone, with modest differences in the rate of toxic effects.2 This regimen was first administered on a schedule of once every three weeks and then, more recently, once every two weeks, after a comparative trial demonstrated improved efficacy (a 7 percent absolute improvement in disease-free survival and a 2 percent improvement in overall survival at three years) with the schedule involving more frequent administration (referred to as dose-dense therapy).4 Thus, investigators who would initiate a randomized trial of the adjuvant treatment of node-positive breast cancer in 2005 would choose not FAC but another taxane-containing regimen as the control.
Whether the ratio of efficacy to toxicity for TAC warrants the general use of this combination for the adjuvant treatment of breast cancer remains a compelling question. Some important facts must be kept in mind: there are many other studies to be considered, with important differences in numbers of patients enrolled, median ages, menopausal status, rates of estrogen-receptor positivity, and use or nonuse of hormonal treatments. All studies that have evaluated the addition of a taxane to an anthracycline-based regimen have demonstrated improvements in disease-free survival, overall survival, or both, except for the recently reported National Surgical Adjuvant Breast and Bowel Project trial B-27.5,6 This study showed that treatment with doxorubicin and cyclophosphamide followed by docetaxel did not improve rates of disease-free or overall survival among patients with early breast cancer, a surprising result in light of the positive results of other large trials involving taxanes. These exceptions and differences illustrate the difficulty inherent in cross-study comparisons and the problems encountered when large-scale studies that take years to complete are conducted in an area in which standards of care can change. Several other trials have been designed to optimize the role of taxanes in the adjuvant-therapy setting, including new schedules of the same agents, the addition of other chemotherapy drugs, the introduction of targeted biologic agents, and the integration of molecular predictors of response.7,8,9,10,11
In conclusion, on the basis of the available data, one can consider TAC to be a standard of care, as is the dose-dense regimen of doxorubicin and cyclophosphamide followed by paclitaxel, for patients with resected node-positive breast cancer. However, the exclusion of patients older than 70 years and the toxic effects associated with TAC in the Breast Cancer International Research Group trial cannot be minimized. With this regimen, prophylactic growth-factor support is necessary to ameliorate myelosuppression and febrile neutropenia. A recommendation for the selection of one regimen over the other must await completion of the prospective National Surgical Adjuvant Breast and Bowel Project trial B-38, for which the accrual of data is expected to be complete in the next few years.8 Although standards of care will continue to evolve as the results of these trials become available, we must offer our patients with node-positive breast cancer the therapies that have already been demonstrated to improve disease-free and overall survival, as compared with older regimens such as those involving cyclophosphamide, methotrexate, and fluorouracil; FAC in previously administered doses and delivery schedules; or doxorubicin and cyclophosphamide. This means adjuvant treatment with TAC or with a regimen of doxorubicin and cyclophosphamide followed by paclitaxel, or participation in a clinical trial.
Source Information
From the Mayo Clinic, Jacksonville, Fla.
References
Martin M, Pienkowski T, Mackey J, et al. Adjuvant docetaxel for node-positive breast cancer. N Engl J Med 2005;352:2302-2313.
Henderson IC, Berry DA, Demetri GD, et al. Improved outcomes from adding sequential paclitaxel but not from escalating doxorubicin dose in an adjuvant chemotherapy regimen for patients with node-positive primary breast cancer. J Clin Oncol 2003;21:976-983.
Mamounas EP, Bryant J, Lembersky C, et al. Paclitaxel (T) following doxorubicin/cyclophosphamide (AC) as adjuvant chemotherapy for node-positive breast cancer: results from NSABP B-28. Proc Am Soc Clin Oncol 2003;22:4. abstract.
Citron ML, Berry DA, Cirrincione C, et al. Randomized trial of dose-dense versus conventionally scheduled and sequential versus concurrent combination chemotherapy as postoperative adjuvant treatment of node-positive primary breast cancer: first report of Intergroup Trial C9741/Cancer and Leukemia Group B Trial 9741. J Clin Oncol 2003;21:1431-1439.
Perez E. Adjuvant therapy approaches to breast cancer: should taxanes be incorporated? Curr Oncol Rep 2003;5:66-71.
Bear HD, Anderson S, Smith RE, et al. A randomized trial comparing preoperative (preop) doxorubicin/cyclophosphamide (AC) to preop AC followed by preop docetaxel (T) and to preop AC followed by postoperative (postop) T in patients (pts) with operable carcinoma of the breast: results of NSABP B-27. Breast Cancer Res Treat 2004;88:Suppl 1:S16-S16.(Edith A. Perez, M.D.)