30 years' follow up of randomised studies of adjuvant CMF in operable
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《英国医生杂志》
1 Istituto Nazionale Tumori, 20133 Milan, Italy
Correspondence to: G Bonadonna gianni.bonadonna@istitutotumori.mi.it
Abstract
In 1975 we presented our first report on the efficacy of cyclophosphamide, methotrexate, and fluorouracil (CMF) as adjuvant treatment for node positive breast cancer.1 2 These results, along with those reported in a similar population of patients by the National Surgical Adjuvant Breast and Bowel Project,3 raised hopes that chemotherapy could have a more central role in the primary management of this common cancer. The worldwide overview confirmed that, when the long term benefits of this treatment modality are balanced against its risks, adjuvant chemotherapy can be worth while in many patients with breast cancer.4 Nevertheless, questions have been raised in the past years concerning the true effectiveness of adjuvant CMF for specific subgroups of patients.5 6 We report the results of 30 years of experience with adjuvant CMF in a series of successive clinical trials.
Methods
First CMF study
Table 1 shows the summary of all four CMF studies carried out at our institute. In the first study, after a median follow up of 28.5 years and a minimal follow up of 25.4 years, both relapse free survival and overall survival (figure 1) remained significantly superior in women receiving adjuvant CMF than in women treated with surgery alone. As already reported,7 16 patients who received optimal doses of CMF (3 85% of the planned doses) showed a long lasting, superior benefit (relapse free survival 42%, 95% confidence interval 26% to 59%; overall survival 40%, 26% to 55%) compared with patients who received lower doses (26%, 19% to 33%; 21%, 14% to 26%). Table 2 shows the rates of relapse free and overall survival relative to main characteristics; no detrimental effect of adjuvant chemotherapy is shown for any of the subsets of patients. The lower rates of overall survival, especially in women aged 50 or older at study entry, can be explained by deaths not due to progression of breast cancer or new primary malignancies. They accounted for 22 events after surgery (median age at death 78 years, range 72-95) and for 24 events in the CMF group (median age at death 74 years, range 54-90).
Fig 1 Treatment outcome in the first randomised CMF study after a median observation of 28.5 years. Left: Relapse free survival after surgery alone (179 patients) v CMF (207 patients). Univariate analysis: hazard ratio 0.71 (95% confidence interval 0.56 to 0.91; P=0.005). Right: Overall survival after surgery alone (179 patients) v CMF (207 patients). Univariate analysis: hazard ratio 0.79 (0.63 to 0.98; P=0.04)
Table 2 Relapse free and overall survival in the first CMF randomised study (enrolment June 1973 to September 1975). Median observation period 28.5 years
The regression analyses of the joint effects of treatment and prognostic indicators confirmed the significant benefit of adjuvant chemotherapy (P = 0.002 for relapse free survival, P = 0.04 for overall survival). As reported in table 3, CMF contributed to reducing the relative risk of disease relapse by 34% and of death from all causes by 22%. The extent of nodal involvement remained a significant prognostic factor; patients with three or more positive nodes were also at an increased risk of relapse and death in this long term analysis. Neither age group nor menopausal status, oestrogen receptor status, or tumour size influenced relapse free survival significantly. As far as overall survival is concerned, patients aged 50 or more years at study entry had a significantly higher risk of dying (hazard ratio 1.43, 95% confidence interval 1.12 to 1.82, P = 0.004) than younger women.
Table 3 Multivariate analysis of the first CMF study in 337 patients with known oestrogen receptor status. Final model
Table 4 shows the cumulative incidence of first relapse according to anatomical sites. The main therapeutic effect of adjuvant CMF was to reduce the incidence of distant metastases (we found an absolute difference of 11% in our long term analysis between patients who received CMF and those who did not).
Table 4 Cumulative incidence of first recurrence of cancer in the first CMF randomised study. Values are percentage estimates derived by applying the method of Marubini and Valsecchi
New malignancies other than contralateral breast cancers were documented in 12 patients (seven after surgery alone and five after CMF), with no prevailing distinctive pattern in either treatment group.
CMF for six cycles compared with 12 cycles in premenopausal patients
After a median follow up of 25 years, the outcome of treatment was not improved with a longer duration of adjuvant CMF. The pattern of relapse free survival was the same in the two treatment groups, and the estimated, relapse free, survival rates were 39% after 12 cycles and 38% after six cycles of CMF. At 25 years, the overall survival rates were 40% in both treatment arms. In the multivariate analysis, the only variable able to influence treatment outcome was the extent to which axillary nodes were affected; patients with three or more affected nodes had a significantly higher risk of disease relapse and death (hazard ratio 2.3, 95% confidence interval 1.61 to 3.16, P = 0.0001). Neither oestrogen receptor status nor size of the primary tumour were able to affect therapeutic outcome significantly.
CMF and amenorrhoea
Grouping together all patients given CMF (first three studies in table 1), a total of 397 women had monthly periods before starting the 12 cycle regimen, and 145 had monthly periods before starting the six cycle regimen. In all these women, planned physical examinations included a diary of the women's monthly cycle. We defined drug induced amenorrhoea as the irreversible cessation of menstrual periods during chemotherapy treatment or in the first year of follow up, in the absence of disease relapse. Table 5 reports the incidence of iatrogenic amenorrhoea in the two regimens by age group. Overall, drug induced amenorrhoea was reported more often in the longer regimen (75% v 62%) than in the shorter one. However, in women aged 45 or older the incidence of amenorrhoea was unrelated to the duration of treatment (97% v 96%).
Table 5 Incidence of iatrogenic amenorrhea in premenopausal women who had monthly periods at study entry (first three studies in table 1)
To assess whether amenorrhoea induced by CMF could influence the outcome of treatment, we carried out an analysis that excluded all patients who had a relapse during the first nine months of chemotherapy.10 We selected this time period because in most women whose menstrual bleeds ceased irreversibly, this effect was observed during the first nine months, and because we wanted to allow comparisons between different studies.17-19 Figure 2 shows relapse free survival in patients who had monthly periods before starting 12 cycles of CMF and shows only a modest and non-significant advantage favouring patients with CMF induced amenorrhoea (P = 0.2). A multivariate analysis including amenorrhoea, extent of nodal involvement, oestrogen receptor status, and age group confirmed that ovarian suppression induced by adjuvant CMF had no significant role in treatment outcome (hazard ratio 1.13, 95% confidence interval 0.69 to 1.57, P = 0.6); the only significant prognostic indicator remained the extent of nodal involvement. Results were similar in the 145 women allocated to receive six cycles of CMF (data not shown).
Fig 2 Relapse free survival in premenopausal women who had monthly periods at entry to the study and given 12 cycles of CMF. Influence of iatrogenic amenorrhoea
Intravenous CMF in node negative tumours
Bonadonna G, Brusamolino E, Valagussa P, Veronesi U. Adjuvant study with combination chemotherapy in operable breast cancer. Proc Am Assoc Cancer Res Am Soc Clin Oncol 1975;16: 254.
Bonadonna G, Brusamolino E, Valagussa P, Rossi A, Brugnatelli L, Brambilla C, et al. Combination chemotherapy as an adjuvant treatment in operable breast cancer. N Engl J Med 1976;294: 405-10.
Fisher B, Carbone P, Economou SG, Frelick R, Glass A, Lerner H, et al. l-Phenylalanine mustard (L-PAM) in the management of primary breast cancer: a report of early findings. N Engl J Med 1975;292: 117-22.
Early Breast Cancer Trialists' Collaborative Group. Polychemotherapy for early breast cancer: an overview of randomised trials. Lancet 1998;352: 930-42.
Pritchard KI. Adjuvant therapy for premenopausal women with breast cancer: is it time for another paradigm shift? J Clin Oncol 2002;20: 4611-4.
Ross JS, Fletcher JA. The HER-2/neu oncogene in breast cancer: prognostic factor, predictive factor, and target for therapy. Stem Cells 1998;16: 413-28.
Bonadonna G, Valagussa P, Moliterni A, Zambetti M, Brambilla C. Adjuvant cyclophosphamide, methotrexate, and fluorouracil in node-positive breast cancer: the results of 20 years of follow-up. N Engl J Med 1995;332: 901-6.
Tancini G, Bonadonna G, Valagussa P, Marchini S, Veronesi U. Adjuvant CMF in breast cancer: comparative 5-year results of 12 versus 6 cycles. J Clin Oncol 1983;1: 2-10.
Zambetti M, Bonadonna G, Valagussa P, Daidone MG, Coradini D, Bignami P, et al. Adjuvant CMF for node-negative and estrogen receptor-negative breast cancer. J Natl Cancer Inst Monogr 1992;11: 79-85.
Anderson JR, Cain KC, Gelber RD. Analysis of survival by tumor response. J Clin Oncol 1983;1: 710-9.
Kaplan EL, Meier P. Nonparametric estimation from incomplete observations. J Am Stat Assoc 1958;53: 457-81.
Peto R, Peto J. Asymptotically efficient rank invariant test procedures. J R Stat Soc A 1972;135: 185-207.
Cox DR. Regression models and life-tables (with discussion). J R Stat Soc B 1972;34: 187-220.
Miller RG. Survival analysis. New York: John Wiley, 1981.
Marubini E, Valsecchi M. Analysing survival data from clinical trials and observational studies. Chichester: John Wiley, 1995.
Bonadonna G, Valagussa P. Dose-response effect of adjuvant chemotherapy in breast cancer. N Engl J Med 1981;304: 10-51.
Goldhirsch A, Gelber RD, Castiglione M. The magnitude of endocrine effects of adjuvant chemotherapy for premenopausal breast cancer patients. Ann Oncol 1990;1: 183-8.
Jakesz R, Hausmaninger H, Kubista E, Gnant M, Menzel C, Bauernhofer T, et al. Randomized adjuvant trial of tamoxifen and goserelin versus cyclophosphamide, methotrexate, and fluorouracil: evidence for the superiority of treatment with endocrine blockade in premenopausal patients with hormone-responsive breast cancer—Austrian Breast and Colorectal Cancer Study Group trial 5. J Clin Oncol 2002;20: 4621-7.
Jonat W, Kaufmann M, Sauerbrei W, Blamey R, Cuzick J, Namer M, et al. Goserelin versus cyclophosphamide, methotrexate, and fluorouracil as adjuvant therapy in premenopausal patients with node-positive breast cancer: the Zoladex early breast cancer research association study. J Clin Oncol 2002;20: 4628-35.
Zambetti M, Valagussa P, Bonadonna G. Adjuvant cyclophosphamide, methotrexate, and fluorouracil in node-negative and estrogen receptor-negative breast cancer. Ann Oncol 1996;7: 481-5.
Fisher B. The evolution of paradigms for the management of breast cancer: a personal perspective. Cancer Res 1992;52: 2371-83.
Peto R, Boreham J, Clarke M, Davies C, Beral V. UK and USA breast cancer deaths down 25% in year 2000 at ages 20-69 years. Lancet 2000;355: 1822.
Early Breast Cancer Trialists' Collaborative Group. Tamoxifen for early breast cancer: an overview of the randomised trials. Lancet 1998;351: 1451-67.
Ménard S, Valagussa P, Pilotti S, Gianni L, Biganzoli E, Boracchi P, et al. Response to CMF in lymph-node positive breast cancer according to HER2 overexpression and other tumours biologic variables. J Clin Oncol 2001;19: 329-35.
Eifel P, Axelson JA, Costa J, Crowley J, Curran WJ Jr, Deshler A, et al. National Institutes of Health Consensus Development Conference Statement: adjuvant therapy for breast cancer, November 1-3, 2000. J Natl Cancer Inst 2001;93: 979-89.
((Gianni Bonadonna, consultant, Department)
Correspondence to: G Bonadonna gianni.bonadonna@istitutotumori.mi.it
Abstract
In 1975 we presented our first report on the efficacy of cyclophosphamide, methotrexate, and fluorouracil (CMF) as adjuvant treatment for node positive breast cancer.1 2 These results, along with those reported in a similar population of patients by the National Surgical Adjuvant Breast and Bowel Project,3 raised hopes that chemotherapy could have a more central role in the primary management of this common cancer. The worldwide overview confirmed that, when the long term benefits of this treatment modality are balanced against its risks, adjuvant chemotherapy can be worth while in many patients with breast cancer.4 Nevertheless, questions have been raised in the past years concerning the true effectiveness of adjuvant CMF for specific subgroups of patients.5 6 We report the results of 30 years of experience with adjuvant CMF in a series of successive clinical trials.
Methods
First CMF study
Table 1 shows the summary of all four CMF studies carried out at our institute. In the first study, after a median follow up of 28.5 years and a minimal follow up of 25.4 years, both relapse free survival and overall survival (figure 1) remained significantly superior in women receiving adjuvant CMF than in women treated with surgery alone. As already reported,7 16 patients who received optimal doses of CMF (3 85% of the planned doses) showed a long lasting, superior benefit (relapse free survival 42%, 95% confidence interval 26% to 59%; overall survival 40%, 26% to 55%) compared with patients who received lower doses (26%, 19% to 33%; 21%, 14% to 26%). Table 2 shows the rates of relapse free and overall survival relative to main characteristics; no detrimental effect of adjuvant chemotherapy is shown for any of the subsets of patients. The lower rates of overall survival, especially in women aged 50 or older at study entry, can be explained by deaths not due to progression of breast cancer or new primary malignancies. They accounted for 22 events after surgery (median age at death 78 years, range 72-95) and for 24 events in the CMF group (median age at death 74 years, range 54-90).
Fig 1 Treatment outcome in the first randomised CMF study after a median observation of 28.5 years. Left: Relapse free survival after surgery alone (179 patients) v CMF (207 patients). Univariate analysis: hazard ratio 0.71 (95% confidence interval 0.56 to 0.91; P=0.005). Right: Overall survival after surgery alone (179 patients) v CMF (207 patients). Univariate analysis: hazard ratio 0.79 (0.63 to 0.98; P=0.04)
Table 2 Relapse free and overall survival in the first CMF randomised study (enrolment June 1973 to September 1975). Median observation period 28.5 years
The regression analyses of the joint effects of treatment and prognostic indicators confirmed the significant benefit of adjuvant chemotherapy (P = 0.002 for relapse free survival, P = 0.04 for overall survival). As reported in table 3, CMF contributed to reducing the relative risk of disease relapse by 34% and of death from all causes by 22%. The extent of nodal involvement remained a significant prognostic factor; patients with three or more positive nodes were also at an increased risk of relapse and death in this long term analysis. Neither age group nor menopausal status, oestrogen receptor status, or tumour size influenced relapse free survival significantly. As far as overall survival is concerned, patients aged 50 or more years at study entry had a significantly higher risk of dying (hazard ratio 1.43, 95% confidence interval 1.12 to 1.82, P = 0.004) than younger women.
Table 3 Multivariate analysis of the first CMF study in 337 patients with known oestrogen receptor status. Final model
Table 4 shows the cumulative incidence of first relapse according to anatomical sites. The main therapeutic effect of adjuvant CMF was to reduce the incidence of distant metastases (we found an absolute difference of 11% in our long term analysis between patients who received CMF and those who did not).
Table 4 Cumulative incidence of first recurrence of cancer in the first CMF randomised study. Values are percentage estimates derived by applying the method of Marubini and Valsecchi
New malignancies other than contralateral breast cancers were documented in 12 patients (seven after surgery alone and five after CMF), with no prevailing distinctive pattern in either treatment group.
CMF for six cycles compared with 12 cycles in premenopausal patients
After a median follow up of 25 years, the outcome of treatment was not improved with a longer duration of adjuvant CMF. The pattern of relapse free survival was the same in the two treatment groups, and the estimated, relapse free, survival rates were 39% after 12 cycles and 38% after six cycles of CMF. At 25 years, the overall survival rates were 40% in both treatment arms. In the multivariate analysis, the only variable able to influence treatment outcome was the extent to which axillary nodes were affected; patients with three or more affected nodes had a significantly higher risk of disease relapse and death (hazard ratio 2.3, 95% confidence interval 1.61 to 3.16, P = 0.0001). Neither oestrogen receptor status nor size of the primary tumour were able to affect therapeutic outcome significantly.
CMF and amenorrhoea
Grouping together all patients given CMF (first three studies in table 1), a total of 397 women had monthly periods before starting the 12 cycle regimen, and 145 had monthly periods before starting the six cycle regimen. In all these women, planned physical examinations included a diary of the women's monthly cycle. We defined drug induced amenorrhoea as the irreversible cessation of menstrual periods during chemotherapy treatment or in the first year of follow up, in the absence of disease relapse. Table 5 reports the incidence of iatrogenic amenorrhoea in the two regimens by age group. Overall, drug induced amenorrhoea was reported more often in the longer regimen (75% v 62%) than in the shorter one. However, in women aged 45 or older the incidence of amenorrhoea was unrelated to the duration of treatment (97% v 96%).
Table 5 Incidence of iatrogenic amenorrhea in premenopausal women who had monthly periods at study entry (first three studies in table 1)
To assess whether amenorrhoea induced by CMF could influence the outcome of treatment, we carried out an analysis that excluded all patients who had a relapse during the first nine months of chemotherapy.10 We selected this time period because in most women whose menstrual bleeds ceased irreversibly, this effect was observed during the first nine months, and because we wanted to allow comparisons between different studies.17-19 Figure 2 shows relapse free survival in patients who had monthly periods before starting 12 cycles of CMF and shows only a modest and non-significant advantage favouring patients with CMF induced amenorrhoea (P = 0.2). A multivariate analysis including amenorrhoea, extent of nodal involvement, oestrogen receptor status, and age group confirmed that ovarian suppression induced by adjuvant CMF had no significant role in treatment outcome (hazard ratio 1.13, 95% confidence interval 0.69 to 1.57, P = 0.6); the only significant prognostic indicator remained the extent of nodal involvement. Results were similar in the 145 women allocated to receive six cycles of CMF (data not shown).
Fig 2 Relapse free survival in premenopausal women who had monthly periods at entry to the study and given 12 cycles of CMF. Influence of iatrogenic amenorrhoea
Intravenous CMF in node negative tumours
Bonadonna G, Brusamolino E, Valagussa P, Veronesi U. Adjuvant study with combination chemotherapy in operable breast cancer. Proc Am Assoc Cancer Res Am Soc Clin Oncol 1975;16: 254.
Bonadonna G, Brusamolino E, Valagussa P, Rossi A, Brugnatelli L, Brambilla C, et al. Combination chemotherapy as an adjuvant treatment in operable breast cancer. N Engl J Med 1976;294: 405-10.
Fisher B, Carbone P, Economou SG, Frelick R, Glass A, Lerner H, et al. l-Phenylalanine mustard (L-PAM) in the management of primary breast cancer: a report of early findings. N Engl J Med 1975;292: 117-22.
Early Breast Cancer Trialists' Collaborative Group. Polychemotherapy for early breast cancer: an overview of randomised trials. Lancet 1998;352: 930-42.
Pritchard KI. Adjuvant therapy for premenopausal women with breast cancer: is it time for another paradigm shift? J Clin Oncol 2002;20: 4611-4.
Ross JS, Fletcher JA. The HER-2/neu oncogene in breast cancer: prognostic factor, predictive factor, and target for therapy. Stem Cells 1998;16: 413-28.
Bonadonna G, Valagussa P, Moliterni A, Zambetti M, Brambilla C. Adjuvant cyclophosphamide, methotrexate, and fluorouracil in node-positive breast cancer: the results of 20 years of follow-up. N Engl J Med 1995;332: 901-6.
Tancini G, Bonadonna G, Valagussa P, Marchini S, Veronesi U. Adjuvant CMF in breast cancer: comparative 5-year results of 12 versus 6 cycles. J Clin Oncol 1983;1: 2-10.
Zambetti M, Bonadonna G, Valagussa P, Daidone MG, Coradini D, Bignami P, et al. Adjuvant CMF for node-negative and estrogen receptor-negative breast cancer. J Natl Cancer Inst Monogr 1992;11: 79-85.
Anderson JR, Cain KC, Gelber RD. Analysis of survival by tumor response. J Clin Oncol 1983;1: 710-9.
Kaplan EL, Meier P. Nonparametric estimation from incomplete observations. J Am Stat Assoc 1958;53: 457-81.
Peto R, Peto J. Asymptotically efficient rank invariant test procedures. J R Stat Soc A 1972;135: 185-207.
Cox DR. Regression models and life-tables (with discussion). J R Stat Soc B 1972;34: 187-220.
Miller RG. Survival analysis. New York: John Wiley, 1981.
Marubini E, Valsecchi M. Analysing survival data from clinical trials and observational studies. Chichester: John Wiley, 1995.
Bonadonna G, Valagussa P. Dose-response effect of adjuvant chemotherapy in breast cancer. N Engl J Med 1981;304: 10-51.
Goldhirsch A, Gelber RD, Castiglione M. The magnitude of endocrine effects of adjuvant chemotherapy for premenopausal breast cancer patients. Ann Oncol 1990;1: 183-8.
Jakesz R, Hausmaninger H, Kubista E, Gnant M, Menzel C, Bauernhofer T, et al. Randomized adjuvant trial of tamoxifen and goserelin versus cyclophosphamide, methotrexate, and fluorouracil: evidence for the superiority of treatment with endocrine blockade in premenopausal patients with hormone-responsive breast cancer—Austrian Breast and Colorectal Cancer Study Group trial 5. J Clin Oncol 2002;20: 4621-7.
Jonat W, Kaufmann M, Sauerbrei W, Blamey R, Cuzick J, Namer M, et al. Goserelin versus cyclophosphamide, methotrexate, and fluorouracil as adjuvant therapy in premenopausal patients with node-positive breast cancer: the Zoladex early breast cancer research association study. J Clin Oncol 2002;20: 4628-35.
Zambetti M, Valagussa P, Bonadonna G. Adjuvant cyclophosphamide, methotrexate, and fluorouracil in node-negative and estrogen receptor-negative breast cancer. Ann Oncol 1996;7: 481-5.
Fisher B. The evolution of paradigms for the management of breast cancer: a personal perspective. Cancer Res 1992;52: 2371-83.
Peto R, Boreham J, Clarke M, Davies C, Beral V. UK and USA breast cancer deaths down 25% in year 2000 at ages 20-69 years. Lancet 2000;355: 1822.
Early Breast Cancer Trialists' Collaborative Group. Tamoxifen for early breast cancer: an overview of the randomised trials. Lancet 1998;351: 1451-67.
Ménard S, Valagussa P, Pilotti S, Gianni L, Biganzoli E, Boracchi P, et al. Response to CMF in lymph-node positive breast cancer according to HER2 overexpression and other tumours biologic variables. J Clin Oncol 2001;19: 329-35.
Eifel P, Axelson JA, Costa J, Crowley J, Curran WJ Jr, Deshler A, et al. National Institutes of Health Consensus Development Conference Statement: adjuvant therapy for breast cancer, November 1-3, 2000. J Natl Cancer Inst 2001;93: 979-89.
((Gianni Bonadonna, consultant, Department)