|
Advertisement |
|
|
||
 |
|
|||||
|
|||||
|
 |
||||||
|
||||||
|
||||||
|
© 1999 American Society for Clinical Oncology Epirubicin Plus Tamoxifen Versus Tamoxifen Alone in Node-Positive Postmenopausal Patients With Breast Cancer: A Randomized Trial of the International Collaborative Cancer GroupFrom the Laurentius Hospital, Roermond, the Netherlands; The Institute of Cancer Research, Sutton, and the Department of Medical Oncology and ICCG Data Centre, Charing Cross Hospital, London, United Kingdom; Hôpital St Louis, Paris, and Center Hospitalier René Dubos, Pontoise, France; Akademisch Ziekenhuis Vrije Universiteit Brussel, Brussels, Belgium; Instituto Valenciano de Oncologia, Valencia, and Hospital Clinico Universitario, Zaragoza, Spain; and St Savvas Hospital, Athens, Greece. Address reprint requests to J.M. Bliss, c/o, ICCG Data Centre, Department of Medical Oncology, Charing Cross Hospital, Fulham Palace Road, London, United Kingdom W6 8RF.
PURPOSE: To assess whether the addition of epirubicin (EPI) therapy to prolonged treatment with tamoxifen (TAM) improves relapse-free and overall survival in postmenopausal women with node-positive primary breast cancer. PATIENTS AND METHODS: Six hundred four patients entered onto a randomized clinical trial were allocated to receive TAM 20 mg/d for 4 years or TAM 20 mg/d for 4 years plus EPI 50 mg/m2 intravenously on days 1 and 8 every 4 weeks for six cycles. Analysis was performed according to allocated treatment, with all randomized patients included (intention to treat), irrespective of eligibility status. RESULTS: After a median follow-up period of 5.7 years, an improvement in relapse-free survival (RFS) was observed for the TAM and EPI–treated patients, compared with those who received TAM alone. The unadjusted hazard ratio was 0.72 (95% confidence interval, 0.54 to 0.96), with a corresponding reduction in the odds of recurrence of 27.9% (SD, 12.3), which was statistically significant (P = .023). Adjustment for prognostic and/or predictive factors did not materially affect the hazard ratio. No difference was observed in terms of overall survival (reduction in odds of death, 11.9% [SD, 16.3]; P = .46). Combined chemohormonal treatment was associated with a higher incidence of acute side effects but without a clear increase in long-term cardiotoxicity. Twelve nonbreast second malignancies, including five hematologic malignancies (two of which were cases of acute myelogenous leukemia), were observed. CONCLUSION: The data show that combined chemohormonal treatment reduces the risk of relapse in postmenopausal patients with node-positive breast cancer. No evidence was found, however, for an improvement in overall survival. The size of benefit observed for both outcomes was consistent with that reported in the Early Breast Cancer Trialists' Collaborative Group overview. The trial presented here, however, provides the first report of an improvement in RFS associated with the provision of a single cytotoxic drug in addition to prolonged TAM.
IN THE ABSENCE OF systemic therapy, the 5-year survival for patients with primary breast cancer and histologic evidence of axillary node involvement is approximately 50%.1 There is ample evidence that treatment with tamoxifen (TAM) for several years will improve this survival, particularly in postmenopausal women.2 Likewise, there is good evidence that systemic cytotoxic chemotherapy with cyclophosphamide, fluorouracil, and methotrexate (CMF) will improve this survival, particularly in premenopausal patients.3
In postmenopausal patients, the role of chemotherapy is less well established. The systematic overview (meta-analysis) published recently by the Early Breast Cancer Trialists' Collaborative Group (EBCTCG) reported that women aged Some of these trials investigated the specific issue of adjuvant anthracycline-containing chemoendocrine treatment versus adjuvant endocrine treatment in postmenopausal patients. The National Surgical Adjuvant Breast and Bowel Project (NSABP) trial showed that a combination of melphalan, fluorouracil, and doxorubicin resulted in a superior RFS (P = 0.003) and survival (P = 0.05) in postmenopausal patients with "TAM-unresponsive" tumors, compared with melphalan and fluorouracil.4 By contrast, patients considered to be "TAM-responsive" did not seem to benefit from the addition of doxorubicin. An Italian study in pre- and postmenopausal patients also investigated the comparative benefits of TAM versus TAM with CMF for 6 months, followed by epirubicin (EPI) for four courses, but was unable to demonstrate any benefit for the combination arm.5 The follow-up period in the report of this study, however, was short (median, 40 months). The International (Ludwig) Breast Cancer Study Group (IBCSG) conducted several trials for which 15-year follow-up data are available; with mature follow-up, these trials suggested long-term benefit for combined (non–anthracycline-containing) chemohormonal therapy in postmenopausal patients, especially for those with lower estrogen-receptor (ER) content.6 At the time that the concept of the study presented here was developed, the literature suggested benefit from the addition of an anthracycline to chemotherapy, because it had been reported that women receiving fluorouracil, doxorubicin, and cyclophosphamide chemotherapy had a significant survival benefit over a group of historical controls.7 Also, in that early study, no evidence was observed that suggested an excess of patients with cardiac dysfunction, although the number of anthracycline-treated patients (n = 131) was relatively small. In addition, in 1984, 4 years before patient entry was commenced onto this study, we had begun to enter premenopausal patients onto a trial comparing fluorouracil, EPI, and cyclophosphamide treatment with CMF8 and had not documented any cardiac dysfunction during this period. The configuration of EPI differs from the parent drug doxorubicin by the epimerization of the hydroxyl group on the 4' position. Modest conformational changes, however, might well result in major functional variations. The affinity of the compound for DNA is lowered, but the intracellular levels of the drug are higher, compared with doxorubicin at equivalent doses. The drug seems to be less cardiotoxic in animal studies,9 an issue that is especially relevant in adjuvant treatment. Results from two randomized studies in women with advanced breast cancer demonstrated that EPI has activity similar to that of doxorubicin.10,11 Therefore, in 1988, the International Collaborative Cancer Group (ICCG) embarked on a trial to investigate whether single-agent EPI, when added to prolonged TAM therapy, resulted in improved relapse-free and overall survival in postmenopausal patients with node-positive operable primary breast cancer.
Study Design This study is a randomized multicenter clinical trial designed and performed by the ICCG. Patients were randomly allocated (with equal probability) to one of two treatment arms: TAM alone or EPI plus TAM. Randomization was performed by a telephone call to one of two data centers (London or Paris), with the data center in London providing all randomization documentation and undertaking the data management of all patients. Patients were stratified prospectively by participating center. The method of randomization used was random permuted blocks. The trial was originally designed to recruit 450 patients (to detect a 15% difference in RFS). In 1991, however, the ICCG Steering Committee decided (in the light of the results reported by the EBCTCG3) to extend the trial to 600 patients to be able to detect a more modest difference between treatment arms, again with 90% power. The ICCG recognized that with this number of patients, substantial statistical variability would exist around the estimate of the true treatment-effect size.
Patient Eligibility Patients were required to have had adequate primary local therapy, which consisted of a complete surgical excision of the tumor (either by radical mastectomy, total [simple] mastectomy, or wide local excision for T1/T2 tumors) with a level 1 and 2 axillary dissection recommended. Postoperative radiotherapy was mandatory after breast-conserving surgery. Elective radiotherapy after mastectomy was performed at the discretion of the participating center. The timing of radiotherapy was determined by the participating center. On completion of accrual, the lead investigator undertook a review of major eligibility violations while blinded to each patient's treatment allocation.
Treatment Regimens Chemotherapy-induced, nonhematologic side effects were managed according to local standard procedures at the participating centers. Scalp cooling was used in some centers. Dose-modification procedures in case of hematologic toxicity were outlined in the protocol. Standardized appropriate treatment delays and/or dose reductions were performed according to the hematologic values on days 1 and 8. Nadir values were not recorded unless they were clinically indicated.
Trial Procedures Information about the treatments received and chemotherapy-induced side effects, including the dates and doses of chemotherapy, was requested. Complete blood cell count measurements on the day of treatment and any toxicity were recorded on the same treatment form according to World Health Organization (WHO) criteria. Severe toxicity was classed as WHO grades 3 or 4. An ECG was requested at each follow-up visit. All disease-related events were to be reported to the data center, with information on histologic or radiologic evidence of recurrence provided when possible. In the case of second primary cancers, histologic verification was requested if confirmation was in doubt. Treatment after disease recurrence was performed at the discretion of the participating center. Non–disease-related serious illnesses were recorded on the follow-up form; all reported incidences of cardiac-related morbidity were reviewed by the lead investigator, and thromboembolic events were discussed by the steering committee, who were blind to the treatment administered for each case.
Statistical Methods The calculation of survival was performed on the basis of all-causes mortality, irrespective of preceding events. In the principal calculation of RFS, all disease recurrences were included as events (with the exception of local recurrence after breast-conserving surgery and no primary radiotherapy, although no such cases were reported), along with second primary cancers in the contralateral breast. The inclusion of all contralateral breast disease cases in the principal analysis reflects the anticipated clinical difficulties in distinguishing between new, second primary breast cancers and disease relapse. A secondary analysis was also conducted, which excluded those events classified by the investigators as second primary breast tumors, to verify that no systematic bias had been introduced by the analysis strategy. In the analysis of RFS, patients dying of other causes before disease relapse were censored at the time of death. In the case of nonbreast second malignancies, relapse-free follow-up was censored at the time of second primary cancer. An event-free analysis was also performed, which included all relapses, second primary cancers, and deaths from any cause (results not shown).
Patients Between April 1988 and February 1995, 604 patients were entered onto the trial from 13 centers in six European countries (see Appendix). Of these 604 patients, 303 were randomized to receive EPI plus TAM and 301 to receive TAM alone. Subsequently, 11 patients were judged as having major eligibility violations for the following reasons: metastases at presentation (n = 3), bilateral malignancy (n = 2), previous history of breast cancer (each > 5 years previously) (n = 3), and low WBC count (< 3.0 x 109/L) at randomization (n = 3). The theoretical median follow-up period is now 5.7 years (range, 2.5 to 9.5 years). In those patients who were last known to be alive, the observed median follow-up period was 4.8 years (range, 0.2 to 9.1 years) (Inter Quartile Range [IQR]), 3.5 to 6.3 years), and all but 19 patients had had information recorded in the last 2 years.
Patient Characteristics
Treatment Thirty-one patients in the EPI plus TAM arm of the study did not receive any EPI. The reasons for not being treated with EPI were as follows: patient refusal (n = 19), detection of metastatic or locally recurrent disease (n = 4), premenopausal patient (alternatively receiving a combination chemotherapy regimen) (n = 4), persisting wound infection (n = 1), axillary vein thrombosis (n = 1), abnormal ECG after randomization (n = 1), and administration error (n = 1). Four patients allocated to receive TAM alone also received EPI: two because of patient request and two because of administrative errors. Of the patients in the EPI plus TAM arm, 240 (79%) completed six cycles of treatment. Ten percent did not receive any treatment (described above). Eleven (4%) refused further treatment after one to four cycles, four patients stopped prematurely because of early relapse, and for one patient, the reason why treatment was discontinued is not known. The remainder (15 patients) who stopped prematurely did so for toxicity reasons related to treatment. One patient died suddenly after five courses, shortly after a grade 4 leukopenia was recorded; thus the death was possibly related to the treatment. Median dose-intensity (expressed as mg/m2/wk and as percentage of intended dose) was 23.3 mg/m2/wk (IQR, 18.7 to 24.7 mg/m2/wk), which represented 95.1% (IQR, 75.7% to 99.4%) of the planned dose overall, including the patients who did not receive any EPI. The median dose-intensity between centers varied between 72.0% and 100.0%.
Toxicity
In 13% of the patients on the EPI plus TAM arm and 2% of those on the TAM alone arm, some infectious episode was recorded. Severe nausea and vomiting was seen in 14% of patients on the EPI plus TAM arm and in 1% of patients in the TAM alone arm. Grade 3 alopecia was reported in 46% of patients allocated to receive EPI plus TAM. Severe mucositis was recorded in 2% of patients on the EPI plus TAM arm. Hematologic acute toxicity reported on day 1 of treatment was evaluated over the first 12 months of follow-up (before distant relapse) (Table 3). Severe anemia was never reported. Two patients in the EPI plus TAM arm reported a grade 3 thrombocytopenia. In the EPI plus TAM arm, five patients recorded WBC values within the grade 3 range, as did one patient on the TAM alone arm. No incidences of grade 4 WBC toxicity on the day of treatment were reported. Because of the way the hematologic values were recorded (on day 1 of treatment and with no routine nadir values), it is likely that the figures reported represent an underreporting of the true nadir toxicity. As stated above, one patient died suddenly after five courses, shortly after a grade 4 leukopenia was recorded. A variety of other side effects were reported in 28% of patients in the EPI plus TAM arm and in 15% of the patients on TAM alone arm. Reports of other toxicity were reviewed, and—with the exception of the cardiac and thromboembolic events discussed below—none was considered to be clinically important. Most were related to the vasomotor symptoms associated with the administration of TAM. Two patients in the EPI plus TAM arm developed congestive heart failure, one after 9 months and the other after 13 months, versus none in the TAM alone arm, a difference that was not statistically significant. Three patients in the EPI plus TAM arm had a myocardial infarction (after 8, 11, and 106 months). On the other hand, three patients in the TAM alone arm also had cardiovascular events (one complete heart block, one coronary ischemia, and one sudden death at home diagnosed as cardiorespiratory insufficiency). Although congestive heart failure is a well-known side effect of anthracycline treatment, a slightly increased risk of cardiovascular events in patients who receive EPI at levels below the maximum cumulative dose cannot be totally excluded. In addition, nine patients reported thromboembolic events (excluding phlebitis in the arm) within 12 months of randomization (and before relapse or diagnosis of second primary cancer). Eight of these patients were allocated to the EPI plus TAM treatment arm and one patient to the TAM alone arm (log-rank test = 4.01; df = 1; P = .045).
Outcome
RFS. Eighty-one and 106 patients on the EPI plus TAM arm and the TAM alone arm, respectively, have relapsed. In addition, seven patients (three on the EPI plus TAM arm and four on the TAM alone arm) had contralateral breast primary tumors (one of these patients had a local relapse before the occurrence of a second primary cancer). Kaplan-Meier curves for RFS are shown in Fig 1, and fixed-term RFS estimates are listed in Table 5. The reduction in odds of recurrence associated with EPI plus TAM was 27.9% (SD, 12.3), which was statistically significant (P = .023). Adjustment for known prognostic and predictive factors (number of nodes involved, pathologic tumor stage, grade, ER status, primary local therapy) did not materially affect the hazard ratio (unadjusted hazard ratio, 0.72; 95% confidence interval [CI], 0.54 to 0.96; and adjusted hazard ratio, 0.67; 95% CI, 0.49 to 0.92). Ignoring breast second primary cancers, the reduction in odds of relapse observed (28.6%; SD, 12.4) was very similar.
Tests for interaction between treatment and other prognostic or predictive factors were not significant. The effect of combined treatment was observed to be similar in patients with one to three positive nodes and those with four or more nodes (test for interaction P = .37). Receptor status did not seem to influence the results (test for interaction P = .42). However, in a trial of this size, the statistical power is inadequate for a reliable comparison of differential effects between subgroups. Overall survival. One hundred thirty-four patients have died, 64 in the EPI plus TAM arm and 70 in the TAM alone arm. Figure 2 shows the Kaplan-Meier curves for both groups, and Table 5 lists the fixed-term survival estimates. Survival seemed to be similar for the two treatment groups (P = .46); however, the observed reduction in odds of death was consistent with a small benefit for combined chemohormonal treatment (11.9%; SD, 16.3). The reduction in risk as assessed by the hazard ratio (HR) seemed to be slightly increased if adjustment was made for known prognostic factors (unadjusted HR, 0.88; 95% CI, 0.63 to 1.24; and adjusted HR, 0.82; 95% CI, 0.57 to 1.18); however, in neither analysis was there statistically reliable evidence for a true treatment benefit. Ten patients died of causes unrelated to their breast cancer, with no evidence of breast cancer relapse: five of these patients died of second primary cancers; one died of Alzheimer's disease at the age of 79; one committed suicide; and one died in a car accident. The remaining two died suddenly: one died at home 2 years after randomization, with no reported disease relapse and no autopsy, and the other died after the fifth cycle of EPI (as described above)—her death was possibly related to treatment.
Second primary cancers. Twenty-one patients had a second primary cancer diagnosed; seven of these were in the contralateral breast (see above). Nine patients had solid tumors of cancer types that are common in this patient population. There were five hematologic malignancies, all in the EPI plus TAM arm of the trial: acute myelogenous leukemia (AML) (M4 type) (n = 2), non-Hodgkin's lymphoma (n = 1), myeloma (n = 1), and chronic myeloid leukemia (n = 1). It should be noted, however, that two of these five patients (one with non-Hodgkin's lymphoma and one with chronic myeloid leukemia) did not actually receive EPI, so it is difficult to speculate on a potential causal relation with EPI. Moreover, the two cases with AML were additionally treated with irradiation. Treatment after relapse. Treatment after relapse was performed at the discretion of the investigator and mirrored the range of treatments, both conventional and experimental, that are typically used to treat advanced breast cancer. The details of treatment are known for those patients who have died and are listed in Table 6. There is some suggestion that patients in the TAM alone arm of the trial received more extensive treatment for metastatic relapse than did those who had received adjuvant EPI; particularly, 72% received chemotherapy for advanced disease in the TAM alone group, compared with 54% in the EPI plus TAM group. The overall survival percentage 1 year after metastatic relapse was 43% (95% CI, 32% to 55%) for the EPI plus TAM group and 68% (95% CI, 58% to 78%) for the TAM alone group. Overall, a log-rank comparison of survival after metastatic relapse indicated longer survival for the TAM alone arm (P = .004).
This trial has demonstrated that EPI can be safely added to TAM at the dosages described, and an analysis of RFS indicates that the addition of EPI to TAM reduces the chances of breast cancer recurrence (P = .023). At the time of this analysis, with 604 patients and a median follow-up period of 5.7 years, this study has failed to demonstrate an overall survival advantage for anthracycline chemotherapy in the adjuvant treatment of postmenopausal women with axillary node-positive operable breast cancer. The number of fatal events observed is reasonably small, and a longer follow-up is needed to assess the effect on overall survival more reliably. Other studies of chemotherapy in primary breast cancer have shown that an effect on RFS observed at an early analysis13 may translate into an impact on overall survival with a longer follow-up.14 The modest (nonsignificant) risk reduction observed in the study presented here is consistent with both a null effect and a clinically important benefit, and further follow-up from this and other trials will allow a more accurate quantification of the true impact on overall survival of adding chemotherapy to TAM in postmenopausal breast cancer patients. Several features of our study deserve comment because they could relate to the outcome currently observed. The first is the fact that 31 patients, after agreeing to enter the study, did not receive the EPI that they were allocated. In 19 cases, this was because they had subsequently refused chemotherapy; in the remaining cases, the reasons for the patient's not receiving chemotherapy were related either to disease status or to administrative error. Furthermore, 11 patients were subsequently found to be ineligible. However, a separate analysis of the study, in which ineligible patients were excluded, showed that this did not change the outcome (hazard ratio for relapse, 0.70; 95% CI, 0.53 to 0.94; P = .016; hazard ratio for deaths, 0.85; 95% CI, 0.61 to 1.21; P = .37). We also considered whether the treatment effect was influenced by extent of nodal involvement or by receptor status, but no interactions between treatment effect and these factors were observed. The side-effect profile of EPI at this dose-intensity is well established in patients with metastatic breast cancer, but this study gave us the opportunity to study side effects in the non-metastatic setting. The acute toxicity, which consisted primarily of nausea/vomiting and alopecia, was moderate, and it can be anticipated that with the use of 5-hydroxytryptamine-3 antagonists, the incidence of severe nausea/vomiting can be further reduced. A principal concern with chemotherapy in this age group is the incidence of severe leukopenia, which, however, was rare. Longer-term side effects include a possible slight increase in cardiovascular and thromboembolic events, but only two patients developed congestive heart failure, which could possibly be attributed to EPI. We observed five hematologic malignancies, all in the TAM plus EPI arm. These included two cases of M4 AML, which could possibly be attributed to the administration of EPI.15 Both cases received six cycles of EPI and also received radiotherapy (one concurrent with chemotherapy and one on completion of chemotherapy); the two AML cases occurred 18 and 50 months after randomization, respectively. Both patients remain free from disease at the latest follow-up. It has also been suggested, however, that the concomitant use of fluorouracil, doxorubicin, and cyclophosphamide and radiotherapy or intense fluorouracil, EPI, and cyclophosphamide slightly increases the risk of leukemia.16,17 If so, however, the benefits of adjuvant chemotherapy for most patients clearly exceed the risk of treatment-related leukemia. Furthermore, it is interesting that AML has also been described in relation to TAM therapy.18 The other three hematologic malignancies were myeloma, chronic myeloid leukemia, and non-Hodgkin's lymphoma (one case each), but of these three cases, only one (the case with myeloma) actually received EPI. Therefore, a potential relationship remains speculative. We did not observe an increase in risk of thromboembolic complications of the magnitude reported by the National Cancer Institute of Canada with the combined use of adjuvant CMF and TAM,19 although a small increase was observed. It is not clear whether the reported increases are due to the concurrent administration of chemotherapy and TAM or whether they simply reflect the problems associated with the administration of adjuvant chemotherapy in this patient population. An ongoing ICCG trial aims to address this issue. The outcome of this study is entirely consistent with that of the EBCTCG overview,3 which suggested a role for adjuvant chemotherapy in addition to TAM in postmenopausal patients with breast cancer. Our results raise the question of specific benefit with anthracyclines either as single agents or in combination chemotherapy. The EBCTCG overview furthermore concluded that although polychemotherapy had its maximal effect in younger women, it still produces a highly significant reduction in risk of recurrence even among women 60 to 69 years of age and the treatment outcome difference between younger and older women is probably quantitative rather than qualitative. Other studies have recently reported on the addition of polychemotherapy to TAM in postmenopausal patients. The IBCSG randomized 1,266 node-positive postmenopausal patients to receive TAM alone or TAM with early, delayed or both early and delayed CMF chemotherapy. They observed that early or delayed CMF improved disease-free survival when compared with TAM alone (P = .03), but at a median follow-up duration of 60 months, the differences in overall survival were not significant. Considering only TAM with early CMF versus TAM alone, a benefit in disease-free survival was also observed (hazard ratio, 0.79; 95% CI, 0.66 to 0.95; P = .01).20 Interestingly, the greatest benefit seemed to accrue to patients with ER-positive carcinomas. This was in contrast to the group's previous study, which suggested that ER-negative patients were most likely to benefit.6 This apparent discrepancy illustrates the difficulties of evaluating subgroup effects in these trials. A recent update of the NSABP B-20 trial, which compared CMF plus TAM with TAM alone in node-negative, ER-positive breast cancer,21 showed that the addition of CMF caused an improvement in disease-free survival of approximately 5%, with an improvement in overall survival of approximately 3%, similar to results of the EBCTCG overview. A recent study has been reported in abstract form,22 in which postmenopausal ER-positive, node-positive patients were randomly allocated to TAM or cyclophosphamide, doxorubicin, and fluorouracil and TAM. The combination arm had an improved disease-free survival (P = .001), although further follow-up is needed to determine the impact on overall survival. In contrast to these reports of improvements in disease-free survival, the National Cancer Institute of Canada recently reported a study in which they had randomized 705 postmenopausal patients with node-positive and ER-positive or progesterone receptor–positive breast cancer to receive CMF with TAM (2 years) or TAM alone. The study currently fails to demonstrate any benefit in terms of either recurrence-free or overall survival associated with combined treatment.23 The authors implied that one difference between their study and those of the IBCSG may be the fact that the IBCSG trials included prednisolone in the treatment regimens. An additional difference cited was the potential impact of having a larger number of patients with ER-negative carcinomas in the National Cancer Institute of Canada study. However, the principal difference between that study and the study presented here and the NSABP B-16 study was that both of the latter two trials involved anthracycline chemotherapy. With regard to anthracycline-containing chemotherapy, the NSABP B-16 trial randomized a subgroup of postmenopausal patients to receive anthracycline-containing chemotherapy with TAM and showed that this was significantly better for both RFS and overall survival than treatment with TAM alone.24 Sequential chemotherapy with doxorubicin followed by CMF chemotherapy in postmenopausal women with more than three positive nodes led to a highly significant improvement in disease-free and overall survival (42% alive and well at 10 years, compared with 28% who received alternating CMF and doxorubicin). However, the result was marred by the development of four cases of congestive cardiac failure (three in the sequential arm), two of which were fatal.25 An important issue that remains unresolved is the magnitude of benefit, if any, for combined chemohormonal treatment in terms of overall survival in postmenopausal breast cancer patients. There are several explanations for the much more modest impact on overall survival than on disease-free survival observed in this study. First, the follow-up period might be too short, and some relapses, especially local relapses, have a prolonged survival. Second, many patients who relapse after adjuvant chemotherapy have a shorter survival than patients who did not receive adjuvant cytotoxic agents. In most studies, treatment after relapse is performed at the discretion of the investigator, and it is quite possible that the use of combination chemotherapy is more effective or more frequently prescribed for patients who relapse after TAM alone than after combined chemohormonal treatment. The question remains as to whether treatment with combined chemohormonal therapy of all patients in the adjuvant setting is worthwhile if chemotherapy could have been targeted at the time of disease recurrence in those patients who relapsed, with the same overall impact on long-term survival. However, the impact on the patient's life quality of having a longer disease-free interval prior to relapse would need to be taken into consideration in such a strategy. The prolongation of RFS observed in this study seems to be important, compared with that observed in a meta-analysis,26 and the kind and duration of chemotherapy proposed here seem to be more favorable than other combinations. Until recently, few treatments have been shown to be effective in patients who fail after treatment with anthracyclines. With the advent of agents such as the taxanes, however, which have been shown to be active in patients who relapse after anthracycline treatment,27,28 it is possible that greater improvements in long-term survival may be possible. Finally, long-term survival might be compromised by the incidence of acute or late side effects, but no such increased mortality has been observed in this study yet. The questions for future studies are whether the chemotherapy can be improved and whether sequential chemohormonal treatment is preferred over combined treatment. For improvement of the chemotherapy regimen, either higher doses of EPI or a combination of EPI with other drugs may be considered. A 50% increase in the dose of EPI would result in a cumulative dose of 900 mg/m2, which is close to the limit for an increased risk of cardiotoxicity. Among other drugs to be included in the treatment regimen, the taxanes certainly seem to be of interest. Other problems that may arise if more aggressive chemotherapy is used are linked to the more advanced age and concomitant illnesses of the patient population. In conclusion, the addition of EPI to prolonged TAM results in an improved RFS, as compared with TAM alone, in postmenopausal patients with node-positive early breast cancer. This is the first trial to report such a benefit associated with single-agent chemotherapy.
Comprehensive Cancer Centre, Limburg, the Netherlands [n = 216]: J.A. Wils (St Laurentius Hospital, Roermond, the Netherlands); H. Bron, F. Erdkamp (Maasland Hospital, Sittard, the Netherlands); J. Wals (Gregorius Hospital, Brunssum, the Netherlands); M. Fickers (De Wever Hospital, Heerlen, the Netherlands); P. Hupperets (AZM, Maastricht, the Netherlands). Hôpital St Louis, Paris, France [n = 192]: M. Marty, N. Bedaïria, S. Bonfils, F. Calvo, C. Cuvier, P. de Cremoux, D. Delfieu, M. Espié, J.M. Extra, G. Ganem, A. Gorins, M. Le Bonniec, J. Lipszyc, H. Nowak, F. Perret, B. Tournant, P. Tresca; L. Mignot (Centre Médico-Chirurgical, Foch, Suresnes, France). Charing Cross Hospital, London, United Kingdom [n = 50]: R.C. Coombes. Instituto Valenciano de Oncologia, Valencia, Spain [n = 50]: T. Olmos, V. Guillem, A. Ruiz. Hospital Clinico Universitario, Zaragoza, Spain [n = 20]: F.R. Pérez-López, J. Hergueta. St Savvas Hospital, Athens, Greece [n = 18]: P. Vassilopoulos, J. Karaitrenos. Akademisch Ziekenhuis Vrije Universiteit Brusel, Brussels, Belgium [n = 17]: J. De Greve, C. Fontaine. St Vincentius Hospital, Ghent, Belgium [n = 14]: F. Bouttens. Centre Hospitalier René Dubos, Pontoise, France [n = 11]: F. Morvan, A. Botton, H. Berseneff, F. Hoche, F. Rousseau. University General Hospital, Herakleion, Crete [n = 8]: D. Tsiftsis. Policlinique Oncologie Medicale, Reims, France [n = 3]: G. Netter Pinon. University Hospital Gent, Ghent, Belgium [n = 3]: S. Van Belle, V. Cocquyt. St Vincentius Hospital, Antwerp, Belgium [n = 2]: H. Wassenaar. International Collaborative Cancer Group [Data Center], London, United Kingdom: E. Woods (Charing Cross Hospital, London, United Kingdom); J.M. Bliss, G. Coombes, J. Davidson, L. Meyer (Institute of Cancer Research, Sutton, Surrey, United Kingdom). *The number of patients included is indicated in brackets.
Supported in part by grants from Pharmacia & Upjohn, Milan, Italy, and the Cancer Research Campaign, London, United Kingdom.
1. Fisher B, Redmond C, Wolmark N, et al: Disease-free survival at intervals during and following completion of adjuvant chemotherapy: The NSABP experience from three breast cancer protocols. Cancer 48:1273-1280, 1981[Medline] 2. Early Breast Cancer Trialists' Collaborative Group: Tamoxifen for early breast cancer: an overview of the randomised trials. Lancet 351:1451-1467, 1998[Medline] 3. Early Breast Cancer Trialists' Collaborative Group: Polychemotherapy for early breast cancer: an overview of the randomised trials. Lancet 352:930-942, 1998[Medline] 4. Fisher B, Redmond C, Wickerham DL, et al: Doxorubicin-containing regimens for the treatment of stage II breast cancer: The National Surgical Adjuvant Breast and Bowel Project experience. J Clin Oncol 7:572-582, 1989[Abstract] 5. Boccardo F, Rubagotti A, Bruzzi P, et al: Chemotherapy versus tamoxifen versus chemotherapy plus tamoxifen in node-positive, estrogen receptor-positive breast cancer patients: Results of a multicentric Italian study—Breast Cancer Adjuvant Chemo-Hormone Therapy Cooperative Group. J Clin Oncol 8:1310-1320, 1990[Abstract]
6.
Castiglione-Gertsch M, Johnsen C, Goldhirsch A, et al: The International (Ludwig) Breast Cancer Study Group Trials I-IV: 15 years follow-up. Ann Oncol 5:717-724, 1994 7. Buzdar AU, Gutterman JU, Blumenschein GR, et al: Intensive postoperative chemoimmunotherapy for patients with stage II and stage III breast cancer. Cancer 41:1064-1075, 1978[Medline] 8. Coombes RC, Bliss JM, Wils J, et al: Adjuvant cyclophosphamide, methotrexate, and fluorouracil versus fluorouracil, epirubicin, cyclophosphamide chemotherapy in premenopausal women with axillary node-positive operable breast cancer: Results of a randomized trial—The International Collaborative Cancer Group. J Clin Oncol 14:35-45, 1996[Abstract] 9. Villani F, Favelli L, Piccinini F: Relationship between the effect on calcium turnover and early cardiotoxicity of doxorubicin and 4'-epi-doxorubicin in guinea pig heart muscle. Tumori 66:689-697, 1980[Medline]
10.
Italian Multicentre Breast Study With Epirubicin: Phase III randomized study of fluorouracil, epirubicin, and cyclophosphamide v fluorouracil, doxorubicin, and cyclophosphamide in advanced breast cancer: An Italian multicentre trial. J Clin Oncol 6:976-982, 1988 11. French Epirubicin Study Group: A prospective randomized phase III trial comparing combination chemotherapy with cyclophosphamide, fluorouracil, and either doxorubicin or epirubicin. J Clin Oncol 6:679-688, 1988[Abstract] 12. Bliss JM, Heath E, Bryant TN, et al: Improving the quality of data in clinical trials in cancer. Br J Cancer 63:412-415, 1991[Medline] 13. Mansour EG, Gray R, Shatila A, et al: Efficacy of adjuvant chemotherapy in high-risk node-negative breast cancer. N Engl J Med 320:485-490, 1989[Abstract] 14. Mansour EG, Gray R, Shatila A, et al: Survival advantage of adjuvant chemotherapy in high-risk node-negative breast cancer: Ten-year analysis—An Intergroup Study. J Clin Oncol 16:3486-3492, 1998[Abstract]
15.
Riggi M, Riva A: Therapy-related leukemia: What is the role of 4-epi-doxorubicin? J Clin Oncol 11:1430-1435, 1993
16.
Diamandidou E, Buzdar AU, Smith TL, et al: Treatment-related leukemia in breast cancer patients treated with fluorouracil-doxorubicin-cyclophosphamide combination adjuvant chemotherapy: The University of Texas M.D. Anderson Cancer Center experience. J Clin Oncol 14:2722-2730, 1996 17. Levine MN, Bramwell VH, Pritchard KI, et al: Randomized trial of intensive cyclophosphamide, epirubicin, and fluorouracil chemotherapy compared with cyclophosphamide, methotrexate, and fluorouracil in premenopausal women with node-positive breast cancer. J Clin Oncol 16:2651-2658, 1998[Abstract] 18. Yalcin S, Guillu I, Demiroglu H, et al: Acute leukaemia during tamoxifen therapy. Med Oncol 14:61-62, 1997[Medline]
19.
Pritchard KI, Paterson AHG, Paul N, et al: Increased thromboembolic complications with concurrent tamoxifen and chemotherapy in a randomized trial of adjuvant therapy for women with breast cancer: National Cancer Institute of Canada Clinical Trials Group Breast Cancer Site Group. J Clin Oncol 14:2731-2737, 1996 20. International Breast Cancer Study Group: Effectiveness of adjuvant chemotherapy in combination with tamoxifen for node-positive postmenopausal breast cancer patients. J Clin Oncol 15:1385-1394, 1997[Abstract]
21.
Fisher B, Dignam J, Wolmark N, et al: Tamoxifen and chemotherapy for lymph node-negative, estrogen receptor-positive breast cancer. J Natl Cancer Inst 89:1673-1682, 1997 22. Albain K, Green S, Osborne K, et al: Tamoxifen (T) versus cyclophosphamide, adriamycin and 5-FU plus either concurrent or sequential T in postmenopausal, receptor (+), node (+) breast cancer: A Southwest Oncology Group Phase III intergroup trial (SWOG-8814, INT-0100). Proc Am Soc Clin Oncol 16:128a, 1997 (abstr 450)
23.
Pritchard KI, Paterson AHG, Fine S, et al: Randomized trial of cyclophosphamide, methotrexate and fluorouracil chemotherapy added to tamoxifen as adjuvant therapy in postmenopausal women with node-positive estrogen and/or progesterone receptor-positive breast cancer: A report of the National Cancer Institute of Canada Clinical Trials Group. J Clin Oncol 15:2302-2311, 1997 24. Fisher B, Redmond C, Legault-Poisson S, et al: Postoperative chemotherapy and tamoxifen compared with tamoxifen alone in the treatment of positive-node breast cancer patients aged 50 years and older with tumors responsive to tamoxifen: Results from the National Surgical Adjuvant Breast and Bowel Project B-16. J Clin Oncol 8:1005-1018, 1990[Abstract] 25. Bondonna G, Zambetti M, Valagussa P: Sequential or alternating doxorubicin and CMF regimens in breast cancer with more than three positive nodes: Ten-year results. JAMA 273:542-547, 1995[Abstract] 26. Gelber RD, Cole BF, Goldhirsch A, et al: Adjuvant chemotherapy plus tamoxifen compared with tamoxifen alone for postmenopausal breast cancer: Meta-analysis of quality-adjusted survival. Lancet 347:1066-1071, 1996[Medline] 27. Ravdin PM, Burriss III HA, Cook G, et al: Phase II trial of docetaxel in advanced anthracycline-resistant or anthracenedione-resistant breast cancer. J Clin Oncol 13:2879-2885, 1995[Abstract] 28. Archer CD, Lowdell C, Sinnett HD, et al: Docetaxel: Response in patients who have received at least two prior chemotherapy regimes for metastatic breast cancer. Eur J Cancer 34:816-819, 1998 Submitted August 31, 1998; accepted February 22, 1999. This article has been cited by other articles:
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
TOP
ABSTRACT
INTRODUCTION
50 years who received adjuvant chemotherapy showed a significant (11.3% ± 2.9%) (± SD) reduction in the annual odds of dying of breast cancer. The overview included randomized trials that had been initiated before 1990, and 10-year survival data were available for many of the trials.
