1 Institut Gustave-Roussy, Villejuif, France; 2 Instituto de Radiomedicina, Santiago, Chile; 3 Centre François Baclesse, Caen, France
Received 15 May 2002; revised 30 May 2002; accepted 4 June 2002
![]() |
Abstract |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
We studied the effect of adjuvant anthracycline-based chemotherapy in postmenopausal patients with resected early breast cancer treated with adjuvant tamoxifen.
Patients and methods:
The trial included 835 patients with either axillary lymph node involvement, or tumors with histological grade II or III. They were randomized after local surgery to receive either tamoxifen (TAM group) or tamoxifen plus chemotherapy (TAM-CT group) consisting of six courses of 5-fluorouracil, doxorubicin and cyclophosphamide (FAC), or 5-fluorouracil, epidoxorubicin and cyclophosphamide (FEC). Radiotherapy was given after completion of adjuvant chemotherapy in the TAM-CT group and after surgery in the TAM group.
Results:
The 5-year disease-free survival (DFS) rates were 73% in the TAM group and 79% in the TAM-CT group (log-rank test, P = 0.06). The 5-year overall survival rates were 82% and 87%, respectively (P = 0.06). The 5-year distant metastasis rates were 22% and 16% (P = 0.02), and the 5-year local recurrence rates were 6% and 4%, respectively (P = 0.23). There were no significant differences for contralateral breast cancer or other new primary malignancies. Chemotherapy tended to be more effective for patients who had tumors without estrogen receptors (trend test, P = 0.05).
Conclusions:
Anthracycline-based chemotherapy administered to postmenopausal patients receiving adjuvant tamoxifen gave a borderline significant benefit on overall and DFS, mainly by a reduction in distant metastases. Delaying radiotherapy after six courses of chemotherapy did not affect local control after up to 10 years of follow-up.
Key words: adjuvant chemotherapy, adjuvant tamoxifen, early breast cancer, postmenopausal patients, randomized trial
![]() |
Introduction |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
![]() |
Patients and methods |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
Thus, women with no nodal involvement and grade I tumors were excluded. Other criteria for exclusion were age >69 years, World Health Organization (WHO) performance status >1, histology other than primary infiltrating carcinoma, inflammatory cancer, bilateral breast tumor or history of previous cancer, except skin basal-cell carcinoma or in situ carcinoma of the cervix. Patients with hepatic, renal or cardiac failure, or previous myocardial infarction contra-indicating anthracycline-based chemotherapy were also excluded.
Trial design
Eligible patients who consented to participate in the study were randomized after primary surgery between the two following arms: tamoxifen 20 mg/day for at least 2 years (TAM group) or the same tamoxifen schedule plus six courses of anthracycline-based chemotherapy (TAM-CT group). In the TAM-CT group, chemotherapy was to start within 6 weeks of surgery, and tamoxifen was given at the end of chemotherapy. When postoperative radiotherapy was indicated, it was given within 1 month of surgery in the TAM group and after completion of chemotherapy in the TAM-CT group. Radiotherapy was given concomitantly with adjuvant tamoxifen. Patients included were allowed to participate in the French trial on tamoxifen treatment duration [3] comparing 2 years versus long-term treatment.
Treatment and follow-up
The general treatment policy for primary surgery was a tumorectomy for patients with tumors of a macroscopic diameter of 3 cm and a mastectomy for patients with larger tumors. All patients underwent axillary dissection. After surgery, they started tamoxifen as described above.
Patients allocated to the TAM-CT arm started chemotherapy 24 weeks after surgery. The chemotherapy regimen consisted of six courses of 5-fluorouracil (F) 500 mg/m2, doxorubicin (A) or epirubicin (E) 50 mg/m2, and cyclophosphamide (C) 500 mg/m2, delivered intravenously on day 1. The interval between each chemotherapy course varied from 21 to 28 days according to hematological tolerance. Doses were reduced by 20% and/or intervals between courses were increased by 1 week when blood count showed <2000/µl neutrophils or <100 000/µl platelets. Anti-emetic treatment was given according to each centers policy.
Postoperative radiotherapy was given according to the protocol of each center, but general principles were common. Radiotherapy was always given to the breast after tumorectomy at a total dose of 4550 Gy in conventional fractionation, followed by a boost dose (15 Gy) to the tumor bed. Supraclavicular and internal mammary chain were irradiated only in patients with positive axillary nodes. Also, patients treated with total mastectomy received postoperative radiotherapy (chest wall, supraclavicular and internal mammary chain) only if the axillary nodes were positive.
After treatment completion, patients were seen every 6 months for the first 5 years, and yearly afterwards, with a yearly mammogram and a clinical examination at each visit. Complementary examinations were conducted according to each centers policy.
Statistical methods
Central randomization was done at the Institut Gustave-Roussy by phone or fax and stratified on each center.
A sample size of 1200 patients was planned for, in order to have a 90% chance of detecting a 7% difference in 5-year overall survival (OS) rates, from 76% to 83%, with a type 1 error of 5% (one-sided test).
All evaluable patients were included in the analysis in the randomly allocated treatment group (intention-to-treat analysis).
Overall survival and disease-free survival (DFS) were the main end points. They were analyzed by the KaplanMeier method (Rothman confidence interval) and compared using the log-rank test. Overall survival was defined as the time between the date of randomization and the date of last follow-up or death. Disease-free survival was defined as the time between date of randomization and date of last follow-up or date of best available evidence of the first unfavorable event: locoregional recurrence, distant metastasis, contralateral breast tumor or death.
A subsidiary question was to determine whether postponing radiation therapy after adjuvant chemotherapy might or might not have an effect on local control. Local recurrence and distant metastasis rates were determined using KaplanMeier estimators ignoring the occurrence of other events except death [4], and compared with the log-rank test.
The heterogeneity of treatment effect was tested for all prognostic parameters to detect groups of patients differing from others by their re-sponse to treatment. For parameters with at least three ordered categories, a test for trend was calculated [5]. To account for multiple comparisons, tests performed in the different categories used a 0.01 significance level. The significance tests for the overall population are at the 0.05 significance level. All P values are two-sided.
![]() |
Results |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
Patient characteristics
The distribution of baseline characteristics according to treatment group is shown in Table 1. There are no significant imbalances between the two groups. Hormone receptor determination with a value of 9 fmol/mg was defined as negative.
|
Radiotherapy was delivered according to the practice of each center. Among the 568 patients who had a tumorectomy, all but one received breast irradiation at a total dose ranging from 45 to 75 Gy, including the boost dose on the tumor bed. Among the 267 patients who had a mastectomy, 156 received radiotherapy to the chest wall at a dose ranging from 45 to 65 Gy, including boost dose to the scar. Seven per cent of patients received axillary radiation at a dose ranging from 45 to 60 Gy. The internal mammary nodes received radiotherapy in 55% of cases at doses between 45 and 65 Gy, and the supraclavicular area was irradiated in 54% of patients at doses between 45 and 60 Gy. The proportions of patients who received radiotherapy were 85% and 87% for the TAM and TAM-CT groups, respectively.
Treatment compliance
Of 420 patients in the TAM-CT group, 409 received chemotherapy and 11 patients did not (nine refused treatment, one was not given chemotherapy by mistake, one was not treated according to the protocol because of a bilateral tumor).
Among the 415 patients included in the TAM group, eight received chemotherapy: four had distant metastases diagnosed after randomization, three received chemotherapy by mistake and one had her treatment changed from tamoxifen to chemotherapy after developing a phlebitis.
In the TAM-CT group, chemotherapy included epirubicin in 375 patients (89%), doxorubicin in 20 patients and mitoxantrone (12 mg/m2) in 11 patients. One patient received three courses of FAC followed by three courses of FEC, one patient received six courses of CMF, and another six courses of EV (vincristine) CF.
Of 409 women randomized to the TAM-CT group who received chemotherapy, 387 women (95%) received the scheduled six courses of chemotherapy, 12 (3%) five courses and 10 (2%) three courses or less. Thirty-three patients (8%) had an interval period between two courses of chemotherapy of more than 28 days (10% in two or three cycles and 90% in one cycle). In addition, 20 patients had doses different from the doses planned in the protocol (30% in five cycles, 35% in two or three cycles and 35% in one cycle).
Twenty-nine patients (7%) had hematological toxicity which induced delayed administration and a dose reduction in seven patients, delayed administration in 15 patients and a dose reduction in seven patients.
Disease-free survival and overall survival
A total of 147 patients in the TAM group experienced at least one event (locoregional or distant metastasis, contralateral breast cancer or death from any cause), compared with 126 in the TAM-CT group. KaplanMeier curves for DFS are shown in Figure 1A; the difference is statistically borderline significant (P = 0.06).
|
The 5-year DFS and OS rates are shown in Table 2.
|
|
Treatment interactions with tumor or patient parameters
We studied the variations of chemotherapy effect according to tumor or patient characteristicssuch as axillary lymph node involvement, estrogen receptor (ER) status, histological grade and agein terms of DFS. Treatment interaction was borderline significant only for ER status (trend test, P = 0.05) and not significant for the other factors. For instance, age was analyzed in 2-year categories and no differential treatment effect was found (heterogeneity test, 0.98; trend test, 0.92). Chemotherapy seemed to be more effective for patients with ER-negative tumors. However, the P value is not formally significant, as a value of 0.01 was defined for multiple comparisons. Results according to ER and lymph node involvement are shown in Figure 3.
|
![]() |
Discussion |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
Seven other large trials (each including more than 500 patients) have evaluated the role of adjuvant chemotherapy in postmenopausal patients or in patients over 50 years of age, all treated with adjuvant tamoxifen. They are summarized in Table 3 [1420].
|
The two National Surgical Adjuvant Breast and Bowel Project (NSABP) trials [17, 18] showed a beneficial effect of six CMF or four AC, the first schedule only in terms of OS. The other trial evaluating anthracycline-based chemotherapy is the SWOG 8814 trial [19] that showed a beneficial effect on DFS and OS. Finally, the International Collaborative Cancer Group (ICCG) study [20] evaluated mono-chemotherapy with epirubicin (50 mg/m2 twice in each cycle) and the results showed a significant effect on DFS. Overall, >7000 patients were included in these large trials and, in general, they favor the use of chemotherapy. The overall effect of chemo- therapy is a 23% reduction in the risk of relapse or death (odds ratio 0.77, 95% CI 0.710.84), which is highly significant. Of course, a publication bias is possible, since trials that included less than 500 postmenopausal patients and unpublished trials were excluded. This publication bias would tend to increase the overall treatment effect [21].
If we consider the overall results according to the type of chemotherapy, two of the four trials evaluating CMF showed a beneficial significant effect, and the four trials that evaluated an anthracycline-based chemotherapy showed a significant treatment effect. If this difference between the effects of these regimens was real, three kinds of explanations should be discussed: the major effect of anthracyclines, the type of CMF and the dose effect.
Anthracycline-based chemotherapy regimens have been shown to be more effective than CMF-like chemotherapy [6]; even if the difference is moderate it could explain the apparent better results in trials summarized in Table 3. However, a controversy is still ongoing on the different modalities of CMF, and some authors [22, 23] claim that the best effect is obtained with a classical CMF regimen as originally described [8]. Indeed, in Table 3, the two trials evaluating classical CMF [14, 17] found a significant beneficial treatment effect. However, there is no heterogeneity on treatment effects among trials in terms of DFS (heterogeneity test, P = 0.08).
An alternative explanation would be a dose effect. It has been claimed that the smaller effect of adjuvant chemotherapy in postmenopausal patients was related to a poorer tolerance leading to a decrease in the delivered CMF doses within the classical schedule. Taking into account the possibility of this dose effect during the planning of the current trial, we decided to use an anthracycline-based regimen given in one day per course, thus avoiding dose adaptation during the chemotherapy cycle. Indeed, the chemotherapy compliance was quite good, as 95% of patients received the six planned courses, most using epirubicin, and only in 7% of patients was there an alteration in the chemotherapy delivery schedule. The other issue regarding the anthracycline dose is the chosen level of epirubicin dose. When planning the study, three randomized trials evaluating dose equivalence between doxorubicin and epirubicin in advanced breast cancer [2426] showed that a similar tumor effect was obtained with equi-doses of both anthracyclines. Since then, two adjuvant trials [27, 28] have shown that a dose effect exists for epirubicin and now a dose of 100 mg/m2 is considered more effective than 50 mg/m2. Even though the French [27] and Belgian trials [28] included only 276 and 217 postmenopausal patients, respectively, neither of these trials showed a differential chemotherapy effect according to age. It can then be hypothesized that the results of our trial could have been improved with a higher dose of epirubicin or even the use of a classical CMF regimen. In any case, these arguments favor the use of adjuvant chemotherapy in the population studied.
Regarding the exploratory subgroup analyses, in our trial a larger treatment effect was suggested for patients with ER-negative tumors in terms of DFS. This result agrees with those found in the EBCTCG overview [6]. We did not find any other interaction between chemotherapy effect and patient or tumor characteristics. We emphasise, however, that these analyses are only exploratory.
The study of the pattern of failure showed that chemotherapy mainly affected the distant metastasis rate, without a clear effect on the rate of other types of event (Table 2) in the presence of local or locoregional radiotherapy among >85% of patients. It is of importance that long-term control was not affected by the delay of local (regional) radiotherapy introduced by the administration of six courses of chemotherapy. These findings are in agreement with those of the IBCSG studies [29] and contradict the results of a small randomized study evaluating the chronology of radiotherapy and chemotherapy in early breast cancer [30]. At the present time, there is no evidence that a delay of radiotherapy when active adjuvant chemotherapy is given has a deleterious effect. This finding favors the hypothesis that systemic treatments have a beneficial effect on local control [31], even if this effect is rather moderate when compared with that provided by radiotherapy.
The relative reduction of recurrence and death found in the current and other similar trials (Table 3) may be challenged by the small absolute benefit that is obtained in patients with relatively good prognosis with tumors of <30 mm, with positive-ER and node-negative axilla [32]. In this decision-making process, it is advisable to take into account the particular risk factors of each patient to balance the expected benefit with the early toxicity of adjuvant chemotherapy [33].
In conclusion, overall treatment effects are in favor of adjuvant chemotherapy in postmenopausal patients in different subgroups even if there are some quantitative differences. It seems that the beneficial effects of chemotherapy and tamoxifen are at least partially independent.
|
![]() |
Footnotes |
---|
![]() |
References |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
2. Contesso G, Mouriesse H, Friedman S et al. The importance of histologic grade in long-term prognosis of breast cancer. A study of 1010 patients, uniformly treated at the Institut Gustave-Roussy. J Clin Oncol 1987; 5: 13781386.[Abstract]
3. Delozier T, Spielmann M, Mace-Lesech J et al. Tamoxifen adjuvant treatment duration in early breast cancer: Initial results of a randomized study comparing short-term treatment with long-term treatment. J Clin Oncol 2000; 18: 35073512.
4. Arriagada R, Rutqvist LE, Kramar A et al. Competing risks determining event-free survival in early breast cancer. Br J Cancer 1992; 66: 951957.[ISI][Medline]
5. Early Breast Cancer Trialists Collaborative Group. Treatment of Early Breast Cancer, Volume 1. Worldwide Evidence 19851990. Oxford: Oxford University Press 1990; 17.
6. Early Breast Cancer Trialists Collaborative Group. Polychemotherapy for early breast cancer: an overview of the randomized trials. Lancet 1998; 352: 930942.[ISI][Medline]
7. Schemper M, Smith TL. A note on quantifying follow-up in studies of failure time. Control Clin Trials 1996; 17: 343346.[ISI][Medline]
8. Bonadonna G, Brusamolino E, Valagussa P et al. Combination chemotherapy as an adjuvant treatment in operable breast cancer. N Engl J Med 1976; 294: 405410.[Abstract]
9. Brincker H, Mouridsen HT, Andersen KW. Adjuvant chemotherapy with cyclophosphamide or CMF in premenopausal women with stage II breast cancer. Breast Cancer Res Treat 1983; 3: 9195.[ISI][Medline]
10. Bines J, Oleske DM, Cobleigh MA. Ovarian function in premenopausal women treated with adjuvant chemotherapy for breast cancer. J Clin Oncol 1996; 14: 17181729.[Abstract]
11. Goldhirsch A, Gelber RD, Castiglione M. The magnitude of endocrine effects of adjuvant chemotherapy for premenopausal breast cancer patients. The International Breast Cancer Study Group. Ann Oncol 1990; 1: 183188.[ISI][Medline]
12. Rutqvist LE, Cedermark B, Fornander T et al. The relationship between hormone receptor content and the effect of adjuvant tamoxifen in operable breast cancer. J Clin Oncol 1989; 7: 14741484.[Abstract]
13. Early Breast Cancer Trialists Collaborative Group. Tamoxifen for early breast cancer: an overview of the randomised trials. Lancet 1998; 351: 14511467.[ISI][Medline]
14. Crivellari K, Bonetti M, Castiglione-Gersch M et al. Burdens and benefits of adjuvant cyclophosphamide, methotrexate, and fluourouracil and tamoxifen for elderly patients with breast cancer: The International Breast Cancer Study Group Trial VII. J Clin Oncol; 2000; 18: 14121422.
15. Rivkin SE, Green S, Metch B et al. Adjuvant CMFVP versus tamoxifen versus concurrent CMFVP and tamoxifen for postmenopausal, node-positive, and estrogen receptor-positive breast cancer patients: a South West Oncology Group study. J Clin Oncol 1994; 12: 20782085.[Abstract]
16. Pritchard KI, Paterson AMG, 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 1997; 15: 23022311.[Abstract]
17. Fisher B, Dignam J, Wolmark N et al. Tamoxifen and chemotherapy for lymph node-negative, estrogen receptor-positive breast cancer. J Natl Cancer Inst 1997; 89: 16731682.
18. 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 1990; 8: 10051018.[Abstract]
19. Albain K, Green S, Ravdin P et al. Overall survival after cyclophosphamide, adriamycin and 5-FU, and tamoxifen (CAFT) is superior to tamoxifen alone in postmenopausal, receptor (+), node (+) breast cancer: New findings from phase III Southwest Oncology Group Intergroup trial S8814 (INT-0100). Proc Am Soc Clin Oncol 2001; 20: 24a (Abstr 94).
20. Wils JA, Bliss JM, Marty M et al. Epirubicin plus tamoxifen versus tamoxifen alone in node-positive postmenopausal patients with breast cancer: a randomized trial of the International Collaborative Cancer Group. J Clin Oncol 1999; 17: 19881998.
21. Stewart LA, Parmar MKB. Meta-analysis of the literature or of individual patient data: is there a difference? Lancet 1993; 341: 418422.[ISI][Medline]
22. Goldhirsch A, Coates AS, Colleoni M et al. Adjuvant chemoendocrine therapy in postmenopausal breast cancer: cyclophosphamide, methotrexate, and fluorouracil dose and schedule may make a difference. J Clin Oncol 1998; 16: 13581362.[Abstract]
23. Engelsman E, Klijn JC, Rubens RD et al. Classical CMF versus a 3-weekly intravenous CMF schedule in postmenopausal patients with advanced breast cancer: an EORTC Breast Cancer Cooperative Group phase III trial. Eur J Cancer 1991; 27: 966970.[ISI][Medline]
24. French Epirubicin Study Group. A prospective randomized phase III trial comparing combination chemotherapy with cyclophosphamide, fluorouracil, and either doxorubicin or epirubicin. J Clin Oncol 1988; 6: 679688.[Abstract]
25. Italian Multicentre Breast Study with Epirubicin. Phase III randomized study of fluorouracil, epirubicin, and cyclophosphamide versus fluorouracil, doxorubicin, and cyclophosphamide in advanced breast cancer. An Italian multicentre trial. J Clin Oncol 1988; 6: 976982.[Abstract]
26. Lopez M, Papaldo P, Di Lauro L et al. 5-Fluorouracil, adriamycin, cyclophosphamide (FAC) versus 5-fluorouracil, epirubicin, cyclophosphamide (FEC) in metastatic breast cancer. Oncology 1989; 46: 15.[ISI][Medline]
27. French Adjuvant Study Group. Benefit of a high-dose epirubicin regimen in adjuvant chemotherapy for node-positive breast cancer patients with poor prognostic factors: 5-year follow-up results of French Adjuvant Study Group 05 randomized trial. J Clin Oncol 2001; 19: 602611.
28. Piccart MJ, Di Leo A, Beaudoin M et al. Phase III trial comparing two dose levels of epirubicin combined with cyclophosphamide with cyclophosphamide, methotrexate, and fluorouracil in node-positive breast cancer. J Clin Oncol 2001; 19: 31033109.
29. Wallgren A, Bernier J, Gelber RD et al. Timing of radiotherapy and chemotherapy following breast-conserving surgery for patients with node-positive breast cancer. International Breast Cancer Study Group. Int J Radiat Oncol Biol Phys 1996; 35: 649659.[ISI][Medline]
30. Recht A, Come SE, Henderson IC et al. The sequencing of chemotherapy and radiation therapy after conservative surgery for early stage breast cancer. N Engl J Med 1996; 334: 13561361.
31. Goldhirsch A, Gelber RD, Price KN et al. Effect of systemic adjuvant treatment on first sites of breast cancer relapse. Lancet 1994; 343: 377381.[ISI][Medline]
32. Grogan M, Tabar L, Chua B et al. Estimating the benefits of adjuvant systemic therapy for women with early breast cancer. Br J Surg 2001; 88: 15131518.[ISI][Medline]
33. Hurny C, Bernhard J, Coates AS et al. Impact of adjuvant therapy on quality of life in women with node-positive operable breast cancer. Lancet 1996; 347: 12791284.[ISI][Medline]