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Adjuvant doxorubicin and cyclophosphamide versus cyclophosphamide, methotrexate, and 5-fluorouracil chemotherapy in premenopausal women with axillary lymph node positive breast carcinoma

Adjuvant Doxorubicin and Cyclophosphamide versus
Cyclophosphamide, Methotrexate, and 5-Fluorouracil
Chemotherapy in Premenopausal Women with Axillary
Lymph Node Positive Breast Carcinoma

Results of a Randomized Controlled Trial
Soo-Mee Bang,
BACKGROUND. This randomized controlled trial was to determine whether a com-
Dae Seog Heo,
bination chemotherapy regimen that contains anthracycline (doxorubicin and Ki Hyeong Lee,
cyclophosphamide [AC]) is superior to the conventional cyclophosphamide, meth- Jae Ho Byun,
otrexate, and 5-fluorouracil [CMF] combination in premenopausal women with Heung Moon Chang,
axillary lymph node positive Stage II breast carcinoma.
Dong-Yong Noh,
METHODS. Premenopausal women with lymph node positive breast carcinoma
Kuk Jin Choe,
were stratified according to age (younger than 35 or 35 years or older) and the Yung-Jue Bang,
number of positive axillary lymph nodes (1–3, 4 –9, or Ն 10) and then randomly Sung Rok Kim,
assigned to receive either doxorubicin 40 mg/m2 and cyclophosphamide 600 Noe Kyeong Kim,
mg/m2 intravenously (i.v.) every 3 weeks or cyclophosphamide 100 mg/m2 orally on Days 1 through 14, methotrexate 40 mg/m2 and 5-fluorouracil 500 mg/m2 i.v. on 1 Department of Internal Medicine and Surgery, Days 1 and 8 every 4 weeks. Both arms were scheduled for six cycles.
Clinical Research Institute, Seoul National Univer- RESULTS. The median follow-up was 57 months. Eighteen of the 55 AC patients
sity College of Medicine, Seoul, Korea.
developed recurrence compared with 16 of the 69 CMF patients. The correspond- 2 Department of Internal Medicine, College of Med- ing 5-year recurrence free survival rates were 64% and 78%, respectively (P ϭ 0.12).
icine, Chung-Buk University, Cheongjue, Korea.
The site of the first recurrence for AC patients was locoregional in 7%, distant in 3 Department of Internal Medicine, College of Med- 22%, and combined in 4%. The corresponding data for the CMF arm were 4%, 16%, icine, In-Jae University, Seoul, Korea.
and 3%, respectively. Six AC patients died compared with 9 CMF patients. The corresponding 5-year survival rates were 90% and 86%, respectively (P ϭ 0.96).
More leukopenia (52%, mostly Grade 1–2) occurred in the CMF arm than in the AC arm (33%, P ϭ 0.001), but no febrile episode was accompanied with leukopenia.
CONCLUSIONS. This study showed no difference between AC and CMF with respect
to both disease free and overall survival rates in premenopausal women with
axillary lymph node positive breast carcinoma. Cancer 2000;89:2521– 6.
KEYWORDS: breast neoplasm, adjuvant chemotherapy, doxorubicin and cyclophos-
Supported in part by 1999-BK21 project for Med- phamide (AC), cyclophosphamide, methotrexate, and 5-fluorouracil (CMF).
Address for reprints: Noe Kyeong Kim, M.D., De- Adjuvant chemotherapy is known to decrease the recurrence and
partment of Internal Medicine, Seoul National Uni- improve the survival rate of women with axillary lymph node versity, Hospital, 28 Yongon-dong, Chongno-gu, positive breast carcinoma.1 The combination chemotherapy regimen Seoul, 110-744 Korea; fax: 82-2-742-6689; of cyclophosphamide, methotrexate, and 5-fluorouracil (CMF), first reported to be effective in lymph node positive breast carcinoma in1976, is still a commonly used adjuvant chemotherapy regimen.2 Received March 20, 2000; revisions received June28, 2000 and August 15, 2000; accepted August However, the results of several clinical trials have failed to show the role of anthracycline in the adjuvant setting in patients with axillary CANCER December 15, 2000 / Volume 89 / Number 12
lymph node positive breast carcinoma. In the National 35 or 35 years or older) and number of positive axillary Surgical Adjuvant Breast and Bowel Project (NSABP- lymph nodes (1–3, 4 –9, or Ն 10). Sequential cards B15) trial, women with axillary lymph node positive were used for the randomization procedure.
breast carcinoma were randomized to receive either Patients in the AC group received doxorubicin 40 CMF or doxorubicin and cyclophosphamide (AC); no mg/m2 and cyclophosphamide 600 mg/m2 i.v., every 3 difference was detected in disease free or overall sur- weeks for 6 cycles. Patients in the CMF group received vival.3 Other trials have compared CMF with CMF cyclophophamide 100 mg/m2 p.o. on Days 1 through followed by doxorubicin,4 CMF with 5-fluorouracil, 14, methotrexate 40 mg/m2 and 5-fluorouracil 500 epirubicin, and cyclophophamide (FEC),5 and CMF mg/m2 i.v. on Days 1 and 8 every 4 weeks for 6 cycles.
with cyclophosphamide, doxorubicin, and 5-fluorou- If on the day of the therapy the leukocyte count was racil (CAF).6 No differences were detected during less than 3.0 ϫ 109/L or the platelet count was less these trials between regimens in disease free and over- than 75 ϫ 109/L, it was recommended that treatment all survival.4–6 However, a French trial showed long be delayed for a maximum of 2 weeks and weekly term survival benefits of anthracycline-based chemo- blood counts were performed. Dose reduction by 25% therapy. In this study, patients were randomized to was recommended for a leukocyte count of 3.0 –3.9 receive 12 cycles of CMF or doxorubicin, vincristine, ϫ 109/L or a platelet count of 75–100 ϫ 109/L.
cyclophosphamide, and 5-fluorouracil (AVCF).7 An- After completion of chemotherapy, patients were other trial that compared FEC with a CMF regimen examined every 3 months until the end of the second showed that patients on the FEC regimen had superior year, then every 6 months for 5 years, and yearly recurrence free and overall survival rates at 5 years.8 thereafter. At each follow-up visit, patients underwent We therefore conducted a trial to investigate a physical examination, and a history was taken, and a whether the AC regimen is superior to the conven- complete blood count, platelet count, and liver func- tional CMF combination in premenopausal women tion test were performed. Chest X-ray, abdominal ul- with lymph node positive operable breast carcinoma.
trasonography, and bone scan were checked everyother visit.
The major outcome measures for the study were Premenopausal women with histologically confirmed recurrence free survival, overall survival, and toxicity.
axillary lymph node positive breast carcinoma who Recurrence free survival, the primary protocol-defined had undergone modified radical mastectomy or outcome measure of the study, was timed from ran- quadrantectomy plus axillary dissection were enrolled domization until recurrence. Locoregional recurrence in this study (T1 or T2N1M0 according to American included recurrences in the breast, local chest wall, Joint Committee on Cancer TNM classification). Post- and regional recurrence. Regional recurrence was de- operative radiotherapy was mandatory after the fined as a recurrent tumor in the lymph nodes of breast-conserving surgery. Elective radiotherapy after ipsilateral axillary, supraclavicular, or internal mam- mastectomy was adopted at the direction of the par- mary chain. Distant recurrence was defined as a ticipating physicians. Radiotherapy was performed af- spread of the disease systemically beyond the limits ter the completion of chemotherapy. Hormone recep- previously described. A carcinoma that developed in tor assays were not available for all patients.
the opposite breast without any evidence of systemic Patients were excluded from the study if they had metastasis was considered as a new primary malig- any evidence of metastasis, a documented history of cardiac disease or previous cancer, inadequate renalfunction (as indicated by a serum creatinine levelϾ 1.5 times the normal upper limit), or elevated levels Statistical Considerations
of liver enzymes (bilirubin Ͼ 3 mg/L, alkaline phos- Survival time and time to recurrence were calculated phatase Ͼ 1.5 times the normal upper limit, or aspar- using the Kaplan–Meier method, and the log rank test tate amintotransferase Ͼ 1.5 times the normal upper was used to compare the curves of the survival times limit), a serious underlying medical illness or locally and the times to progression. The Cox proportional advanced breast carcinoma before surgery, micro- hazards model was used to adjust the observed treat- scopic or macroscopic evidence of residual tumor, or ment effect for the influence of various prognostic if more than 7 weeks has elapsed from the initial factors at study entry, and to detect the effect of un- derlying prognostic factors on outcome. Other char- Patient accrual began on October 1989 and was acteristics of the two treatment arms were compared completed on July 1996. After assignment to the study, using the chi-square test. All calculations were per- patients were stratified according to age (younger than AC vs. CMF in Breast Carcinoma/Bang et al.
Baseline Characteristics of Study Patients

FIGURE 1. Recurrence free survival of AC versus CMF (P ϭ 0.12). Solid black
line, AC; dashed line, CMF.
MRM, modified radical mastectomy; Quad ϩ AND, quadrantectomy with dissection of axillary lymphnode; RT, radiation therapy; ER, estrogen receptor.
a One patient who underwent Quad ϩ AND received radiotherapy after completion of chemotherapy.
Recurrence Free Survival
Eighteen AC patients developed recurrence of their
breast carcinomas compared with 16 CMF patients.
The 5-year recurrence free survival rate of the AC Patient Population
patients was 64% (95% confidence interval, 57–71%) The trial was started in 1989 and was closed in 1996.
The median follow-up was 57 months. Fifty-eight 72– 84%) for the CMF patients (P ϭ 0.12; Fig. 1). The women were allocated to AC therapy and 70 to CMF site of the first recurrence for AC patients was locore- therapy. This discrepancy in the number of patients gional in 4 (7%) patients, distant in 12 (22%) patients, was due to randomization procedure without bloc.
and combined in 2 (4%) patients. The corresponding Three patients in the AC arm and one patient in the data for the CMF arm were 3 (4%), 11 (16%), and 2 CMF arm were lost in follow-up after one to three (3%) patients, respectively. There were three cases of cycles of chemotherapy and were not included for the contralateral breast carcinoma in the AC group com- evaluation of recurrence, survival and toxicity. The pared with two cases in the CMF group.
treatment groups were reasonably similar with respect The 5-year recurrence free survival rates for sub- to baseline characteristics, such as age, type of sur- groups such as age (younger than 35 or 35 years or gery, additional radiotherapy, tumor stage, number of older), tumor stage (T1 or T2), number of the positive positive axillary lymph nodes, and status of estrogen axillary lymph nodes (1–3, 4 –9, or Ն 10), average rel- ative dose intensity (Ͻ 0.8 or Ն 0.8) and average rel-ative dose intensity of doxorubicin (Ͻ 0.8 or Ն 0.8) arelisted in Table 2. In univariate and multivariate anal- Drug Dosages
ysis, both tumor stage and the number of positive Fifty-five patients treated with AC and 69 patients lymph nodes were significant prognostic factors.
treated with CMF completed 6 cycles of chemother-apy. The average relative dose intensity for the drugs Survival
in AC was 0.81 Ϯ 0.08, and the average relative dose Six patients on the AC arm died compared with nine intensity of doxorubicin was 0.83 Ϯ 0.08. The average patients on the CMF arm. All these patients died of relative dose intensity for the drugs in CMF was 0.86 disease progression. The 5-year survival rates were Ϯ 0.10. The average relative dose intensity for the 90% (95% confidence interval, 86 –94%) and 86% (95% drugs in AC was significantly lower than that of CMF confidence interval, 82–90%), respectively (P ϭ 0.96; Fig. 2). The 5-year survival rates for the subgroups are CANCER December 15, 2000 / Volume 89 / Number 12
Recurrence Free Survival and Overall Survival

P valuea
P valueb
P valuea
P valueb
RFS: recurrence free survival; OS: overall survival; RDI: relative dose intensity.
a Univariate analysis.
b Multivariate analysis.
c Of all drugs.
d Of doxorubicin in the doxorubicin and cyclophosphamide arm.
Incidence of Hematologic Toxicity

(P value)
AC: doxorubicin and cyclophosphamide; CMF: cyclophosphamide, methotrexate, and 5-fluorouracil.
a Chi-square test.
episode of Grade 1 anemia and 5 episodes of Grade 2anemia in the CMF arm.
FIGURE 2. Overall survival of AC versus CMF (P ϭ 0.96). Solid black line, AC;
This report indicates that the recurrence free survival,overall survival, and patterns of treatment failure ofpatients treated with AC are nearly identical to those listed in Table 2. Age and the number of positive obtained after the administration of conventional lymph nodes were significant predictors of survival by CMF. Our results are similar to those of the NSABP-15 univariate and multivariate analysis.
trial. However, the schedule of chemotherapy and thedose intensity of doxorubicin were different. Planned Toxicity
dose intensity of doxorubicin was 13.3 mg/m2/week More leukopenia occurred in the CMF arm and no for 18 weeks in our trial; compared with 20 mg/m2/ patients suffered from febrile leukopenia in either week for 12 weeks in NSABP-15.3 The recommenda- arm. No difference was found in the incidence of tion of AC in an adjuvant setting by NSABP-15 was anemia. Two patients who had had iron deficiency made because the toxicity resulting from 12 weeks of anemia before adjuvant chemotherapy developed 1 AC therapy compared favorably with side effects as- AC vs. CMF in Breast Carcinoma/Bang et al.
sociated with 24 weeks of conventional CMF. Doxoru- prospective randomized trial, Peters et al.11 random- bicin and cyclophosphamidechemotherapy was ex- ized 783 patients with Stage II or IIIA breast carcinoma amined for a longer period in our study and this involving 10 or more axillary lymph nodes to receive benefit with respect to duration and toxicity was either high dose CPB (cyclophosphamide, cisplatin, found to be reduced compared with the NSABP-15 and BCNU) with stem cell support or intermediate- trial. In the French trial, the duration of adjuvant dose CPB with granulocyte-colony stimulating factor chemotherapy was 48 weeks, and the dose intensity of support after 4 cycles of CAF. The intent-to-treat event doxorubicin was 7.5 mg/m2/week. Although the dose free survival and overall survival comparisons were intensity of doxorubicin was lower than that of other inconclusive after a median follow-up of 37 months.
trial, the total dose of doxorubicin was 2.5 times larger Therapy-related deaths (7%) occurred only in the high than that of NSABP-15 and our trials. In addition, the dose CPB arm. This result needs cautious application dose intensity of cyclophosphamide was also 1.5 times of high dose chemotherapy. Another approach to im- and vincristine was added. During the median follow- prove the outcome of high risk group is adding tax- up of 13 years, benefits of recurrence free and overall anes to adjuvant doxorubicin-based chemotherapy.
survival increased evidently in the AVCF arm.7 In a Henderson et al.12 reported that the addition of pac- Canadian trial, epirubicin was substituted for doxoru- litaxel reduced the recurrence rate by 22% and the bicin, and the dose intensity of epirubicin was 30 death rate by 26% by multivariate analysis. This in- mg/m2/week for 24 weeks. Patients with ECF chemo- terim analysis will be reevaluated after longer follow-up.
therapy had better survival.8 The Cancer and Leuke-mia Group B have indicated that the total dose re-mains a critical determinant of outcome and dose REFERENCES
Early Breast Cancer Trialists Collaborative Group. Systemic reduction, perhaps less than a threshold, leads to a treatment of early breast cancer by hormonal, cytotoxic or relatively worse outcome of the CAF regimen.9 These immune therapy: 133 randomized trials involving 31,000 results suggest that anthracycline itself is not a prog- recurrences and 24,000 deaths among 75,000 women. Lan- nostic indicator, but that both the drug dose of an- thracycline and other combined drugs may be the Bonadonna G, Brusamolino E, Valagussa P, Rossi A, Brug-natelli L, Brambilla C, et al. Combination chemotherapy as major prognostic factor. Our study was designed with an adjuvant treatment in operable breast cancer. N Engl lower dose of doxorubicin and the actual relative dose intensity of AC arm was lower than that of the CMF Fisher B, Brown AM, Dimitrov NV, Poisson R, Redmond C, arm (P ϭ 0.006). The second factor is that a longer Margolese RG, et al. Two months of doxorubicin-cyclo- follow-up period is needed to ascertain the role of phophamide with and without interval reinduction therapycompared with six months of cyclophophamide, methotrex- anthracycline in adjuvant chemotherapy in lymph ate and 5-fluorouracil in positive-node breast cancer pa- node positive breast carcinoma. These factors may tients with tamoxifen-nonresponsive tumors: results from have contributed to our negative result.
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Levine MN, Bramwell VH, Prichard KI, Norris BD, Shepherd resectable breast cancer with more than three positive axil- LE, Abu-Zahra H, et al. Randomized trial of intensive cyclo- lary modes. J Clin Oncol 1991;9:2134 – 40.
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