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Background The prognosis for women with primary breast cancer and 10 or more involved axillary lymph nodes is poor. High-dose chemotherapy with autologous hematopoietic stem-cell transplantation has been reported to be effective in the adjuvant setting for patients at high risk for relapse.
Methods We randomly assigned 540 female patients with primary breast cancer and at least 10 involved ipsilateral axillary lymph nodes to receive either six cycles of adjuvant chemotherapy with cyclophosphamide, doxorubicin, and fluorouracil (CAF) or the same adjuvant chemotherapy followed by high-dose chemotherapy with cyclophosphamide and thiotepa and autologous hematopoietic stem-cell transplantation.
Results Among the 511 eligible patients, there was no significant difference in disease-free survival, overall survival, or the time to recurrence between those who received CAF alone and those who received CAF plus high-dose chemotherapy and stem-cell transplantation. Among 417 patients fulfilling strict eligibility criteria, the time to recurrence was longer for patients who underwent stem-cell transplantation than for those who received CAF alone. In the transplantation group, nine patients died of transplantation-related complications and a myelodysplastic syndrome or acute myeloid leukemia developed in nine.
Conclusions The addition of high-dose chemotherapy and autologous hematopoietic stem-cell transplantation to six cycles of adjuvant chemotherapy with CAF may reduce the risk of relapse but does not improve the outcome among patients with primary breast cancer and at least 10 involved axillary lymph nodes. Conventional-dose adjuvant chemotherapy remains the standard of care for such patients.
Methods
Eligibility for Study Entry
Female patients were eligible to enter the study if they had been given a biopsy-proven diagnosis of epithelial carcinoma of the breast; had at least 10 involved ipsilateral axillary lymph nodes; had undergone a radical, modified radical, or breast-sparing procedure plus axillary dissection with margins that were histologically free of tumor within 12 weeks before study entry; had normal blood counts; were 15 to 60 years of age; had liver-function tests whose results were no more than 1.2 times the normal values; had no evidence of breast cancer in bilateral bone marrow core-biopsy specimens and on bone scanning; had a left ventricular ejection fraction of at least 50 percent on multiple gated acquisition scanning; had a forced expiratory volume in one second (FEV1) and a diffusing capacity for carbon monoxide that were at least 60 percent of the predicted values; and had an Eastern Cooperative Oncology Group performance status of 0 or 1. Patients provided written informed consent. Patients with T4 disease (extension into the chest wall), bilateral infiltrating cancers that occurred more than six weeks apart, or distant metastases were excluded. No prior therapy was permitted before enrollment except tamoxifen for 21 days or less and one or two cycles of doxorubicin-based chemotherapy. Patients with apocrine, adenocystic, squamous-cell, or inflammatory carcinoma or sarcoma; those who were pregnant or lactating; and those who had symptomatic central nervous system disease of any cause were also excluded. Prior hormone-replacement therapy was allowed, but it had to have been discontinued before enrollment.
Eligibility for Autologous Hematopoietic Stem-Cell Transplantation
Eligibility for autologous hematopoietic stem-cell transplantation included an Eastern Cooperative Oncology Group performance status of 0 or 1, the absence of active infection, a serum creatinine level of 2.0 mg per deciliter (177 µmol per liter) or less, alkaline phosphatase and alanine aminotransferase values that were no more than 1.2 times the normal value, a total serum bilirubin level of 2.0 mg per deciliter (34 µmol per liter) or less, the absence of evidence of breast cancer, and an FEV1 and a diffusing capacity for carbon monoxide that were at least 60 percent of the predicted values.
Treatment
Adjuvant Chemotherapy
All patients received adjuvant chemotherapy consisting of 100 mg of cyclophosphamide per square meter of body-surface area per day given orally on days 1 through 14, 30 mg of doxorubicin per square meter per day given intravenously on days 1 and 8, and 500 mg of fluorouracil per square meter per day given intravenously on days 1 and 8 (CAF) every 28 days for a total of six cycles.14 The doses were based on actual body weight. Patients who were randomly assigned to receive CAF alone were to receive a 50-Gy dose of radiation therapy to the breast and chest wall and regional nodes beginning within four weeks after the completion of chemotherapy or when the white-cell count exceeded 2900 per cubic millimeter and the platelet count exceeded 100,000 per cubic millimeter. Tamoxifen, at a daily dose of 20 mg orally, was to be given for 5 years to patients whose tumors were estrogen-receptor–positive or progesterone-receptor–positive (or both), beginning 28 days after the start of the last CAF cycle.
Preparative Regimen for Transplantation
Patients who were assigned to receive CAF plus autologous hematopoietic stem-cell transplantation received high-dose chemotherapy as follows: a continuous intravenous infusion of 6 g of cyclophosphamide per square meter and 800 mg of thiotepa per square meter over a four-day period. High-dose chemotherapy was given on days 6, 5, 4, and 3 before the infusion of autologous bone marrow, peripheral-blood stem cells, or both.15 For patients who received stem cells derived from bone marrow, a minimum of 1x108 nucleated cells per kilogram of actual body weight was required. For patients who received stem cells derived from peripheral blood, at least 1x109 nucleated cells per kilogram were required. Radiation therapy to the breast and chest wall and regional nodes (total, 50 Gy) was to be initiated within eight weeks after transplantation. Patients with estrogen-receptor–positive or progesterone-receptor–positive tumors (or both) were to begin tamoxifen after transplantation when the white-cell count exceeded 4000 per cubic millimeter or the absolute neutrophil count exceeded 2000 per cubic millimeter (or both criteria were met).
Modifications to the Treatment Plan
In July 1994, three years after the study began, the protocol was amended to permit the administration of up to one cycle of CAF before enrollment. In December 1995, a second amendment allowed up to two cycles of any doxorubicin-based chemotherapy to be given before study entry. In the original protocol, patients assigned to autologous hematopoietic stem-cell transplantation after completing adjuvant CAF were to be randomly assigned to one of three regimens of granulocyte–macrophage colony-stimulating factor (GM-CSF): 250 µg per square meter per day over a 2-hour period, 250 µg per square meter per day over a 6-hour period, or 250 µg per square meter per day over a 24-hour period. The amendment in July 1994 eliminated this randomization scheme and left the dose and schedule of growth factors to the discretion of the treating physician. The use of GM-CSF at a dose of 250 µg per square meter per day was recommended. Originally, only autologous bone marrow transplants were allowed. The amendment in July 1994 also allowed the use of peripheral-blood stem-cell transplants alone or in combination with autologous marrow. Initially, tamoxifen was given to patients who were positive for either estrogen receptors or progesterone receptors. The amendment in July 1994 required tamoxifen to be given only to patients whose tumors were positive for estrogen receptors.
Statistical Analysis
Disease-free survival was defined from the time of randomization to the earliest sign of a recurrence, a new primary breast cancer, or death without recurrence; data were censored on the date a patient was last known to be alive. Survival was defined as the time from randomization to death from any cause. The time to recurrence was defined as the time from randomization to recurrence or a new primary breast cancer; data were censored on the date a patient was last known to be disease-free.
The rates of failure in each group were estimated with use of the method of Kaplan and Meier16 and compared with use of the log-rank test.17 A Cox proportional-hazards model was used to estimate hazard ratios and to perform regression analysis.18 Comparisons were conducted according to the intention-to-treat principle. All P values are based on two-sided tests, and P values of less than 0.05 were considered to indicate statistical significance.
The primary analysis was originally planned to include the subgroup of eligible patients. However, owing to the high rates of ineligibility, this policy was reviewed in July 1999, whereupon we decided to divide protocol violations into major and minor categories and to include patients with minor violations in the primary analysis. Major protocol violations included the lack of a bone scan in one patient, positive resected margins in five patients, the lack of a bone marrow core biopsy in six, the presence of inflammatory carcinoma or peau d'orange in five, possible metastatic disease in one, invasive prior breast cancer in one, diabetes in one, prior therapeutic oophorectomy in two, the lack of a documented left ventricular ejection fraction at base line in one, the lack of a documented pulmonary-function test at base line in three, residual disease in the axilla in one patient, and fewer than 10 positive axillary lymph nodes in one patient. Minor violations included the failure to obtain bilateral bone marrow aspirates and biopsy specimens in a patient with negative findings on unilateral biopsy; the failure to meet the requirements for the assessment of lung volume and diffusing capacity for carbon monoxide in a patient with adequate pulmonary function; violations of prestudy laboratory requirements (mostly in patients who started chemotherapy before entry); failure to document performance status, insurance coverage, or a negative pregnancy test; the receipt of chemotherapy before entry that was not allowed in the protocol; the failure to submit an operative report; and the failure to perform multiple gated acquisition scanning in a patient with adequate cardiac function. Secondary analyses of the subgroups of all randomized patients and eligible patients were also performed.
Three formal interim analyses of disease-free survival were performed. The results were released by the data-monitoring committee when 92 percent of the planned information was available, since it was clear that the primary end point of a difference in disease-free survival would not become significant.
Results
Enrollment
Between August 1991 and August 1998, 540 patients were enrolled. Data have been analyzed as of September 2002. Of the 540 patients enrolled, 1 had no data submitted and 28 had major protocol violations, leaving 511 patients in the primary analysis (Table 1). An additional 94 patients — 49 in the group assigned to receive CAF alone and 45 in the group assigned to receive CAF, high-dose chemotherapy, and a hematopoietic stem-cell transplant — had minor protocol violations. Among patients who were disease-free after the completion of CAF, 7 percent of those assigned to CAF alone received some form of transplantation therapy, and of those assigned to high-dose chemotherapy with stem-cell transplantation, 14 percent did not receive a transplant and 7 percent underwent transplantation outside the study.
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The base-line characteristics of the patients were similar in the two groups (Table 2). The median age of the 511 patients was 44 years. Approximately one third of the patients in each group were younger than 40 years of age, and approximately one fourth of the patients in each group were postmenopausal. In one fourth of the patients in each group, the size of the primary tumor exceeded 5 cm, and 60 percent of the patients in each group were positive for estrogen receptors, progesterone receptors, or both.
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CAF Adjuvant Chemotherapy
There were no drug-related fatalities in the group that received CAF alone. The most common grade 3 (severe) or grade 4 (life-threatening) nonhematologic adverse effects included nausea (11 percent), vomiting (8 percent), stomatitis (4 percent), neurologic effects (6 percent), hyperglycemia (2 percent), phlebitis (1 percent), hepatotoxicity (1 percent), and pulmonary effects (1 percent). Grade 3 or 4 granulocytopenia and thrombocytopenia occurred in 90 percent of patients.
Stem-Cell Transplantation
The most common nonhematologic adverse effects related to autologous hematopoietic stem-cell transplantation included nausea (32 percent), stomatitis (grade 3 in 26 percent and grade 4 in 11 percent), infection (grade 3 in 19 percent and grade 4 in 2 percent), diarrhea, hyperglycemia, hepatotoxicity, and rash (Table 3).
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Nine patients died between 2 days before and 55 days after receiving the transplant (Table 4). All but one death occurred early in the trial, generally when bone marrow–derived stem cells, rather than stem cells from the peripheral blood, were infused (six patients received only bone marrow–derived stem cells, two received stem cells derived from both bone marrow and peripheral blood, and one received stem cells derived from peripheral blood). The use of stem cells derived from bone marrow was invariably associated with more prolonged aplasia than the use of stem cells derived from peripheral blood. The causes of death were as follows: cyclophosphamide-induced myocarditis with pericardial tamponade in one patient, cerebral hemorrhage in one, aspergillosis in two, capillary leak syndrome with multiorgan failure in one, pulmonary toxicity with multiorgan failure in one, graft failure in one, sepsis in one, and infection in one (Table 4).
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The incidence of second (non-breast) cancers is summarized in Table 5. In the group that received CAF alone, one case of myeloma, one case of lymphoma, and seven solid tumors developed. In the group assigned to high-dose chemotherapy with stem-cell transplantation, solid tumors developed in six patients, a myelodysplastic syndrome developed in six, and acute myelogenous leukemia developed in three. Of the last three patients, two had had a myelodysplastic syndrome 1.9 and 8.7 years after study entry. Six of the nine patients with a myelodysplastic syndrome or leukemia have died.
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All first occurrences of treatment failure in the opposite breast were included as new primary breast cancers, whereas first treatment failures in the ipsilateral breast were regarded as recurrences. Among the 257 patients in the CAF group who were included in the primary analysis, 124 (48 percent) had a recurrence, 4 (2 percent) had new primary breast cancers, and 4 (2 percent) died before the disease recurred. The respective values among the 254 patients assigned to high-dose chemotherapy with stem-cell transplantation were 99 (39 percent), 7 (3 percent), and 19 (7 percent).
Disease-free Survival
The median follow-up of patients was 6.1 years. The difference in disease-free survival between the two groups was not significant (P=0.55) (Figure 1A). The six-year disease-free survival rate was 47 percent in the group given CAF alone and 49 percent in the group assigned to high-dose chemotherapy with stem-cell transplantation.
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The difference in overall survival between the two groups was not significant (P=0.32) (Figure 1B). The six-year overall survival rate was 62 percent in the group given CAF alone and 58 percent in the group assigned to high-dose chemotherapy with stem-cell transplantation.
Time to Recurrence
Time to recurrence in the two groups was not significantly different in the primary analysis (P=0.12) (Figure 1C). At six years, 48 percent of the patients in the group given CAF alone were free of recurrence, as compared with 55 percent of the patients in the group assigned to high-dose chemotherapy with stem-cell transplantation. When only the 417 patients fulfilling strict eligibility were analyzed, the time to recurrence was longer among patients in the group assigned to high-dose chemotherapy with stem-cell transplantation (P=0.045). At six years 45 percent of patients in the group given CAF alone were free of recurrence, as compared with 55 percent of patients in the other group.
Outcome Related to Estrogen-Receptor Status
There were no significant differences in disease-free survival, overall survival, or time to recurrence between the two groups when estrogen-receptor status was considered (data not shown).
Analysis of Prognostic Factors
To evaluate the possible influence of the patients' characteristics and disease-related characteristics, we designed proportional-hazards regression models incorporating a variety of factors, including treatment assignment, estrogen-receptor status, tumor size (≤2 cm, >2 to 5 cm, or >5 cm), the number of involved lymph nodes (10 to 14 vs. more than 14), age at study entry (younger than 40 years vs. 40 years or older), and menopausal status, for each of the three end points (disease-free survival, overall survival, and time to recurrence). Estrogen-receptor status was significant for all three end points (P=0.006 for disease-free survival, P<0.001 for overall survival, and P=0.005 for time to recurrence), with estrogen-receptor–positive patients having lower rates of treatment failure. Estrogen-receptor status was the only significant factor in the models for disease-free survival and time to recurrence. The only other significant factor in the model for overall survival was age (P=0.04), with better overall survival among patients who were 40 years of age or older. Treatment assignment was not a significant factor with respect to any of the end points (P=0.82 for disease-free survival; P=0.15 for overall survival, with slightly worse overall survival among the patients assigned to high-dose chemotherapy with stem-cell transplantation; and P=0.27 for time to recurrence).
Discussion
We found that the addition of autologous stem-cell transplantation to six cycles of conventional-dose CAF adjuvant chemotherapy did not significantly increase either disease-free survival or overall survival among women with stage II or III breast cancer and at least 10 involved ipsilateral axillary lymph nodes. However, in a subgroup analysis that excluded patients with minor protocol violations, the time to recurrence was longer among patients assigned to high-dose chemotherapy with stem-cell transplantation, suggesting that the addition of stem-cell transplantation may enhance the antitumor effect more than does six cycles of adjuvant chemotherapy with CAF alone. An apparent late divergence in the rates of disease-free survival, overall survival, and time to recurrence suggests that longer follow-up will be important to determine whether such differences persist or increase. If so, further subgroup analyses may prove useful in future clinical trials.
Five other randomized trials have addressed the potential benefits of autologous hematopoietic stem-cell transplantation after adjuvant chemotherapy in patients with 10 or more involved axillary lymph nodes, and our results are generally consistent with those of other studies. In a small, single-institution trial, 78 high-risk patients who were given eight cycles of conventional-dose adjuvant chemotherapy were randomly assigned to either two cycles of high-dose chemotherapy with cyclophosphamide, etoposide, and cisplatin plus autologous hematopoietic stem-cell transplantation or no further chemotherapy.19 No significant difference in relapse-free or overall survival was observed. Investigators at the Netherlands Cancer Institute randomly assigned 81 patients to receive either a fourth cycle of adjuvant chemotherapy with fluorouracil, epirubicin, and cyclophosphamide (FEC) or high-dose chemotherapy with cyclophosphamide, thiotepa, and carboplatin and stem-cell transplantation.20 (The final results are reported elsewhere in this issue.21) After a follow-up of more than six years, no significant difference was observed in relapse-free or overall survival. In a large intergroup trial, patients were randomly assigned to receive either high doses of cyclophosphamide, cisplatin, and carmustine with stem-cell support or intermediate doses of this regimen with granulocyte colony-stimulating factor support after four cycles of adjuvant chemotherapy with CAF.22 No statistically significant differences in event-free survival were observed. In a study from Scandinavia, patients were assigned to receive either nine cycles of FEC, with the doses adjusted to achieve targeted nadir blood counts, or three cycles of conventional-dose (unadjusted) FEC followed by cyclophosphamide, thiotepa, and carboplatin with autologous hematopoietic stem-cell transplantation.23 Follow-up was not long enough to allow a survival analysis, but myelodysplastic syndrome or acute myelogenous leukemia developed in eight patients in the adjusted-dose FEC group. In the Anglo-Celtic trial, 605 patients with 4 or more involved axillary lymph nodes (median, 9+) were randomly assigned to conventional adjuvant chemotherapy with cyclophosphamide, methotrexate, and 5-fluorouracil or high-dose chemotherapy.24 No difference was observed in event-free survival (54 percent vs. 51 percent, respectively) or overall survival (62 percent vs. 63 percent, respectively). All five treatment-related deaths occurred in the high-dose chemotherapy group.
Roche et al. randomly assigned 314 women who were younger than 60 years of age, had more than seven involved lymph nodes, and received four cycles of fluorouracil, cyclophosphamide, and epirubicin to receive either no further chemotherapy or high-dose chemotherapy with cyclophosphamide, mitoxantrone, and melphalan with autologous hematopoietic stem-cell transplantation.25 After a median follow-up of 39 months, an intention-to-treat analysis showed that the 3-year disease-free survival rate was 55 percent in the conventional-treatment group and 71 percent in the high-dose group (P<0.003), and the overall survival rates were 84 percent and 86 percent, respectively (P=0.33). This was the only trial to show an improvement in disease-free survival, but it included patients at somewhat lower risk for recurrence (7 to 10 involved lymph nodes) than our patients and had a relatively short median follow-up.
Our results do not confirm the promise of earlier phase 2 trials.6,7,8,9,10 Most such studies included relatively small numbers of patients, were not randomized, and were subject to selection bias.12,13 Factors that may have contributed to the lack of improvement in disease-free survival and overall survival in this trial included nine transplantation-related deaths, most occurring before the introduction of stem cells derived from peripheral blood as a source of hematopoietic reconstitution, and the development of a secondary myelodysplastic syndrome or acute myelogenous leukemia in nine patients in the transplantation group. Although the number of relapses may be reduced by the addition of stem-cell transplantation, the benefit was offset in part by treatment-related deaths. An additional theoretical limitation of high-dose chemotherapy and autologous hematopoietic stem-cell transplantation is the risk of contaminating the harvested stem cells with malignant cells.26 The degree of contamination may be influenced by the mobilization methods used.27
The development of myelodysplastic syndrome or acute myelogenous leukemia in nine patients is a serious concern, since this has become an increasingly recognized, but uncommon, complication of adjuvant chemotherapy27,28,29,30,31 or autologous hematopoietic stem-cell transplantation32,33 for breast cancer, and the median survival among patients in whom these therapy-related complications develop is only six months after transplantation.34 Prior reports suggested a relatively low incidence of these complications: a four-year probability of 1.6 percent in the series by Laughlin et al.32 and a five-year probability of 3.2 percent in the series by Nichols et al.33 However, these complications developed in 4 percent of our patients. The individual contribution of the adjuvant chemotherapy or high-dose chemotherapy with two alkylating agents cannot be determined. Furthermore, the two treatments may have an additive effect with respect to leukemogenicity. We speculate that the development of secondary myelodysplastic syndrome or acute myelogenous leukemia could be avoided and disease-free survival and overall survival improved by collecting peripheral-blood stem cells after one or two cycles of adjuvant chemotherapy, since the type and intensity of pretransplantation chemotherapy with alkylating agents have an important influence on the development of these disorders and conventional-dose chemotherapy before transplantation damages hematopoietic stem cells.35,36
Although the addition of autologous hematopoietic stem-cell transplantation to conventional adjuvant chemotherapy did not improve disease-free survival or overall survival, the increased time to recurrence suggests that the long-term outcome may improve if transplantation-related mortality and the development of secondary myelodysplastic syndrome and acute myelogenous leukemia can be avoided. Transplantation-related mortality has been all but eliminated through the use of peripheral-blood stem cells, and less potentially leukemogenic preparative regimens may decrease the risk of secondary myelodysplastic syndrome or acute myelogenous leukemia. Whether the use of such contemporary transplantation strategies will translate into a survival benefit must be determined in a prospective randomized trial. Conventional-dose adjuvant chemotherapy remains the standard of care for women with primary breast cancer and a high risk of recurrence.
This study was coordinated by the Eastern Cooperative Oncology Group (Robert L. Comis, M.D., chair) and supported in part by grants from the Public Health Service (CA23318, CA66636, CA21115, CA17145, CA32102, CA28926, CA13650, CA16116), the National Cancer Institute, National Institutes of Health, and the Department of Health and Human Services. Its contents are solely the responsibility of the authors and do not necessarily represent the official views of the National Cancer Institute.
Dr. Robert reports having received consulting and lecture fees from Bristol-Myers Squibb and consulting fees from Genentech, Astra Pharmaceuticals, and Aventis. Dr. Osborne reports having received consulting fees from Merck and grant support from AstraZeneca. Dr. Fetting reports having received lecture fees from AstraZeneca. Dr. Lazarus reports having received consulting fees from Pfizer and Wyeth–Ayerst.
Source Information
From the Division of Hematology–Oncology, Northwestern University Feinberg School of Medicine, Robert H. Lurie Comprehensive Cancer Center, Chicago (M.S.T., W.JG.); Dana–Farber Cancer Institute, Boston (R.G.); Inova Fairfax Hospital, Falls Church, Va. (N.J.R.); Texas Transplant Institute, San Antonio (C.F.L.); Breast Center, Baylor College of Medicine and Methodist Hospital, Houston (C.K.O.); University of Alabama at Birmingham, Birmingham (W.P.V.); the Division of Radiation Oncology, Mayo Clinic, Rochester, Minn. (T.M.P.); the Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore (J.F.); Our Lady of Mercy Cancer Center, New York Medical College, Bronx (E.P.); and Case Western Reserve University School of Medicine, Ireland Cancer Center, Cleveland (H.M.L.).
Drs. Robert and Lazarus contributed equally to the article.
Address reprint requests to Dr. Tallman at the Division of Hematology–Oncology, Northwestern University Feinberg School of Medicine, Robert H. Lurie Comprehensive Cancer Center, 676 N. St. Clair St., Suite 850, Chicago, IL 60611, or at m-tallman{at}northwestern.edu.
References
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Related Letters:
High-Dose Chemotherapy for Breast Cancer
Wheatley K., Gray R. G., Ives N. J., Tartarone A., Iodice G., Di Renzo N., Mangano M. M., Dazzi C., Cariello A., Rodenhuis S., van Tinteren H., de Vries E. G.E., Tallman M. S., Robert N. J., Lazarus H. M., Elfenbein G. J.
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N Engl J Med 2003;
349:1476-1479, Oct 9, 2003.
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