Affiliations of authors: G. N. Hortobagyi, A. U. Buzdar, R. L. Theriault, V. Valero, D. Frye, D. J. Booser, F. A. Holmes (Department of Breast Medical Oncology), S. Giralt, I. Khouri, B. Andersson, J. L. Gajewski, G. Rondon, R. E. Champlin (Department of Blood and Marrow Transplantation), T. L. Smith (Department of Biomathematics), S. E. Singletary, F. C. Ames (Department of Surgical Oncology), N. Sneige (Department of Pathology), E. A. Strom, M. D. McNeese (Department of Radiation Oncology), The University of Texas M. D. Anderson Cancer Center, Houston; A. B. Deisseroth, Yale University School of Medicine, New Haven, CT.
Corrrespondence to: Gabriel N. Hortobagyi, M.D., Department of Breast Medical Oncology, The University of Texas M. D. Anderson Cancer Center, 1515 Holcombe Blvd., Box 56, Houston, TX 77030 (e-mail: ghortoba{at}notes.mdacc.tmc.edu).
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ABSTRACT |
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INTRODUCTION |
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There is a steep dose-response curve for many cytotoxic agents in experimental in vivo systems. Hryniuk and colleagues reviewed a number of clinical trials of chemotherapy for patients with metastatic breast cancer (9) or clinical trials of adjuvant chemotherapy for primary breast cancer (10) by use of a combination chemotherapy with cyclophosphamide, methotrexate, and 5-fluorouracil (CMF) or cyclophosphamide, doxorubicin (Adriamycin), and 5-fluorouracil (CAF). These data suggested that the dose intensity-response relationship was linear, and the slope of this linear association was steep once the threshold dose intensity had been surpassed. Although this analysis had multiple inherent limitations (11), it had a substantial impact on the direction of clinical research and the design of clinical trials over the subsequent decade. A few prospective randomized trials (12) within the standard-dose range supported the existence of a dose-response relationship for cisplatin and the anthracyclines. The development of bone marrow and blood stem cell autografts supported hematopoietic recovery and allowed substantial escalation in the dose of myelosuppressive chemotherapy. Dose-intensive therapy has curative effects in acute and chronic leukemias, relapsing lymphoma, multiple myeloma, and, perhaps, other malignancies (13). In metastatic breast cancer, the results of uncontrolled trials suggested that high-dose chemotherapy produced high, complete remission (CR; the disappearance of all evidence of tumor for at least one cycle of therapy for 4 weeks) rates of 40%-70% (14). In addition, 10%-25% of the patients remained in an unmaintained CR for periods that now exceed 10 years (15). However, the median duration of remission and the median survival rates in patients treated with high-dose chemotherapy were not substantially changed compared with those parameters achieved with standard-dose therapy. Some studies [(16) and references therein] suggested that the proportion of patients with long-term CRs increased if dose intensification was administered to patients achieving a CR. The best outcomes were reported for patients with good performance status, those with minimal tumor burden at diagnosis of metastasis, and those who had not been exposed to prior adjuvant cytotoxic therapy. The introduction of peripheral blood stem cells has accelerated hematopoietic recovery, and treatment-related mortality has been reduced to less than 5% in most series. It logically followed that patients with high-risk, stage II or III breast cancer would be the ideal subjects to evaluate high-dose chemotherapy because all of these patients can be rendered free of clinically detectable disease by combined modality therapy. Numerous phase II trials have been reported with 60%-70% extended relapse-free survival rates for patients with stage II or III breast cancer who also have more than 10 positive axillary lymph nodes (17-21). These results appeared superior to the published results obtained with standard adjuvant chemotherapy, but interpreting the results of these trials was complicated by patient selection and rigorous staging of patients (excluding many with subclinical metastatic disease). To test this hypothesis more rigorously, we performed a prospective randomized trial in patients with high-risk primary breast cancer. The trial compared our best standard combination chemotherapy versus the same therapy followed by high-dose consolidation chemotherapy with autologous hematopoietic stem cell support and is reported below. Preliminary results have been presented (22).
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PATIENTS AND METHODS |
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Two types of patients were considered eligible. The first group of patients had operable stage
II or III primary breast cancer and 10 or more involved axillary lymph nodes at the time of
primary mastectomy (or breast-conserving surgery); these patients consulted our service after
primary surgical therapy. The second group of patients had stage III or locally advanced breast
cancer and was treated with induction (neoadjuvant) chemotherapy. They had surgery after
receiving four cycles of chemotherapy and became eligible if they had four or more involved
axillary lymph nodes at the time of surgical resection. In our institutional experience, these two
groups had similar 5- and 10-year relapse-free and overall survival rates (4,5). Other eligibility criteria are shown in Table 1. All patients
provided written informed consent, indicating that they were aware of the investigational nature
of this study, in keeping with institutional guidelines and in accordance with an assurance filed
with and approved by the U.S. Department of Health and Human Services.
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All patients were prospectively registered. Registration and random assignment to treatment
occurred on the same day and were preceded by consultation with a member of the bone marrow
transplantation team and written informed consent. Randomization was performed by remote
computer access; blocks of four patients (1122, 1221, 1212, 2121, etc.) were used in random
order to ensure balance between the two treatment arms. Access to the computerized
randomization program was restricted to research nurses and was not available to treating
physicians. Patients who were treated first with surgery became eligible; they were then
registered and randomly assigned to treatment before receiving any chemotherapy. Patients who
were treated first with chemotherapy became eligible; they were then registered and randomly
assigned to treatment after four cycles of chemotherapy and surgical resection. Patients were
stratified by initial stage (stage II versus stage III). The plan was for all patients to receive eight
cycles of standard-dose chemotherapy with 5-fluorouracil, doxorubicin (Adriamycin), and
cyclophosphamide (FAC). After eight cycles of standard-dose combination chemotherapy, the
patients were randomly assigned 1) to stop all cytotoxic therapy or 2) to receive two cycles of
high-dose chemotherapy with cisplatin, etoposide, and cyclophosphamide (CEP), each cycle with
autologous blood stem cell or bone marrow transplantation (Fig. 1). All
patients in both groups were referred for radiotherapy after completion of all chemotherapy.
Patients older than 50 years who had estrogen receptor-positive breast cancer received 20 mg of
tamoxifen daily for 5 years. The doses and schedules for the standard-dose chemotherapy with
FAC and for the high-dose chemotherapy with CEP are shown in Table 2.
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Autologous hematopoietic cells were collected after cycle 3 of induction FAC chemotherapy. Twenty-three patients had bone marrow harvested under general anesthesia, and six (including three who had bone marrow stored) had peripheral stem cells collected by apheresis. At least 4 x 108 mononuclear cells/kg were collected from each patient. Since two cycles of high-dose chemotherapy were recommended, one half of the stored hematopoietic cells were reinfused on day 6 of each cycle of high-dose chemotherapy. The second cycle of high-dose chemotherapy was administered as soon as hematologic recovery (granulocyte count >1000 cells/µL and platelet count >100 000 platelets/µL) occurred and reversible nonhematologic toxicity had resolved. Patients were treated in private hospital rooms at The University of Texas M. D. Anderson Cancer Center, Houston. All patients treated with high-dose chemotherapy received prophylactic oral antibiotics after the appropriate cultures of the oropharynx, blood, urine, and stools were obtained shortly before the initiation of high-dose chemotherapy. If patients developed clinical infections, prophylactic antibiotics were discontinued, and broad-spectrum antibiotics, appropriate for their infection, were started.
Evaluation Before and During Treatment
Pretreatment evaluation included a complete medical history and physical examination, with quantitative documentation of all measurable disease signs and symptoms and performance status. In addition, we obtained complete blood cell counts, including a differential and platelet count, and measurements of levels of urea nitrogen, creatinine, bilirubin, alanine aminotransferase, alkaline phosphatase, albumin, total protein, calcium, phosphate, serum electrolytes and magnesium, creatinine clearance, carcinoembryonic antigen (CEA), CA 15-3, and other appropriate compounds. The work-up also included a chest x-ray, liver imaging (ultrasound or computerized tomography), a bone scan, mammograms of the contralateral and, if present, the ipsilateral breast, a cardiac blood pool scan, spirometry, and analysis of arterial blood gases and carbon monoxide diffusion capacity. Bilateral bone marrow aspirations and biopsies, an electrocardiogram, and tests for cytomegalovirus, toxoplasmosis, and human immunodeficiency virus completed the evaluation.
During induction chemotherapy, patients were followed with weekly blood cell counts; during high-dose chemotherapy intensification, patients were followed with daily blood cell counts. During induction chemotherapy, blood chemistry was evaluated before each cycle of treatment; tumor markers were also evaluated if abnormal at baseline. During high-dose chemotherapy, blood chemistry was evaluated at least twice weekly, and tumor markers were evaluated with each cycle, if initially abnormal.
A full metastatic work-up was performed at the completion of eight cycles of FAC chemotherapy. This work-up included a patient medical history; a physical examination; evaluation of blood chemistry, including CEA and CA 15-3; a chest radiograph; a bone scan; and a computerized tomography of the abdomen. A patient medical history, a physical examination, and an evaluation of blood chemistry, including CEA and CA 15-3, were done at 3- to 4-month intervals during the first 2 years after diagnosis and after the completion of treatment. These tests were done twice per year during years 3-5 and yearly thereafter. Mammograms of the contralateral breast and, if present, the ipsilateral breast were obtained yearly.
Time to relapse was the period between registration in the study and the first evidence of relapse. Survival was the period between registration and death or the last documented contact.
Statistical Considerations
We assumed that the group of patients treated with standard combined modality therapy
would have a 3-year relapse-free survival rate of 55% at our institution on the basis of our
previous clinical trials. We considered that a 30% improvement in a 3-year relapse-free
survival rate would be of interest, considering the morbidity and mortality of the regimens under
consideration. When we used the assumed exponential relapse-free survival distributions defined
by these parameters, we calculated that this difference could be detected with a power of 0.8 and
a two-sided test of statistical significance of P = .05, with 40 patients randomly
assigned to each treatment arm. Our initial design required the observation of 24 patients who
failed to respond to treatment to achieve planned power. We have observed 41 patients who
failed to respond to treatment; therefore, the trial has more than adequate power to achieve its
original stated objectives. Frequencies of pretreatment characteristics in FAC and FAC/high-dose
chemotherapy groups were compared by 2 tests. Values for relapse-free
survival and total survival distributions were based on product-limit estimates (23). Survival distributions were compared by log-rank tests (24), with a two-sided level of statistical significance. An estimate of the recurrence risk ratio for the
two treatment groups was based on a proportional hazards model (25).
All P values are from two-sided tests.
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RESULTS |
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Compliance With Treatment
In the group randomly assigned to receive FAC alone, 36 patients received treatment as scheduled (four of these patients developed recurrent/metastatic disease during FAC chemotherapy). However, three patients, after signing the informed consent, elected to receive high-dose chemotherapy at other institutions. One patient received high-dose CEP; another received high-dose cyclophosphamide, carmustine, and thiotepa; and the third received a high-dose chemotherapy regimen unknown to us.
Among the 39 patients randomly assigned to the FAC/high-dose chemotherapy arm, 31 received treatment as scheduled, including four who relapsed during the FAC induction therapy (similar to the four who developed metastases during FAC chemotherapy in the FAC-alone group). Four patients received only one cycle of high-dose chemotherapy (three for reasons of toxicity during the first cycle and one who refused to have a second cycle). Two patients received high-dose chemotherapy with regimens different from those dictated by the protocol (one received one cycle of CEP followed by a second cycle of cyclophosphamide, carmustine, thiotepa, and interleukin 2; the other received high-dose cyclophosphamide, paclitaxel, and carboplatin). Therefore, 33 (85%) of 39 patients in this arm received high-dose chemotherapy or relapsed during assigned treatment.
Six additional patients received only FAC: one because of insurance denial, three because they refused high-dose chemotherapy after completing the eight cycles of FAC, one because she developed a hepatitis B viral infection after being randomly assigned to treatment, and the sixth who was considered ineligible because of age and general health by the time high-dose chemotherapy was to start.
Doses of FAC were administered with no change to 23 patients in the FAC group and to 22 patients in the FAC/high-dose chemotherapy group. In eight additional patients, the doses were increased; in 25 others equally distributed between the two arms, the doses were decreased. In five patients, incomplete information about doses of FAC prevented this analysis.
Table 3 shows the characteristics of patients in the two arms of the
study when they entered the study. Approximately 60% of the patients in both arms were
treated with surgery first and had 10 or more positive lymph nodes. The remaining patients
received four cycles of neoadjuvant FAC chemotherapy and had four or more positive lymph
nodes at the time of surgery. By definition, this was a young patient population, with a median
age of 45 years and the oldest being 66 years of age. The oldest patient who received high-dose
chemotherapy was 63 years old. The distribution of patients by initial clinical stage, estrogen
receptor status, and ethnic origin was similar. The types of surgical procedures used were also
similarly distributed. There was no difference in terms of histologic type.
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Data on outcomes are presented by intention to treat and by actual treatment administered. By intention to treat, all patients were considered in their randomized group, regardless of treatment received. In the analysis by actual treatment received, patients who received FAC alone without high-dose chemotherapy (n = 42) were compared with patients who received FAC/high-dose chemotherapy (n = 36). However, the four patients who relapsed while receiving the induction FAC regimen in each group were kept with the original group assigned.
At the time of this analysis, the median follow-up of live patients for both groups was 6.5
years. Forty-one patients have relapsed: 19 patients in the FAC arm and 22 in the FAC/high-dose
chemotherapy arm. Fig. 2, A, shows the relapse-free survival from the
date of initiation of therapy by random assignment to treatment. The estimated 3-year
relapse-free survival rates were 62% and 48% for patients in the FAC and
FAC/high-dose chemotherapy groups, respectively (P = .35). Although the
relapse-free survival rate at 3 years was 14% higher for the FAC group, the 95%
confidence interval (CI) ranged from -9% to +36%. Fig. 2,
B, shows the
relapse-free survival by actual treatment administered. The 3-year relapse-free survival rates were
59% and 52% for the FAC and FAC/high-dose chemotherapy groups, respectively.
The P value for this comparison was .70. Fig. 3,
A, shows the
overall survival comparisons by intention to treat.
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Thirty-one patients died of metastatic breast cancer (14 in the group assigned to FAC and 17
in the group assigned to FAC/high-dose chemotherapy). One patient treated with high-dose
chemotherapy had a septic death, without evidence of metastatic disease. Nine patients (five in
the FAC group and four in the FAC/high-dose chemotherapy group) are alive with relapsed or
metastatic breast cancer. The remaining 37 patients (20 in the FAC group and 17 in the
FAC/high-dose chemotherapy group) remain alive and without evidence of relapsed or metastatic
breast cancer. The calculated 3-year survival rates were 77% and 58% for the FAC
and FAC/high-dose chemotherapy groups, respectively (P = .23). Fig. 3, B,
shows the same comparison by actual treatment administered. The 3-year survival figures in this
comparison were 73% and 61% for the FAC and FAC/high-dose chemotherapy
groups, respectively (P = .54).
Analyses were performed to determine whether the outcomes were different for patients treated with primary surgery and postoperative adjuvant therapy and for patients treated with neoadjuvant chemotherapy followed by surgery. Although the numbers of patients were small, no evidence was noted of major differences between those receiving preoperative and postoperative therapy. Because there were technical improvements in hematopoietic support during the conduct of the study, we assessed whether there were any differences in outcome between patients treated during the first half of the study and those treated in the second half. There was no evidence of improvement in outcome during the conduct of the study.
Toxicity
The hematologic toxicity observed during induction FAC therapy was similar to that observed in our previous publications (27,28) about adjuvant chemotherapy with this regimen. During the induction phase, nine patients in the FAC group and 13 in the FAC/high-dose chemotherapy group required admission to the hospital for the management of infectious or febrile episodes. All recovered fully.
In the FAC group, one patient had a cerebrovascular accident, a second had a myocardial infarction, and a third developed hepatic fibrosis. The third patient died with metastatic breast cancer, but the immediate cause of death was uncertain.
In the FAC/high-dose chemotherapy group, one patient developed acute myeloid leukemia;
she was treated with high-dose chemotherapy and matched-sibling allogeneic bone marrow
transplantation and achieved a CR. She has since developed metastatic breast cancer and is alive
and receiving treatment. One patient developed avascular necrosis of the femur requiring a
hip-joint replacement. One patient had an acute but transient cardiac episode characterized by
pulmonary congestion, arrhythmias, and decreased left ventricular ejection fraction. This episode
resolved with medical intervention. One patient had overt congestive heart failure, which
eventually resolved. One patient had congestive heart failure with recurrent exacerbations and
died 3 years later (and 2 years after developing relapsed breast cancer) because of congestive
heart failure. Three patients developed persistent peripheral neuropathy, and another had
transient grade 3 (National Cancer Institute common toxicity criteria) peripheral neuropathy. One
patient developed a fatal septic episode during severe myelosuppression after high-dose
chemotherapy. Two patients developed a hearing loss; the loss resolved in one patient but not in
the other who required a permanent hearing aid. The patient who received high-dose
cyclophosphamide, carboplatin, and paclitaxel at another institution developed acute renal
failure, pulmonary emboli, and hearing loss; these conditions resolved, and the patient survived.
One patient from the FAC/high-dose chemotherapy group developed syncope, and four in this
group developed Herpes zoster infections. Additional toxic effects are shown in Table
4.
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DISCUSSION |
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It is of note that the relapse rate during the first 5 years was lower than expected based on historic data. Although additional relapses may occur with extended follow-up, the prognosis of patients selected for this clinical trial was better than expected, possibly because of patient selection based on eligibility criteria for high-dose chemotherapy and a rigorous metastatic work-up. This is an important point when the outcomes of this trial are compared with the results of uncontrolled trials in high-risk primary breast cancer (16,19,21,31-35).
The power of the selection process in identifying a group with improved prognosis compared with the overall denominator has been well established by several investigators (36-38). These findings underscore the limitations in interpreting phase II data and the need to critically evaluate novel therapies in randomized controlled trials.
Although it is preferable to randomly assign patients to treatment at the point when treatment differs, this possibility was precluded by the need to collect stem cells while patients were receiving standard-dose FAC. There was also a built-in delay to negotiate insurance payment. This part, even today, might require several weeks.
High-dose chemotherapy as used in this program had acceptable toxicity. Only one toxic death was experienced, confirming the marked improvement in the safety profile of high-dose chemotherapy programs (16). Although morbidity was more pronounced in the high-dose chemotherapy arm, the regimen was certainly tolerable. Furthermore, it is important to note that, between the time this trial was initiated and the submission of this article, additional improvements in supportive care and symptom management have been achieved. These changes, including the routine use of hematopoietic growth factors, newer antiemetics, newer antibiotics, and better management of oral mucositis, have led to better tolerance and reduced morbidity from high-dose chemotherapy programs. In fact, high-dose chemotherapy as delivered during this trial is currently being administered on an outpatient basis with a clear-cut demonstration of the safety of this approach.
The therapeutic results of this randomized clinical trial were disappointing. There was no evidence of a substantial advantage in relapse-free or overall survival of two consecutive cycles of the high-dose chemotherapy when administered after standard-dose adjuvant or neoadjuvant chemotherapy for high-risk breast cancer. Although this was a small trial designed to detect a 30% difference in 3-year relapse-free survival, it accomplished its goal and ruled out a large reduction in risk associated with high-dose chemotherapy. Smaller differences in outcome in favor of either therapy are not ruled out by these results. It is also possible that longer follow-up may shift results somewhat, although more than one half of the patients have already been followed to disease recurrence.
The CEP regimen used in this study is not myeloablative and not as intensive as other high-dose chemotherapy regimens under evaluation. However, the data from the North American Autologous Bone Marrow Transplant Registry (16) did not show obvious differences in the efficacy of the various high-dose chemotherapy regimens used. Rodenhuis et al. (39) recently published the results of a similar clinical trial with the same conclusions. In that study, patients with primary breast cancer and a positive apical node were treated with three cycles of neoadjuvant chemotherapy with 5-fluorouracil, epirubicin, and cyclophosphamide (FEC) and surgical resection followed by one cycle of postoperative FEC. They were then randomly assigned to receive either high-dose chemotherapy (one cycle of cyclophosphamide, thiotepa, and carboplatin, also known as STAMP 5) or no additional treatment. That study, similar in size to our study, also failed to demonstrate a clinically or statistically significant difference in relapse-free or overall survival.
There are several large prospective randomized trials conducted by the cooperative group system in the United States and in Europe that will further explore the possibility of a small therapeutic benefit with this intervention in patients with high-risk primary breast cancer. These trials will be able to detect smaller differences in outcomes. The two large randomized trials run by the Cancer and Leukemia Group B (CALGB) and the Southwest Oncology Group (SWOG), respectively, have now completed accrual. The CALGB trial (40) recruited more than 750 patients; preliminary evaluation, after a median follow-up of 37 months, showed no statistically significant differences in event-free survival or overall survival between the treatment groups. The SWOG trial included more than 400 patients; no results have been reported. The Scandinavian Breast Cancer Study Group (41) recently reported the preliminary results of a randomized adjuvant breast cancer study with high-dose chemotherapy after standard-dose adjuvant treatment (SBG 9401) in 525 women. The control arm consisted of individually tailored doses of FEC without hematopoietic support. At a median follow-up of 20 months, there were no differences in relapse rate or survival between the two arms. A third study by Bezwoda (42) randomly assigned 154 patients to receive either high-dose or standard-dose therapy. After more than 5 years of follow-up, a statistically significant benefit in relapse rate and survival was reported for the high-dose arm. These last three trials have greater statistical power to detect relatively modest differences in outcome, and complete analysis of mature data is awaited with interest.
A substantial minority of patients registered on our trial failed to comply with treatment recommendations. Four patients in each group developed recurrent/metastatic disease before completing the eight cycles of FAC chemotherapy. Three patients in the FAC-alone group elected to receive high-dose chemotherapy, whereas six in the high-dose chemotherapy group did not receive the allocated high-dose therapy. This rate of noncompliance is similar to the compliance rates of other randomized trials of high-dose chemotherapy reported recently (40,43).
Physician and patient bias was evident during the accrual phase of this study. As a result, fewer than 20% of the potentially eligible patients participated in this study. Premature enthusiasm based on the early results of several uncontrolled clinical trials probably delayed accrual to this and other randomized trials.
The analysis by actual treatment received, although not usually performed in randomized trials, was provided as additional proof that the protocol deviations by a minority of patients did not substantially influence the outcome of this program.
It is evident that the technology to harvest and reinfuse autologous hematopoietic stem cells has undergone tremendous development, and it is reasonably safe. This technology will likely find increased utilization in approaches to gene transfer, immunomodulation, and other ex vivo modifications of hematopoietic stem cells. The major weakness of this approach is the relative inefficacy of the high-dose chemotherapy regimens. The higher rates of CR and overall response observed in metastatic breast cancer with high-dose chemotherapy have not translated into prolongation of time to disease progression or survival (14,16). Therefore, in retrospect, it was perhaps overly optimistic to expect such substantial improvements in outcome by introducing only two cycles of high-dose therapy. The relatively modest increment in dose achievable for these agents before the limitations imposed by nonhematologic toxicity may be insufficient to overcome most mechanisms of resistance. Alternative preparative regimens might prove to be more effective than the CEP regimen evaluated in this study.
The final results of the large, multicenter randomized trials conducted in the United States and in Europe are awaited with interest to determine the role of high-dose chemotherapy in the management of high-risk breast cancer. On the basis of our trial and the trial by Rodenhuis (39), it is unlikely that large differences will be observed between the standard-dose and high-dose arms. Until a benefit is definitely demonstrated by randomized trials, we suggest that high-dose chemotherapy for primary breast cancer be restricted to clinical trials. At this point, there is insufficient evidence of benefit to justify its routine use in clinical practice.
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NOTES |
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Supported in part by Public Health Service grant 2P30CA1667223 from the National Cancer Institute, National Institutes of Health, Department of Health and Human Services; by the Nylene Eckles Professorship in Breast Cancer Research; and by the Nellie B. Connally Chair in Breast Cancer.
We thank Suzette Stine and Lisa Chaput for their help in the preparation of this manuscript and Kim Herrick for her editorial assistance.
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Manuscript received May 29, 1999; revised November 16, 1999; accepted November 29, 1999.
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