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Clinical Trials |
Departments of Breast Medical Oncology [A. U. B., V. V., D. J. B., N. K. I., Z. R., R. L. T., R. W., E. R., F. A. H., D. K. F., N. M., S-W. K., E. T., G. N. H.], Surgical Oncology [S. E. S., K. H., F. A.], Biostatistics [T. L. S., E. H., D. B.], and Radiation Oncology [M. D. M., E. S.], The University of Texas M. D. Anderson Cancer Center, Houston, Texas 77030
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ABSTRACT |
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Experimental Design: Five hundred twenty-four patients were randomized to be treated either with 4 cycles of paclitaxel followed by 4 cycles of combination therapy with 5-fluorouracil, Adriamycin, and cyclophosphamide (Pac/FAC) or with 8 cycles of FAC alone. Patients with intact primary breast cancer received the initial 4 cycles of paclitaxel or 4 cycles of FAC in a neoadjuvant setting. Planned duration of therapy was the same in all patients. After completion of 8 cycles of chemotherapy, those patients who were 
50 years and whose tumors were positive for estrogen receptors received tamoxifen for 5 years.
Results: Ninety-two patients have had a recurrence after a median follow-up of 60 months with a range of 5–89 months. Estimated disease-free survival at 48 months was 0.83 for FAC and 0.86 for Pac/FAC group. The difference between the two groups was not statistically significant (P = 0.09). The overall estimated hazard ratio for Pac/FAC compared with FAC derived by fitting the Cox regression model and incorporating terms for prognostic factors was 0.66.
Conclusion: Preliminary results suggest that the addition of paclitaxel to a FAC regimen of adjuvant or neoadjuvant therapy may further reduce the risk of disease recurrence; however, differences were not statistically significant. At the time of this analysis, there have been 47 deaths. The survival data are too preliminary to permit meaningful evaluation of the impact of paclitaxel on mortality.
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INTRODUCTION |
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TopABSTRACTINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONREFERENCES |
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In an initial Phase II study of patients with breast cancer, paclitaxel was evaluated at a dose of 250 mg/m2 given as a 24-h continuous infusion (7) . In this small study (n = 25), 56% of patients showed a major objective response, with 12% having a complete response and 44% having a partial response. All patients in this study had received one prior doxorubicin- containing chemotherapy regimen. The median time to progression in this study was 9 months, and the median duration of survival was 20 months. These efficacy results were confirmed in a subsequent study using the same dose and schedule in a similar patient population (8) .
After these initial encouraging results of paclitaxel as a single agent in treatment of metastatic breast cancer, we prospectively evaluated paclitaxel as neoadjuvant and adjuvant therapy in patients with early breast cancer. The preliminary data for patients treated in the neoadjuvant setting have been published previously (9) . This report presents the preliminary results of the prospective randomized trial of patients treated in both the adjuvant and neoadjuvant setting and the overall impact of paclitaxel in reducing the risk of recurrence in patients receiving systemic chemotherapy. In a study conducted by the CALGB,3 an early report (10) suggested that the addition of paclitaxel after four cycles of doxorubicin and cyclophosphamide combination reduced the risk of recurrence and death, although a subsequent report was less conclusive (11) . One other criticism of that study (10) has been that improvement may not be related to the addition of paclitaxel, but could be attributable to longer duration of therapy (i.e., four cycles versus eight cycles of therapy). Our study was designed to administer the same number of chemotherapy cycles to all patients, with the difference between the two arms of the study being the substitution of paclitaxel in the initial four cycles of chemotherapy. Preliminary results were reported in abstract form (12) ; in this paper, we present updated results after a median follow-up of 60 months.
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PATIENTS AND METHODS |
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TopABSTRACTINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONREFERENCES |
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1500/mm3 and a platelet count 100,000/mm3. Patients were required to have adequate liver function, as indicated by a bilirubin value of 
1.0 mg%, and adequate renal function, defined as serum creatinine 2.5 mg%. Patients with a history of uncompensated congestive heart failure were excluded. Patients with concomitant or prior history of other invasive carcinoma, except for localized squamous cell or basal cell carcinoma of the skin or in situ squamous cell carcinoma of the cervix, were excluded. Patients with a history of previous breast cancer of a higher stage were also excluded. This protocol was reviewed and approved by the Institutional Review Board. Each patient was informed about the investigational nature of the study in keeping with institutional policy, and a written consent was obtained from each patient.
Treatment Plan.
All patients were prospectively registered for the study, in our online institutional research database, and were stratified by age (<50 or 50 years), by tumor status (T2 or T3) and by nodal status (N0 or N1). Patients were randomized to receive treatment with either eight cycles of FAC or four cycles of paclitaxel followed by four cycles of FAC (Pac/FAC).
Patients who had intact primary tumors underwent an initial four cycles of systemic therapy with either paclitaxel or FAC before local therapy and then received the remaining four cycles of FAC after surgery (the neoadjuvant group; Fig. 1
). Patients who had already received local therapy at the time of study entry received all eight cycles of assigned treatment adjuvantly. Regardless of the timing of local therapy, systemic therapy was identical for patients in both cohorts.
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Patients assigned to receive paclitaxel were given 250 mg/m2, administered as a 24-h continuous infusion every 3 weeks. Premedication was required for all cycles; 12 and 6 h before administration of paclitaxel, each patient received 20 mg of dexamethasone (p.o.); 1 h before FAC chemotherapy, each patient received 300 mg of cimetidine i.v. or 50 mg of Ranitidine and 50 mg of diphenhydramine i.v. Patients who were 50 years of age and whose tumors were positive for ER were subsequently treated with tamoxifen for 5 years.
Chemotherapy Modification Criteria.
The dose of chemotherapy drugs was escalated by 20% for a given patient, if the lowest granulocyte count in the previous cycle was >1,000/mm3, the platelet count was >100,000/mm2, and the patient had no other organ toxicity of grade 2 or higher. The dose of drug was not altered in patients whose lowest granulocyte count was <250/mm3, provided that the patient had no organ toxicity of grade 2 or higher, and the patient’s lowest platelet count was >50,000/mm3. Patients were not given hematopoietic growth-factor support unless they experienced neutropenic fever. In these patients, instead of dose modification, hematopoietic growth-factor (G-CSF) was added to the treatment in the next cycle at 5 µg/kg from day 5 to 18 or until the granulocyte count was >2,000/mm3. For patients who had fever during the neutropenic phase in a subsequent cycle, despite the addition of G-CSF, the drug(s) was reduced by 20%. The doses were also reduced by 20% if patients had other organ toxicities of grade 3 or higher.
Radiation Therapy.
Patients who had undergone breast preservation surgery, or were candidates for radiation therapy for other indications, received irradiation after completion of all chemotherapy. Radiation therapy was started within 6 weeks of completion of cytotoxic chemotherapy. Before initiation of radiation therapy, patients had to have recovered hematological functions (WBC count, 3,000/mm2; platelet count, 100,000/mm2) and recovered from any toxicity of the chemotherapy. The objective of radiation therapy was to treat the skin, muscle, and lymphatics of the ipsilateral chest wall. The chest wall was treated with either appositional electron-beam fields or medial and lateral tangential photon fields. The choice of technique used was based on each individual patient’s anatomy. The entire target was optimally treated and excluded the normal tissue not at risk.
Patients who initially had intact tumors but had undergone segmental mastectomy and axillary dissection received radiotherapy to the breast only, except in patients with four or more positive nodes. For those patients with four or more positive lymph nodes after neoadjuvant therapy, comprehensive radiation therapy was delivered to the chest wall, peripheral lymphatics, and the supraclavicular fossa and axillary apex. The axilla was treated, to 40 Gy, if extra-nodal extension of >2 mm was seen, or to 50 Gy if no axillary dissection was performed. Megavoltage radiation was used to deliver 50 Gy at 9–10 Gy/week to the chest wall and the supraclavicular fossa/axillary apex. Patients with medial quadrant lesions also had internal mammary nodes treated either by including them in tangential photon fields or with electrons. A 10–15-Gy boost was delivered to the primary tumor bed with either electrons or photons.
Evaluation before and during Treatment.
A complete history and physical examination was performed on all patients before the start of treatment. CBC, sequential multiple analysis, carcinoembryonic antigen testing, CA 15-3 (27–29), chest X-ray, liver ultrasound or computed tomography, bone scan, and mammogram were performed; breast ultrasound was also performed to evaluate the axilla. CBCs, differential counts, and platelet counts were performed weekly to monitor the myelotoxicity of FAC in the first cycle; in subsequent cycles, blood counts were assessed on days 1 and 21 of each cycle. Patients on the paclitaxel arm underwent weekly CBC, platelet, and differential counts during each cycle. Chest X-ray, blood urea nitrogen, serum glutamate pyruvate transaminase, lactic dehydrogenase, alkaline phosphatase, and glucose analyses were repeated at 4-month intervals during the initial 2-year period of study. Subsequently, these assessments were repeated at 6-month intervals for an additional 1 year, with mammogram and bone scans performed on a yearly basis. After 3 years of follow-up, patients were evaluated on a yearly basis with the following: (a) complete history; (b) physical evaluation; (c) tests of CBC, lactic dehydrogenase, serum glutamate pyruvate transaminase, alkaline phosphatase, glucose, carcinoembryonic antigen, and CA 15-3 (27–29); (d) chest X-ray; and (d) mammogram.
Statistical Considerations.
The study was designed to include 518 patients randomized in equal numbers to receive therapy either with paclitaxel followed by FAC or with FAC alone. The objective of this study was to detect an absolute improvement of 15% in a 5-year response to the combination therapy compared with our previous experience with FAC alone. In our previous adjuvant studies, the estimated disease-free survival rate after 5 years was 60%, and it was anticipated that there would be a 15% improvement with the addition of paclitaxel, leading to a 75% increase in disease-free survival after 5 years. It was estimated that with a sample size of 518, there would be an 80% power to detect this difference. Disease-free survival was estimated by the Kaplan-Meier method, and experience was compared between treatment groups by log-rank test. All P values were based on two-tailed tests. Hazard ratios were estimated by fitting a Cox regression model (13)
. Plots of hazard rates for the ER-negative and ER-positive subsets using a smoothing technique are presented elsewhere (14)
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RESULTS |
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presents characteristics for the total patient population and by treatment group. Patients were similar in age, surgery status (pre- or postsurgery), tamoxifen use, and radiation-treatment experience. There were some differences in ER status between the treatment groups. The Pac/FAC arm of the study had a higher proportion of ER-positive patients (62%) compared with the FAC-alone arm (55%). The two groups also differed somewhat with respect to presurgery clinical stage and postsurgery surgical stage. For both factors, the Pac/FAC arm had a higher proportion of patients with stage I disease. These differences were not statistically significant.
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20% of the participants were from other racial groups. The median follow-up for the study population was 60 months, with a range of follow-up between 5 and 89 months. At the time of this analysis, there have been 92 recurrences, with 53 (58%) of these recurrences observed in the FAC-only arm.
Table 1
also presents the total number of cycles that were given to patients. The recommended number of cycles that each patient should have received was eight. For the total group and for each individual treatment arm, the majority of patients received eight cycles. However, a larger percentage of Pac/FAC patients received the planned number of cycles (88%) compared with the FAC-alone arm (71%). In the FAC-alone group, 92% of the patients completed at least six cycles of chemotherapy, and in Pac/FAC group, 95% received at least six cycles of treatment. In both groups, patients who did not receive the planned number of cycles often received fewer rather than additional cycles.
Overall RFS.
The original study protocol specified that analysis would take place after 105 failures, so these data should be considered preliminary. However, at this time, 92 recurrences have occurred. The overall RFS rate for the two treatment arms is shown in Fig. 2A
. Estimated RFS at 48 months was 0.83 (95% CI, 0.79–0.88) for FAC alone and 0.86 (95% CI, 0.82–0.91) for the Pac/FAC arm. The difference between the two groups was not statistically significant (P = 0.09). The overall estimated hazard ratio for the two treatment arms, derived by fitting a Cox regression model, found a 30% reduction in risk associated with the Pac/FAC arm (hazard ratio, 0.70). However, the 95% confidence interval for this hazard ratio ranged from 0.47 to 1.07, indicating the relatively imprecise estimate of the treatment effect associated with a patient sample of this size. When the same approach of fitting a regression model was repeated with the addition of terms indicating ER status, status of surgery (pre- or postsurgery), and tamoxifen use, the resulting estimated hazard ratio associated with treatment was 0.66 (95% CI, 0.43–1.01).
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, RFS curves are plotted for ER-positive and ER-negative patients by treatment group. The slightly more favorable RFS rate associated with Pac/FAC treatment is apparent only among ER-negative cases.
The experience of the FAC alone and Pac/FAC-treated groups is summarized in Fig. 3
by hazard rates. The curves express risk of recurrence per month by treatment group for ER-positive (Fig. 3A)
and ER-negative (Fig. 3B)
groups. Results indicate a higher risk of recurrence (0.6%/month) in the first year for patients with ER-negative disease treated with FAC alone, in contrast to lower risk during this period in the Pac/FAC group. Hazard rates thereafter were similar for the two treatments. In the ER-positive group, hazard rates were similar throughout the first 3 years of treatment. The notable increase in risk after that time in the FAC alone group is attributable to 17 recurrences among 124 patients who were free of disease for at least 36 months (compared with recurrences for 5 of 137 patients in the Pac/FAC ER-positive group, 5 of 77 in the FAC alone ER-negative group, and 3 of 67 in the Pac/FAC ER-negative group). Results for the first 3 years are mostly complete, but estimates are less reliable after that time.
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Safety Results.
Therapy-related toxicity information by patient is shown in Table 2
. A higher percentage of patients experienced febrile neutropenia in the Pac/FAC group (17%) compared with the FAC-alone group (9%). In this protocol, prophylactic use of G-CSF was not considered initially. As the study progressed, however, it was our policy to have either growth factor support or antibiotics added for patients treated on the Pac/FAC arm to maintain the dose intensity of the therapy. Patients who experienced febrile neutropenia were treated with G-CSF for all subsequent cycles of chemotherapy, and dose reduction was reserved for patients in both treatment arms who had nonhematological toxicities of grade 3 or higher. Documented infectious complications of grade 3 occurred in a few patients. A significant fraction of patients had neurotoxicity during treatment, but these had resolved in all patients by subsequent follow-ups. Thirty-three percent of patients in the Pac/FAC arm had grade 3 myalgias and were treated symptomatically. Two patients in the FAC-alone arm developed clinical evidence of congestive heart failure. Of those, one patient had received radiation therapy to the left breast and axilla in addition to chemotherapy. In the Pac/FAC arm, one patient developed congestive heart failure 10 days after the first dose of paclitaxel. This patient had multiple risk factors for congestive heart failure and had not received prior radiation therapy or doxorubicin. Her congestive heart failure was considered to be secondary to other cardiac risk factors and not treatment with Pac/FAC. There have been no toxic deaths in either arm of the study, and no instances of leukemia have been observed among patients in either treatment arm of the study up to the present time.
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After completion of chemotherapy, five patients became pregnant. Of these, four had received Pac/FAC and one had received FAC alone. The data regarding chemotherapy-induced amenorrhea were retrospectively collected by a questionnaire in patients <50 years of age (Table 2)
. One hundred five patients provided adequate information (FAC alone, n = 42; Pac/FAC, n = 63). A higher fraction of women in Pac/FAC arm maintained their ovarian function, but the differences were not significant (P = 0.2).
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DISCUSSION |
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TopABSTRACTINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONREFERENCES |
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The timing of initiation of chemotherapy has no significant impact on the RFS and overall survival (15) . This study was prospectively planned to evaluate the impact of the addition of paclitaxel to the FAC regimen given in either an adjuvant or neoadjuvant setting. This report includes data for the total study patient population registered in that protocol. The preliminary results of this prospective study suggest that the addition of paclitaxel to FAC in patients with early breast cancer can result in a further reduction in the risk of recurrence. The differences between the two treatment regimens observed in this study are not statistically significant because the sample size was small and the study was designed to be evaluated after a larger number of recurrences. Moreover, the initial trial design anticipated a higher rate of recurrence in the FAC alone arm; if we had initially assumed the lower recurrence rate that was actually observed, the trial would have provided 70% power to detect a halving in the rate of recurrence attributable to the addition of paclitaxel (approximately the change in rate for which the trial was designed) and only 21% power to detect a 25% reduction in recurrence rate.
One larger trial (CALGB 9344 study), which had a similar study design, evaluated the role of paclitaxel with AC combination therapy. Although early results of that study showed a substantial reduction in the risk of recurrence and also a favorable impact on survival, updated results were less conclusive (13) . The National Surgical Adjuvant Breast Project study B-28 data (presented at the 2000 NIH Consensus Conference of Adjuvant Therapy for Breast Cancer) did not show a significant benefit in terms of disease-free or overall survival with the addition of paclitaxel, although there was a similar beneficial trend with addition of paclitaxel in patients who did not receive tamoxifen. These differences for either disease-free or overall survival did not reach statistical significance.
The findings of our study are consistent with those of the CALGB 9344. One of the potential criticisms of the CALGB study design has been that patients on the AC arm received only four cycles of chemotherapy, whereas those on the paclitaxel/AC arm received eight cycles of chemotherapy. Therefore, the noted therapeutic advantage might have resulted from a longer duration of treatment, and not necessarily from the addition of paclitaxel to the AC combination. In our study, both cohorts of patients received the same duration of chemotherapy. As of this follow-up, there was a 30% reduction in the risk of recurrence in the group of patients who received paclitaxel followed by FAC; these findings are more favorable than the reduction in the risk of recurrence associated with paclitaxel/AC in the CALGB 9344 study with additional follow-up.
Both treatment regimens were well tolerated, and there has been no treatment-related mortality in this study. Cardiac dysfunction was not observed among patients in the Pac/FAC arm, and the risk of cardiac dysfunction was minimal in patients who received eight cycles of FAC. The dose of paclitaxel was higher in this study compared with that used in the CALGB study because we selected the dose that had led to the highest response rates in the previous Phase II studies in metastatic disease.
The objective of this study was to deliver the optimal dose of the drug in an adjuvant setting. In the National Surgical Adjuvant Breast Project study, a 3-h infusion of paclitaxel was compared against a 24-h infusion (16) . The 24-h infusion was associated with higher morbidity, but patients treated with the infusion schedule had a significantly higher objective response rate, although the differences in survival were not statistically significant.
Additional studies of paclitaxel in metastatic disease have further evaluated and expanded on the optimal schedules of administration. There are limited data to suggest that weekly administration of this drug may have a better antitumor activity and certainly a better toxicity profile (17) . At our institution, we have recently completed a randomized study that compared the activity and safety of a weekly paclitaxel treatment to once every 3 weeks, and early results suggest an advantage for the weekly paclitaxel schedule with regard to pathological complete response (18) . In view of emerging evidence regarding the ability of paclitaxel to further reduce the risk of recurrence in high-risk breast cancer patients, the addition of paclitaxel to an adjuvant regimen should be considered. This decision should be made regardless of ER status because antitumor activity of chemotherapy drugs is independent of hormonal receptor status of tumor.
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FOOTNOTES |
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1 This research has been partially supported by the Nellie B. Connally Breast Cancer Research Fund and a research grant from Bristol Myers Squibb. 
2 To whom requests for reprints should be addressed, at University of Texas M. D. Anderson Cancer Center, Department of Breast Medical Oncology, Box 424, 1515 Holcombe Boulevard, Houston, TX 77030. Phone: (713) 792-2817; E-mail: abuzdar{at}mdanderson.org
3 The abbreviations used are: CALGB, Cancer and Leukemia Group B; FAC, 5-fluorouracil, Adriamycin, and cyclophosphamide; ER, estrogen receptor; G-CSF, granulocyte colony-stimulating factor; CBC, complete blood count; RFS, relapse-free survival; AC, Adriamycin and cyclophosphamide.
Received 10/19/01; revised 2/ 1/02; accepted 2/ 4/02.
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