Evaluation of Paclitaxel in Adjuvant Chemotherapy for Patients with Operable Breast Cancer: Preliminary Data of a Prospective Randomized Trial1

Vol. 8, 1073–1079, May 2002 Clinical Cancer Research 1073

Aman U. Buzdar,2 S. Eva Singletary, Results: Ninety-two patients have had a recurrence af- Vicente Valero, Daniel J. Booser, ter a median follow-up of 60 months with a range of 5–89 Nuhad K. Ibrahim, Zia Rahman, months. Estimated disease-free survival at 48 months was 0.83 for FAC and 0.86 for Pac/FAC group. The difference ؍ Richard L. Theriault, Ronald Walters, between the two groups was not statistically significant (P Edgardo Rivera, Terry L. Smith, 0.09). The overall estimated hazard ratio for Pac/FAC com- Frankie A. Holmes, Emma Hoy, Debra K. Frye, pared with FAC derived by fitting the Cox regression model Nikki Manuel, Shu-Wan Kau, and incorporating terms for prognostic factors was 0.66. Marsha D. McNeese, Eric Strom, Eva Thomas, Conclusion: Preliminary results suggest that the addition of paclitaxel to a FAC regimen of adjuvant or neoad- Kelly Hunt, Fred Ames, Donald Berry, and juvant therapy may further reduce the risk of disease re- Gabriel N. Hortobagyi currence; however, differences were not statistically Departments of Breast Medical Oncology [A. U. B., V. V., D. J. B., significant. At the time of this analysis, there have been 47 N. K. I., Z. R., R. L. T., R. W., E. R., F. A. H., D. K. F., N. M., S- deaths. The survival data are too preliminary to permit 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 meaningful evaluation of the impact of paclitaxel on mor- [M. D. M., E. S.], The University of Texas M. D. Anderson Cancer tality. Center, Houston, Texas 77030 INTRODUCTION Systemic therapy can significantly reduce the risk of re- ABSTRACT currence and improve the chances of survival in women with Purpose: Paclitaxel has significant antitumor activity in primary breast cancer (1–4). As adjuvant therapy, combination patients with metastatic breast cancer who have been pre- chemotherapy regimens are superior to single-agent chemother- viously treated with or exposed to anthracycline-containing apies (2), and doxorubicin-containing combinations are superior chemotherapy. In this prospective randomized trial, the role to non-doxorubicin-containing combinations (3–6). Paclitaxel is of paclitaxel was evaluated in an adjuvant setting to deter- a microtubule-active agent isolated from the stem bark of Taxus mine its impact on reducing the risk of recurrence in pa- brevifolia, the Western Pacific yew tree. Unlike other antimi- tients with operable breast cancer. crotubule agents, paclitaxel acts by promoting formation of Experimental Design: Five hundred twenty-four pa- unusually stable microtubules, inhibiting the normal dynamic tients were randomized to be treated either with 4 cycles of reorganization of microtubule networks required for mitosis and paclitaxel followed by 4 cycles of combination therapy with cell proliferation. 5-fluorouracil, Adriamycin, and cyclophosphamide (Pac/ In an initial Phase II study of patients with breast cancer, FAC) or with 8 cycles of FAC alone. Patients with intact 2 paclitaxel was evaluated at a dose of 250 mg/m given as a 24-h primary breast cancer received the initial 4 cycles of pacli- continuous infusion (7). In this small study (n ϭ 25), 56% of taxel or 4 cycles of FAC in a neoadjuvant setting. Planned patients showed a major objective response, with 12% having a duration of therapy was the same in all patients. After complete response and 44% having a partial response. All completion of 8 cycles of chemotherapy, those patients who patients in this study had received one prior doxorubicin- were >50 years and whose tumors were positive for estrogen containing chemotherapy regimen. The median time to progres- receptors received tamoxifen for 5 years. sion 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). Received 10/19/01; revised 2/1/02; accepted 2/4/02. After these initial encouraging results of paclitaxel as a The costs of publication of this article were defrayed in part by the single agent in treatment of metastatic breast cancer, we pro- payment of page charges. This article must therefore be hereby marked spectively evaluated paclitaxel as neoadjuvant and adjuvant advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. therapy in patients with early breast cancer. The preliminary 1 This research has been partially supported by the Nellie B. Connally data for patients treated in the neoadjuvant setting have been Breast Cancer Research Fund and a research grant from Bristol Myers published previously (9). This report presents the preliminary Squibb. results of the prospective randomized trial of patients treated in 2 To whom requests for reprints should be addressed, at University of Texas M. D. Anderson Cancer Center, Department of Breast Medical both the adjuvant and neoadjuvant setting and the overall impact Oncology, Box 424, 1515 Holcombe Boulevard, Houston, TX 77030. of paclitaxel in reducing the risk of recurrence in patients Phone: (713) 792-2817; E-mail: [email protected]. 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 substi- tution 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.

PATIENTS AND METHODS Fig. 1 Overall schema of therapy.

Patients. All patients with histologically confirmed T1–3, N0–1, and M0 (including T1 and N0) invasive carcinoma of the breast were eligible for the study regardless of whether they had 2 received local therapy for their cancer. All patients had to have follows. 5-Fluorouracil (500 mg/m ) was administered i.v. on adequate bone marrow function, as defined by an absolute days 1 and 4 after completion of doxorubicin infusion. The dose 2 granulocyte count Ն1500/mm3 and a platelet count Ն100,000/ of cyclophosphamide was 500 mg/m , administered i.v. on day 2 mm3. Patients were required to have adequate liver function, as 1 only. Doxorubicin (50 mg/m ) was given as a continuous i.v. indicated by a bilirubin value of Յ1.0 mg %, and adequate renal infusion through a central venous catheter over 72 h (days 1–3 function, defined as serum creatinine Յ2.5 mg %. Patients with of each cycle). Cycles of chemotherapy were repeated at 3–4- a history of uncompensated congestive heart failure were ex- week intervals, depending on adequate recovery of the bone cluded. Patients with concomitant or prior history of other marrow and recovery from other toxicities. invasive carcinoma, except for localized squamous cell or basal Patients assigned to receive paclitaxel were given 250 2 cell carcinoma of the skin or in situ squamous cell carcinoma of mg/m , administered as a 24-h continuous infusion every 3 the cervix, were excluded. Patients with a history of previous weeks. Premedication was required for all cycles; 12 and 6 h breast cancer of a higher stage were also excluded. This protocol before administration of paclitaxel, each patient received 20 mg was reviewed and approved by the Institutional Review Board. of dexamethasone (p.o.); 1 h before FAC chemotherapy, each Each patient was informed about the investigational nature of patient received 300 mg of cimetidine i.v. or 50 mg of Raniti- Ն the study in keeping with institutional policy, and a written dine and 50 mg of diphenhydramine i.v. Patients who were 50 consent was obtained from each patient. years of age and whose tumors were positive for ER were Treatment Plan. All patients were prospectively regis- subsequently treated with tamoxifen for 5 years. tered for the study, in our online institutional research database, Chemotherapy Modification Criteria. The dose of and were stratified by age (Ͻ50 or Ն50 years), by tumor status chemotherapy drugs was escalated by 20% for a given patient, (ՅT or T ) and by nodal status (N or N ). Patients were if the lowest granulocyte count in the previous cycle was 2 3 0 1 Ͼ 3 Ͼ 2 randomized to receive treatment with either eight cycles of FAC 1,000/mm , the platelet count was 100,000/mm , and the or four cycles of paclitaxel followed by four cycles of FAC patient had no other organ toxicity of grade 2 or higher. The (Pac/FAC). dose of drug was not altered in patients whose lowest granulo- Ͻ 3 Patients who had intact primary tumors underwent an ini- cyte count was 250/mm , provided that the patient had no tial four cycles of systemic therapy with either paclitaxel or organ toxicity of grade 2 or higher, and the patient’s lowest Ͼ 3 FAC before local therapy and then received the remaining four platelet count was 50,000/mm . Patients were not given he- cycles of FAC after surgery (the neoadjuvant group; Fig. 1). matopoietic growth-factor support unless they experienced neu- Patients who had already received local therapy at the time of tropenic fever. In these patients, instead of dose modification, study entry received all eight cycles of assigned treatment hematopoietic growth-factor (G-CSF) was added to the treat- ␮ adjuvantly. Regardless of the timing of local therapy, systemic ment in the next cycle at 5 g/kg from day 5 to 18 or until the Ͼ 3 therapy was identical for patients in both cohorts. granulocyte count was 2,000/mm . For patients who had fever The doses and schedule of FAC chemotherapy were as 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 3 The abbreviations used are: CALGB, Cancer and Leukemia Group B; preservation surgery, or were candidates for radiation therapy FAC, 5-fluorouracil, Adriamycin, and cyclophosphamide; ER, estrogen receptor; G-CSF, granulocyte colony-stimulating factor; CBC, complete for other indications, received irradiation after completion of all blood count; RFS, relapse-free survival; AC, Adriamycin and cyclo- chemotherapy. Radiation therapy was started within 6 weeks of phosphamide. completion of cytotoxic chemotherapy. Before initiation of ra-

diation therapy, patients had to have recovered hematological there would be an 80% power to detect this difference. Disease- functions (WBC count, Ն3,000/mm2; platelet count, Ն100,000/ free survival was estimated by the Kaplan-Meier method, and mm2) and recovered from any toxicity of the chemotherapy. The experience was compared between treatment groups by log-rank objective of radiation therapy was to treat the skin, muscle, and test. All P values were based on two-tailed tests. Hazard ratios lymphatics of the ipsilateral chest wall. The chest wall was were estimated by fitting a Cox regression model (13). Plots of treated with either appositional electron-beam fields or medial hazard rates for the ER-negative and ER-positive subsets using and lateral tangential photon fields. The choice of technique a smoothing technique are presented elsewhere (14). used was based on each individual patient’s anatomy. The entire target was optimally treated and excluded the normal tissue not at risk. RESULTS Patients who initially had intact tumors but had undergone Between 1994 and 1998, 524 patients were enrolled in this segmental mastectomy and axillary dissection received radio- study. Table 1 presents characteristics for the total patient pop- therapy to the breast only, except in patients with four or more ulation and by treatment group. Patients were similar in age, positive nodes. For those patients with four or more positive surgery status (pre- or postsurgery), tamoxifen use, and radia- lymph nodes after neoadjuvant therapy, comprehensive radiation-treatment experience. There were some differences in ER tion therapy was delivered to the chest wall, peripheral lymphat- status between the treatment groups. The Pac/FAC arm of the ics, and the supraclavicular fossa and axillary apex. The axilla study had a higher proportion of ER-positive patients (62%) was treated, to 40 Gy, if extra-nodal extension of Ͼ2mmwas compared with the FAC-alone arm (55%). The two groups also seen, or to 50 Gy if no axillary dissection was performed. differed somewhat with respect to presurgery clinical stage and Megavoltage radiation was used to deliver 50 Gy at 9–10 postsurgery surgical stage. For both factors, the Pac/FAC arm Gy/week to the chest wall and the supraclavicular fossa/axillary had a higher proportion of patients with stage I disease. These apex. Patients with medial quadrant lesions also had internal differences were not statistically significant. mammary nodes treated either by including them in tangential The majority of patients were White, and ϳ20% of the photon fields or with electrons. A 10–15-Gy boost was deliv- participants were from other racial groups. The median fol- ered to the primary tumor bed with either electrons or photons. low-up for the study population was 60 months, with a range of Evaluation before and during Treatment. A complete follow-up between 5 and 89 months. At the time of this analysis, history and physical examination was performed on all patients there have been 92 recurrences, with 53 (58%) of these recur- before the start of treatment. CBC, sequential multiple analysis, rences observed in the FAC-only arm. carcinoembryonic antigen testing, CA 15-3 (27–29), chest X- Table 1 also presents the total number of cycles that were ray, liver ultrasound or computed tomography, bone scan, and given to patients. The recommended number of cycles that each mammogram were performed; breast ultrasound was also per- patient should have received was eight. For the total group and formed to evaluate the axilla. CBCs, differential counts, and for each individual treatment arm, the majority of patients platelet counts were performed weekly to monitor the myelo- received eight cycles. However, a larger percentage of Pac/FAC toxicity of FAC in the first cycle; in subsequent cycles, blood patients received the planned number of cycles (88%) compared counts were assessed on days 1 and 21 of each cycle. Patients on with the FAC-alone arm (71%). In the FAC-alone group, 92% the paclitaxel arm underwent weekly CBC, platelet, and differ- of the patients completed at least six cycles of chemotherapy, ential counts during each cycle. Chest X-ray, blood urea nitro- and in Pac/FAC group, 95% received at least six cycles of gen, serum glutamate pyruvate transaminase, lactic dehydrogen- treatment. In both groups, patients who did not receive the ase, alkaline phosphatase, and glucose analyses were repeated at planned number of cycles often received fewer rather than 4-month intervals during the initial 2-year period of study. additional cycles. Subsequently, these assessments were repeated at 6-month in- Overall RFS. The original study protocol specified that tervals for an additional 1 year, with mammogram and bone analysis would take place after 105 failures, so these data should scans performed on a yearly basis. After 3 years of follow-up, be considered preliminary. However, at this time, 92 recurrences patients were evaluated on a yearly basis with the following: (a) have occurred. The overall RFS rate for the two treatment arms complete history; (b) physical evaluation; (c) tests of CBC, is shown in Fig. 2A. Estimated RFS at 48 months was 0.83 (95% lactic dehydrogenase, serum glutamate pyruvate transaminase, CI, 0.79–0.88) for FAC alone and 0.86 (95% CI, 0.82–0.91) for alkaline phosphatase, glucose, carcinoembryonic antigen, and the Pac/FAC arm. The difference between the two groups was CA 15-3 (27–29); (d) chest X-ray; and (d) mammogram. not statistically significant (P ϭ 0.09). The overall estimated Statistical Considerations. The study was designed to hazard ratio for the two treatment arms, derived by fitting a Cox include 518 patients randomized in equal numbers to receive regression model, found a 30% reduction in risk associated with therapy either with paclitaxel followed by FAC or with FAC the Pac/FAC arm (hazard ratio, 0.70). However, the 95% con- alone. The objective of this study was to detect an absolute fidence interval for this hazard ratio ranged from 0.47 to 1.07, improvement of 15% in a 5-year response to the combination indicating the relatively imprecise estimate of the treatment therapy compared with our previous experience with FAC effect associated with a patient sample of this size. When the alone. In our previous adjuvant studies, the estimated disease- same approach of fitting a regression model was repeated with free survival rate after 5 years was 60%, and it was anticipated the addition of terms indicating ER status, status of surgery (pre- that there would be a 15% improvement with the addition of or postsurgery), and tamoxifen use, the resulting estimated paclitaxel, leading to a 75% increase in disease-free survival hazard ratio associated with treatment was 0.66 (95% CI, after 5 years. It was estimated that with a sample size of 518, 0.43–1.01).

RFS by ER Status. In Fig. 2, RFS curves are plotted for ER-positive and ER-negative patients by treatment group. The Table 1 Characteristics of all patients by timing of initiation slightly more favorable RFS rate associated with Pac/FAC treat- of chemotherapy ment is apparent only among ER-negative cases. Total The experience of the FAC alone and Pac/FAC-treated FAC alone, Pac/FAC, patients, groups is summarized in Fig. 3 by hazard rates. The curves no. of no. of no. of express risk of recurrence per month by treatment group for patients patients patients ER-positive (Fig. 3A) and ER-negative (Fig. 3B) groups. Results Variable (%) (%) (%) indicate a higher risk of recurrence (ϳ0.6%/month) in the first Total patients 259 (49) 265 (51) 524 (100) year for patients with ER-negative disease treated with FAC Age, yrs Ͻ50 144 (56) 152 (57) 296 (56) alone, in contrast to lower risk during this period in the Pac/FAC Ն50 115 (44) 113 (43) 228 (44) group. Hazard rates thereafter were similar for the two treat- Race ments. In the ER-positive group, hazard rates were similar White 206 (80) 196 (74) 402 (77) throughout the first 3 years of treatment. The notable increase in Black 15 (6) 24 (9) 39 (7) Hispanic 27 (10) 37 (14) 64 (12) risk after that time in the FAC alone group is attributable to 17 Other 11 (4) 8 (3) 19 (4) recurrences among 124 patients who were free of disease for at ER status least 36 months (compared with recurrences for 5 of 137 pa- Positive 143 (55) 165 (62) 308 (59) tients in the Pac/FAC ER-positive group, 5 of 77 in the FAC Negative 105 (41) 87 (33) 192 (37) alone ER-negative group, and 3 of 67 in the Pac/FAC ER- Unknown 11 (4) 13 (5) 24 (5) Timing of chemotherapy negative group). Results for the first 3 years are mostly com- Neoadjuvant 87 (34) 87 (33) 174 (33) plete, but estimates are less reliable after that time. Adjuvant 172 (66) 178 (67) 350 (67) This trial was initially designed under the assumption there Total patients 257 263 520 would be a 60% RFS rate at 5 years in the control (FAC-alone) No. of cyclesa group, which corresponds to 66% RFS rate at 4 years under an 0–7 cycles 72 (28) 30 (11) 102 (20) exponential distribution. In the present study, we have an esti- 8 cycles 182 (71) 231 (88) 413 (79) Ͼ8 3 (1) 2 (1) 5 (1) mated RFS of 83% at 4 years possibly because of more favor- Irradiation statusb able patients being enrolled in the study than in our earlier Yes 140 (55) 146 (57) 286 (56) studies. These changes reflect the referral patterns of patients No 115 (45) 112 (43) 227 (44) over the years to our institution. Although accrual and follow-up c Tamoxifen are adequate according to the initial study design, results must Yes 108 (42) 117 (44) 225 (43) No 150 (58) 147 (55) 297 (57) be regarded as preliminary attributable to the lower-than- Neoadjuvant patients 87 (50) 87 (50) 174 (100) expected recurrence rate. Furthermore, these differences were Clinical stage not statistically significant. At the time of this analysis, there IIA 27 (31) 32 (37) 59 (34) have been 47 deaths, 24 in the FAC arm and 23 in the Pac/FAC IIB 43 (49) 42 (48) 85 (49) IIIA 17 (20) 13 (15) 30 (17) arm. Seven deaths in the Pac/FAC arm were unrelated to breast Tumor status cancer.

T1 5 (6) 9 (10) 14 (8) Safety Results. Therapy-related toxicity information by T2 56 (64) 56 (64) 112 (64) patient is shown in Table 2. A higher percentage of patients T 26 (30) 22 (25) 48 (28) 3 experienced febrile neutropenia in the Pac/FAC group (17%) Nodal status compared with the FAC-alone group (9%). In this protocol, N 31 (36) 35 (40) 66 (38) 0 prophylactic use of G-CSF was not considered initially. As the N1 56 (64) 52 (60) 107 (62) Adjuvant patients 172 (66) 178 (67) 350 (100) study progressed, however, it was our policy to have either Surgical stage growth factor support or antibiotics added for patients treated on I 23 (13) 28 (16) 51 (13) the Pac/FAC arm to maintain the dose intensity of the therapy. IIA 75 (44) 74 (42) 149 (43) Patients who experienced febrile neutropenia were treated with IIB 61 (36) 60 (34) 121 (35) IIIA 13 (8) 13 (7) 26 (7) G-CSF for all subsequent cycles of chemotherapy, and dose IIIB 0 3 (2) 3 (1) reduction was reserved for patients in both treatment arms who Tumor status had nonhematological toxicities of grade 3 or higher. Docu- T1 81 (47) 78 (44) 159 (45) mented infectious complications of grade 3 occurred in a few T 74 (43) 85 (48) 159 (45) 2 patients. A significant fraction of patients had neurotoxicity T3 16 (9) 15 (8) 31 (9) Unknown 1 (1) 0 (0) 1 (1) during treatment, but these had resolved in all patients by Nodal status at surgeryd subsequent follow-ups. Thirty-three percent of patients in the 0 41 (24) 56 (32) 97 (28) Pac/FAC arm had grade 3 myalgias and were treated symptom- 1–3 72 (42) 59 (33) 131 (37) atically. Two patients in the FAC-alone arm developed clinical 4–10 46 (27) 50 (28) 96 (27) Ͼ10 12 (7) 13 (7) 25 (7) evidence of congestive heart failure. Of those, one patient had received radiation therapy to the left breast and axilla in addition a Complete information not available for four patients. b Information not available for 11 patients. to chemotherapy. In the Pac/FAC arm, one patient developed c Information not available for two patients. congestive heart failure 10 days after the first dose of paclitaxel. d One patient had no axillary dissection. This patient had multiple risk factors for congestive heart failure

Fig. 2 Composite of RFS for all patients (A), ER-negative patients (B), and ER-positive patients (C).

and had not received prior radiation therapy or doxorubicin. Her mias, one on the Pac/FAC arm and two on the FAC alone arm congestive heart failure was considered to be secondary to other of the study. cardiac risk factors and not treatment with Pac/FAC. There have After completion of chemotherapy, five patients became been no toxic deaths in either arm of the study, and no instances pregnant. Of these, four had received Pac/FAC and one had of leukemia have been observed among patients in either treat- received FAC alone. The data regarding chemotherapy-induced ment arm of the study up to the present time. amenorrhea were retrospectively collected by a questionnaire in One patient with preexisting colitis experienced an ex- patients Ͻ50 years of age (Table 2). One hundred five patients acerbation of this condition while on paclitaxel therapy. Two provided adequate information (FAC alone, n ϭ 42; Pac/FAC, other patients had an allergic reaction to paclitaxel despite n ϭ 63). A higher fraction of women in Pac/FAC arm main- premedication, and paclitaxel therapy was discontinued in tained their ovarian function, but the differences were not sig- both patients. Three patients had transient cardiac arrhyth- nificant (P ϭ 0.2).

Fig. 3 Effect of paclitaxel by ER status:hazard rates.

Table 2 Percentage distribution of toxicity data by treatments observed, the trial would have provided 70% power to detect a FAC Pac/FAC halving in the rate of recurrence attributable to the addition of alone (n) (n) paclitaxel (approximately the change in rate for which the trial Toxicities n ϭ 259 n ϭ 265 was designed) and only 21% power to detect a 25% reduction in recurrence rate. Febrile neutropenia 24 44 Infection Ն grade 3 6 9 One larger trial (CALGB 9344 study), which had a similar Myalgias Ն grade 3 4 33 study design, evaluated the role of paclitaxel with AC combi- Paresthesias Ն grade 3 2 15 nation therapy. Although early results of that study showed a Transient arrhythmias 5 3 substantial reduction in the risk of recurrence and also a favor- Clinical CHF-treatment related 1 0 Toxic deaths 0 0 able impact on survival, updated results were less conclusive (13). The National Surgical Adjuvant Breast Project study B-28 Chemotherapy-induced amenorrhea (n ϭ 105) Yes 57 44 data (presented at the 2000 NIH Consensus Conference of Noa 43 56 Adjuvant Therapy for Breast Cancer) did not show a significant a Includes patients experiencing transient amenorrhea. 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 DISCUSSION survival did not reach statistical significance. As previously reported elsewhere (9), the major objective The findings of our study are consistent with those of the of this study in the neoadjuvant setting was to compare the CALGB 9344. One of the potential criticisms of the CALGB antitumor activity of the four cycles of paclitaxel to four cycles study design has been that patients on the AC arm received only of FAC regimen. Clinical objective responses and the degree of four cycles of chemotherapy, whereas those on the pacli- tumor reduction were similar (9). taxel/AC arm received eight cycles of chemotherapy. Therefore, The timing of initiation of chemotherapy has no significant the noted therapeutic advantage might have resulted from a impact on the RFS and overall survival (15). This study was longer duration of treatment, and not necessarily from the ad- prospectively planned to evaluate the impact of the addition of dition of paclitaxel to the AC combination. In our study, both paclitaxel to the FAC regimen given in either an adjuvant or cohorts of patients received the same duration of chemotherapy. neoadjuvant setting. This report includes data for the total study As of this follow-up, there was a 30% reduction in the risk of patient population registered in that protocol. The preliminary recurrence in the group of patients who received paclitaxel results of this prospective study suggest that the addition of followed by FAC; these findings are more favorable than the paclitaxel to FAC in patients with early breast cancer can result reduction in the risk of recurrence associated with paclitaxel/AC in a further reduction in the risk of recurrence. The differences in the CALGB 9344 study with additional follow-up. between the two treatment regimens observed in this study are Both treatment regimens were well tolerated, and there has not statistically significant because the sample size was small been no treatment-related mortality in this study. Cardiac dys- and the study was designed to be evaluated after a larger number function was not observed among patients in the Pac/FAC arm, of recurrences. Moreover, the initial trial design anticipated a and the risk of cardiac dysfunction was minimal in patients who higher rate of recurrence in the FAC alone arm; if we had received eight cycles of FAC. The dose of paclitaxel was higher initially assumed the lower recurrence rate that was actually in this study compared with that used in the CALGB study

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Downloaded from clincancerres.aacrjournals.org on September 27, 2021. © 2002 American Association for Cancer Research. Evaluation of Paclitaxel in Adjuvant Chemotherapy for Patients with Operable Breast Cancer: Preliminary Data of a Prospective Randomized Trial

Aman U. Buzdar, S. Eva Singletary, Vicente Valero, et al.

Clin Cancer Res 2002;8:1073-1079.

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