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© 1999 American Society for Clinical Oncology Combination Versus Sequential Doxorubicin and Docetaxel as Primary Chemotherapy for Breast Cancer: A Randomized Pilot Trial of the Hoosier Oncology GroupFrom the Hoosier Oncology Group and the Walther Cancer Institute, Indianapolis, IN. Address reprint requests to Kathy D. Miller, MD, 3202 N Meridian St, Indianapolis, IN 46202-4646; email kathmill{at}iupui.edu
PURPOSE: To evaluate the efficacy and toxicity of combination and sequential dose-dense chemotherapy with doxorubicin and docetaxel (Taxotere; Rhône-Poulenc Rorer, Collegeville, PA) as primary chemotherapy of breast cancer. PATIENTS AND METHODS: Patients with newly diagnosed stage II or noninflammatory stage III breast cancer were randomly assigned to receive the same total doses of doxorubicin and docetaxel over a 12-week period before definitive surgery. Patients in arm A received sequential therapy with doxorubicin 75 mg/m2 every 2 weeks for three cycles followed by docetaxel 100 mg/m2 every 2 weeks for three cycles. Patients in arm B received combination therapy with doxorubicin 56 mg/m2 plus docetaxel 75 mg/m2 every 3 weeks for four cycles. Granulocyte colony-stimulating factor was administered on days 2 to 12 of each cycle in both groups.
RESULTS: Forty patients were entered onto the trial. Pretreatment tumor size averaged 5.7 cm with clinicallypositive axillary lymph nodes in 23 patients (57%). As expected, myelosuppression was severe in both groups; however, CONCLUSION: Primary chemotherapy with doxorubicin and docetaxel is well tolerated and highly active. A sequential treatment schedule increases toxicity but may result in more substantial lymph node clearance than combination therapy.
THE USE OF PRIMARY chemotherapy (also termed neoadjuvant, preoperative, or induction chemotherapy) is supported by data in animal models that find improved survival when mice were treated with chemotherapy or tamoxifen before surgical resection.1,2 Concern that primary chemotherapy might increase surgical complications or result in inferior survival in patients whose tumors did not respond to treatment limited early clinical trials to patients who presented with locally advanced disease. Initial trials at the M.D. Anderson Cancer Center3 and the Istituto Nazionale Tumori in Milan4 found improved local control and overall survival compared with historical controls. In addition, selected patients whose tumors were initially not amenable to breast-conserving therapy were able to avoid mastectomy after significant tumor downsizing.5 As the safety and efficacy of this approach was proven, primary chemotherapy was offered as an alternative to initial surgical treatment for patients with earlier-stage disease. To date, at least six randomized trials comparing primary chemotherapy with traditional adjuvant treatment have been published (Table 1). Although few trials have found an improvement in overall survival with primary chemotherapy, not a single trial suggested a trend toward inferior results. Surgical complications were not more prevalent, and more patients were able to undergo breast-conserving surgery. As experience grew, it became clear that the amount of residual tumor after primary chemotherapy remained an important prognostic indicator and correlated well with overall survival.6-8
Unfortunately, only a minority of patients treated with primary chemotherapy achieve a complete pathologic response (pCR) with current combination chemotherapy regimens. Improvements will require not only the incorporation of new agents, but optimization of treatment schedules. The Gompertzian kinetic model proposed by Norton and Simon9,10 suggests an alternative treatment schedule to optimize results. In this model, the rate of tumor growth is not constant but, rather, inversely proportional to the total cell population. Growth rate decreases as the tumor increases in size, eventually reaching a plateau. Tumors treated at or near their plateau may re-enter a period of exponential growth with rapid relapse. Success is therefore predicted by decreasing the period available for regrowth between treatments by the use of rapidly cycling "dose-dense" schedules. Survival in two pilot trials was encouraging, with manageable toxicity.11,12 These pilot trials provided the basis for a recently completed lead phase III intergroup trial by the Cancer and Leukemia Group B (CLB 9741). This trial randomized patients with lymph node–positive disease to one of four treatment schedules: (1) combination therapy with doxorubicin and cyclophosphamide followed by paclitaxel every 3 weeks; (2) regimen 1, but every 2 weeks (plus granulocyte colony-stimulating factor [G-CSF] support); (3) sequential therapy with doxorubicin followed by paclitaxel followed by cyclophosphamide every 3 weeks; or (4) regimen 3, but every 2 weeks (plus G-CSF). Although appealing, the value of dose-dense sequential regimens will remain speculative until the results of CLB 9741 are reported. Doxorubicin has a well-established role in the treatment of breast cancer, both in adjuvant therapy and in patients with metastatic disease. Docetaxel (Taxotere; Rhône-Poulenc Rorer, Collegeville, PA) has demonstrated significant single-agent activity in patients with metastatic breast cancer, including those with anthracycline-resistant disease.13,14 The combination of doxorubicin and docetaxel is highly active without increased cardiac toxicity compared with single-agent doxorubicin.15 We undertook this randomized phase II pilot trial to determine the efficacy and toxicity of combination and sequential chemotherapy with doxorubicin and docetaxel as primary chemotherapy for breast cancer.
Patients with histologically confirmed stage II or noninflammatory stage III breast cancer who had not undergone definitive surgical resection were eligible. Patients were required to have disease measurable by physical examination or diagnostic breast imaging with a primary tumor  2 cm. Prior breast or chest wall radiation, chemotherapy, or hormonal therapy was not allowed. Patients had to have adequate renal, hepatic, hematologic, and cardiac function. The protocol was reviewed by the institutional review board, and written informed consent was obtained before treatment.
After eligibility was confirmed, patients were stratified according to tumor size ( Dose modifications were based on nadir blood counts and interval toxicity, considering each drug individually. A 25% dose reduction of the responsible drug was mandated for any of the following: febrile neutropenia, nadir platelet count less than 20,000/µL, bleeding associated with platelet count less than 40,000/µL, grade 3 or 4 mucositis, and grade 3 or 4 diarrhea. All other grade 3 or 4 toxicity resulted in a 50% dose reduction. Patients were evaluated for disease response after the third and sixth cycle of therapy in arm A and after the second and fourth cycles in arm B. Diagnostic breast imaging (mammogram or ultrasound) was repeated before definitive surgery in all patients. Sample size calculations required 15 patients in each arm to ensure 90% power (one-sided alpha = 0.05) to detect a 50% difference in delivered dose-intensity and toxicity. An additional five patients were added per arm to allow more accurate estimation of response rates. Toxicity and efficacy data were compared between the two arms using Fisher's exact test. The mean number of pathologically involved lymph nodes was compared between groups using the Wilcoxon two-sample test. Clinical complete remission (cCR) was defined as the complete disappearance of all evidence of disease by physical examination. Clinical partial remission (cPR) required at least a 50% decrease in the product of the greatest perpendicular tumor diameters. pCR required no evidence of invasive malignancy in the breast or lymph node specimens at the time of definitive surgery.
From March 1997 to June 1998, 40 patients were entered onto the trial. Initial characteristics were well matched (Table 2). The median age was 46.5 years (range, 31 to 63 years). Median pretreatment tumor size was 5.75 cm with clinically positive axillary lymph nodes in 23 patients (57%). Slightly more patients in the combination arm than in the sequential arm had palpable lymph nodes; however, this difference did not reach statistical significance. All patients were assessable for toxicity and response.
Myelosuppression was striking in both treatment arms (Table 3), but grade 4 leukopenia and granulocytopenia were more common (P < .05) in patients who received combination therapy. Despite severe granulocytopenia, infection was rare. Anemia and thrombocytopenia were generally mild; platelet transfusions were not required.
Eight patients (42%) who received sequential therapy developed grade 3 or 4 hand-foot syndrome (acral erythema) after the first docetaxel cycle. Two patients required hospitalization for narcotic analgesia. One patient refused further chemotherapy and was referred for definitive surgery; no residual tumor was identified in the specimen. The remaining seven patients completed treatment with a 50% dose reduction in subsequent docetaxel cycles. Hand-foot syndrome did not recur with re-treatment. Only one patient who received combination therapy developed mild (grade 2) hand-foot syndrome. Other nonhematologic toxicites rarely reached significant levels and did not limit the ability to deliver therapy. Ten patients in the sequential arm and five in the combination arm required dose reductions. Nonetheless, excellent overall dose-intensity was maintained (Table 4). Although more patients in the sequential arm (seven v one) required a delay in treatment, median time from randomization to definitive surgery was similar in both groups.
Objective clinical responses (cCR + cPR) were obtained in 34 patients (87%); eight patients (20%) obtained a cCR (Table 4). More patients who received sequential therapy achieved a cCR; however, this trend did not reach statistical significance. The small number of patients did not allow formal correlation between clinical examination, breast imaging, and pathologic response.16 Nonetheless, clinical status seemed to be a poor predictor of residual pathologic disease. One patient with a cCR and normal diagnostic breast imaging (mammogram and ultrasound) before surgery had extensive invasive disease in the breast and 17 positive lymph nodes. Another patient with a 2-cm palpable mass remaining after chemotherapy had only fibrosis and scar tissue identified at surgery. Altogether, a pCR was confirmed in five patients (12.5%), including one patient with residual ductal carcinoma-in-situ only. Patients who received sequential therapy had fewer positive lymph nodes (mean, 2.17 v 4.81; P = .037) and were more likely to undergo breast-conserving therapy than those who received combination treatment.
Primary chemotherapy with doxorubicin and docetaxel is generally well tolerated and highly active. The pathologic complete remission rate, although respectable, did not differ noticeably from that of other regimens reported previously. Although the frequency of pCRs certainly may have been adversely affected by the large tumor size and poor prognosis of our patient population, we had hoped to see superior efficacy with such aggressive doxorubicin and docetaxel treatment. The substantial myelosuppression observed in this trial was expected; however, the use of G-CSF limited infectious complications and allowed intensive therapy to be delivered. The severe hand-foot syndrome suffered by nearly half of the patients who received sequential therapy was not anticipated. Both doxorubicin and docetaxel can cause hand-foot syndrome; however, grade 3 or 4 toxicity is rarely reported with single-agent or combination therapy. Two centers have recently reported their initial experience with sequential docetaxel followed by doxorubicin. Drug doses and schedules were otherwise nearly identical to our study; no hand-foot syndrome was reported.17,18 Doxorubicin and paclitaxel have also been administered in a similar dose-dense sequential schedule in two pilot trials11,12; the preliminary data presented did not include a report of hand-foot syndrome. Whether this phenomenon was caused by doxorubicin, docetaxel, or a unique dose- or sequence-dependent interaction is unclear. Unfortunately, this pilot trial did not include pharmacokinetic sampling; therefore, we can only speculate on the cause of this toxicity. However, interaction with G-CSF seems unlikely because hand-foot syndrome did not recur with subsequent treatment cycles using the same G-CSF dose and schedule. Additional study to elucidate the cause of the severe hand-foot syndrome observed in some patients is required. This pilot trial is the first reported randomized study to test directly Norton and Simon's dose-dense hypothesis. Doses were calculated to deliver the same total amount of both drugs over a 12-week period to limit any confounding effect of differing dose between the treatment groups. Although the improvement in lymph node clearance with sequential therapy did reach statistical significance, caution is required when interpreting these data. The number of patients studied is small, resulting in wide confidence intervals. In addition, more patients in the combination group had palpable axillary adenopathy at presentation. Although this difference was not statistically significant, the possibility that this imbalance resulted in a perceived benefit with sequential therapy cannot be ignored. Taken alone, this trial cannot provide "proof of principle" of the value of rapidly cycling dose-dense therapy. If improved results with sequential therapy in the adjuvant setting are confirmed in the CLB 9741 trial, a new standard of treatment will be established. Finally, we believe this trial illustrates the need for more effective therapy for breast cancer and the important role of primary chemotherapy as a proving ground for new treatments. The use of pCR as a surrogate marker for overall survival is well established. Although no small pilot trial will (or should) eliminate the need for large phase III studies, promising drugs and schedules can be screened rapidly, both in terms of number of patients needed and length of follow-up required, in the primary chemotherapy setting. In addition, the ability to evaluate histologic specimens before and after treatment offers a unique opportunity to assess the biologic activity of different therapies. Future primary chemotherapy trials should build on these results and exploit the potential for biologic correlation.
Supported in part by unrestricted grants from Rhône-Poulenc Rorer, Collegeville, PA, and Amgen, Inc, Thousand Oaks, CA.
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Copyright © 1999 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
5 cm v > 5 cm) and method of biopsy (incisional v core needle v fine needle) and randomized to one of two treatment groups. Treatment arms were designed to deliver the same total doses of both doxorubicin and docetaxel over a 12-week period before definitive surgery. Patients in arm A received sequential therapy with doxorubicin 75 mg/m2 every 2 weeks for three cycles followed by docetaxel 100 mg/m2 every 2 weeks for three cycles. Patients in arm B received combination therapy with doxorubicin 56 mg/m2 plus docetaxel 75 mg/m2 every 3 weeks for four cycles. All patients received G-CSF as a once-daily subcutaneous injection on days 2 to 11 of each treatment cycle. Dexamethasone (8 mg twice daily) was administered for five doses starting 1 day before each docetaxel-containing cycle; diphenhydramine and cimetidine were given intravenously immediately before docetaxel. 
