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Originally published as JCO Early Release 10.1200/JCO.2005.05.3306 on February 12 2007 © 2007 American Society of Clinical Oncology. Phase II Study of Neoadjuvant Docetaxel, Vinorelbine, and Trastuzumab Followed by Surgery and Adjuvant Doxorubicin Plus Cyclophosphamide in Women With Human Epidermal Growth Factor Receptor 2–Overexpressing Locally Advanced Breast Cancer
From the Carolinas Hematology-Oncology Associates; The Blumenthal Cancer Center, Charlotte, NC; Department of Medicine, Division of Hematology-Oncology, University of Pittsburgh Magee-Womens Hospital, Pittsburgh, PA; Department of Medicine, Tufts-New England Medical Center, Boston, MA; and the Division of Hematology-Oncology, University of Tennessee College of Medicine, Memphis, TN Address reprint requests to Steven A. Limentani, MD, University of North Carolina, Blumenthal Cancer Center, Carolinas Hematology-Oncology Associates, 1100 South Tryon St, Charlotte, NC 28203; e-mail: slimentani{at}carolinas.org
Purpose: To evaluate the combination of docetaxel, vinorelbine, and trastuzumab as neoadjuvant therapy for human epidermal growth factor receptor 2 (HER2) –overexpressing breast cancer. Patients and Methods: Patients with stage IIB or III breast cancer, including inflammatory disease, and HER2 overexpression (determined by fluorescent in situ hybridization) were treated with six cycles of docetaxel 60 mg/m2 and vinorelbine 45 mg/m2 administered every 14 days with granulocyte colony-stimulating factor and quinolone prophylaxis. Trastuzumab was administered as a 4 mg/kg loading dose followed by 2 mg/kg weekly for 12 weeks. The primary efficacy end point was pathologic complete response (pCR) in the breast. Results: Of 31 enrolled patients, 68% had T3 or T4 tumors and 90% were clinically node positive. Twelve patients (39%; 95% CI, 21.6% to 55.9%) achieved pCR in the breast and lymph nodes and 14 patients (45%; 95% CI, 27.6% to 62.7%) achieved pCR in the breast alone, and 19 patients (61%; 95% CI, 44.1% to 78.4%) were node negative after neoadjuvant therapy. Clinical response was documented in 29 patients (94%; 95% CI, 78.6% to 99.2%) with 26 complete responses (84%; 95% CI, 70.9% to 96.8%). The most commonly reported grade 3/4 toxicities were neutropenia (97%), febrile neutropenia (22%), anemia (6%), mucositis/stomatitis (6%), constipation (6%), and skin rash (6%). Conclusion: With clinical response and pCR rates of 94% and 39%, respectively, docetaxel, vinorelbine, and trastuzumab is a highly active neoadjuvant therapy for HER2-overexpressing locally advanced breast cancer. Although well tolerated overall, significant febrile neutropenia was observed despite prophylactic measures; therefore, evaluating a similar regimen using lower docetaxel and/or vinorelbine doses is warranted.
Surgery with or without radiation remains the primary local breast cancer therapy, whereas systemic treatment is guided by biologic and clinical characteristics such as hormone receptor (HR) status, human epidermal growth factor receptor 2 (HER2) expression, and nodal involvement.1 Neoadjuvant chemotherapy for locally advanced breast cancer (LABC) offers a higher likelihood of breast-conserving surgery, and early indication of degree of chemosensitivity and associated long-term prognosis.2,3 However, the most important consideration for new research is using neoadjuvant treatment to evaluate novel regimens. Efficacy can be determined by using pathologic complete response (pCR) as an early surrogate for disease-free and overall survival,3,4 providing rapid information regarding potential curative impact to support testing in large phase III trials.
Docetaxel is regarded as the single most active cytotoxic agent for advanced breast cancer, with substantial objective response rates in previously untreated patients (up to 68% in phase II trials5) and anthracycline-pretreated patients (30% to 43% in phase III trials6). This taxane has been studied in the neoadjuvant setting as a single agent, in combination, and/or sequentially with other agents, conferring clinical response rates consistently Approximately 25% to 30% of breast cancer patients exhibit HER2 amplification and/or overexpression, correlating with poor clinical outcomes.20-23 Trastuzumab, a humanized monoclonal antibody against HER2, has produced first-line and second-line response rates of approximately 26% and 15%, respectively, in HER2-overexpressing MBC.24,25 Studies of trastuzumab plus docetaxel26-28 or vinorelbine29-31 for HER2-overexpressing MBC have reported favorable efficacy and safety. Moreover, drug interaction studies have demonstrated that trastuzumab is synergistic with docetaxel and vinorelbine, but only additive with paclitaxel and doxorubicin.32,33 In a recent phase II study by our group, neoadjuvant docetaxel plus vinorelbine with prophylactic G-CSF and quinolone support demonstrated a 27% pCR rate in the breast alone (T0, Tis, NX) and a 20% response rate in the breast and lymph nodes (T0, Tis, N0).34 We reasoned that given the in vitro synergy between docetaxel and vinorelbine, docetaxel and trastuzumab, and vinorelbine and trastuzumab, docetaxel, vinorelbine, and trastuzumab potentially would be clinically potent. This study was conducted to determine if the addition of trastuzumab to docetaxel and vinorelbine would result in a higher pCR rate and acceptable safety and tolerability in HER2-overexpressing LABC.
Women  18 years of age with histologically confirmed, palpable breast carcinoma (diagnosed by core or incisional biopsy) and HER2 overexpression (determined by fluorescent in situ hybridization) were eligible. The study enrolled patients with stage IIB or III disease, including patients with locoregional stage IV disease (ipsilateral infra- or supraclavicular adenopathy). Patients with T4 tumors, including inflammatory breast cancer, were permitted on study. All patients were required to have a bidimensionally measurable indicator lesion, Eastern Cooperative Oncology Group performance status  2, and normal left ventricular ejection fraction (LVEF). Patients were previously untreated with chemotherapy, immunotherapy, or hormonal therapy for breast cancer (except for chemopreventative tamoxifen when discontinued for 1 year before entry) and recently diagnosed (histologic diagnosis within 3 months of entry).
Exclusion criteria included another malignancy within the last 5 years (except curatively treated basal cell skin carcinoma or carcinoma in situ of the cervix); neutrophils less than 2,000/µL, platelets less than 100,000/µL, hemoglobin less than 10 g/dL, AST more than 1.5x upper limit of normal (ULN), total bilirubin more than ULN, alkaline phosphatase more than 5x ULN; and National Cancer Institute grade
Pretreatment Evaluation
Treatment
All patients received a 3-day course of oral dexamethasone (8 mg bid starting 1 day before docetaxel plus vinorelbine) to minimize docetaxel-related allergic reaction or fluid retention. G-CSF 5 µg/kg was administered subcutaneously 48 hours after treatment for 6 days until absolute neutrophil count 10,000/µL. Patients received ciprofloxacin (500 mg bid) or levofloxacin (500 mg/d) for 7 days, starting 48 hours after each cycle. Surgery. Primary surgery (on hematologic recovery and within 35 days of completing the last docetaxel plus vinorelbine cycle) consisted of mastectomy or lumpectomy with negative microscopic margins. Decisions regarding extent of surgery were made by the local surgeon (not mandated by protocol). Axillary lymph node dissection was required. If positive surgical margins were observed, a second surgery was to be performed within a reasonable time period if possible and clinically indicated. Local reconstruction with or without prosthesis was permitted. Pathologic evaluation was conducted per institutional standards.
Adjuvant.
Doxorubicin 60 mg/m2 was administered by slow IV push followed by cyclophosphamide 600 mg/m2 IV during 30 to 60 minutes. Doxorubicin plus cyclophosphamide (AC) was started Postlumpectomy or postmastectomy radiation was administered after AC if clinically indicated per institutional guidelines; course of action was to be consistent with optimal clinical care. Patients with estrogen receptor–and/or progesterone receptor–positive tumors initiated a 5-year antiestrogen course after adjuvant chemotherapy and radiation.
Dose and Schedule Modifications Docetaxel and vinorelbine were delayed up to 2 weeks for absolute neutrophil counts less than 1500/µL. For patients developing fever (one oral temperature > 38.5°C, or three readings > 38.0°C in 24 hours) and grade 4 neutropenia or prolonged grade 4 neutropenia (> 7 days), treatment was withheld until recovery and resumed with G-CSF during subsequent cycles. If febrile neutropenia persisted despite G-CSF or grade 4 thrombocytopenia developed, docetaxel and vinorelbine dosing was reduced by 25%.
Cycles were delayed up to 2 weeks for recovery of grade
Efficacy/Safety Assessments Adverse events (AEs) recorded throughout the study were graded according to National Cancer Institute Common Toxicity Criteria except for peripheral edema, pleural and pericardial effusions, and ascites (categorized as mild, moderate, or severe). The relationship of each AE to treatment was evaluated by the investigator, recorded with information such as dose modifications or treatment interruptions. Laboratory evaluations occurred before each chemotherapy and radiation cycle and after docetaxel, vinorelbine, and trastuzumab therapy completion; CBC with differential was obtained weekly.
Statistics All patients starting the first docetaxel, vinorelbine, and trastuzumab cycle were assessable for toxicity. Safety analysis included AE incidences; individual toxicities were summarized by type, frequency, and severity.
Thirty-one patients were enrolled (mean age, 48.2 years; range, 27 to 65 years). Clinical characteristics are listed in Table 1. All patients underwent mastectomy or lumpectomy after neoadjuvant chemotherapy.
Treatment Delivery Twenty-four patients (77%) completed all 10 cycles of neoadjuvant and adjuvant chemotherapy, 14 of whom completed all preoperative and postoperative cycles without dose modifications. Regarding delivery of neoadjuvant therapy, docetaxel and/or vinorelbine dose reduction was necessary in 13 patients (42%); febrile neutropenia despite prophylactic G-CSF was the most common reason (n = 6). Constipation and stomatitis led to dose reduction in two patients each. One patient each had the dose reduced for sensory neuropathy, increased liver function tests, and thrombocytopenia. Seven patients did not complete planned treatment because of disease progression (n = 1), noncompliance (n = 3), patient preference (n = 1), or febrile neutropenia (n = 2). Treatment delays during neoadjuvant therapy occurred in five patients, one each for neuropathy, febrile neutropenia, stomatitis, thrombocytopenia, and metabolic abnormalities.
Responses and Survival
Nine patients (29%) had HR-positive tumors. When pCR was evaluated for HR-positive tumors, pCR rates were 33% (T0, Tis, N0) and 44% (T0, Tis, NX); pCR rates were 41% and 45%, respectively, for HR-negative tumors. Although the sample size is small (precluding statistical analysis), this is in contrast to what has been observed in patients without HER2 overexpression, in whom the likelihood of pCR is correlated with the likelihood of an HR-negative tumor. At a median follow-up of 25 months, disease-free and overall survival were 83.9% (95% CI, 70.9% to 96.8%) and 96.8% (95% CI, 83.3% to 99.9%), respectively.
Toxicity
Table 4 summarizes nonhematologic toxicities (grade 2) after neoadjuvant docetaxel, vinorelbine, and trastuzumab therapy. No nonhematologic toxicities were grade 4 severity. Grade 3 nonhematologic AEs with more than a 5% incidence included mucositis/stomatitis (6%), constipation (6%), and skin rash (6%). Nine patients were hospitalized. Of these, seven hospitalizations were due to fever and neutropenia and two were due to constipation and abdominal pain in the setting of neutropenia. One of the patients hospitalized with constipation was the first patient treated on this study. After her hospitalization, it was recommended to all investigators that prophylactic laxatives be administered to avoid constipation. Only one of the 30 subsequently treated patients had constipation that reached grade 3 severity.
No patients exhibited clinical evidence of grade 3/4 cardiac toxicity, nor was there demonstration of a diminution in LVEF on planned evaluations. One patient was noted to have sinus tachycardia at the grade 2 level, which was not associated with any other cardiac findings and resolved.
We recently reported phase II data for neoadjuvant docetaxel and vinorelbine without trastuzumab in patients with LABC,34 which was associated with a pCR rate higher than that seen in other studies using a comparable chemotherapy duration. In our current docetaxel, vinorelbine, and trastuzumab study, toxicities were almost identical to those of docetaxel and vinorelbine alone, suggesting that trastuzumab does not play a role in increasing toxicity. Given the prominent dose-limiting febrile neutropenia in earlier docetaxel and vinorelbine series, our studies were designed based on the lung cancer experience reported by Miller et al19 with the same chemotherapy doses and routine prophylactic G-CSF and quinolone support. Our findings were consistent with those of Miller et al in regard to nonhematologic toxicities. We postulated that in breast cancer patients with more limited comorbidities than the typical lung cancer population, our febrile neutropenia incidence would be lower than the 14% seen by Miller et al. This was not the case, and in fact, the febrile neutropenia incidence exceeded 20% in a data set that now includes 91 patients between our two studies. With evidence supporting that adding trastuzumab to chemotherapy improves outcomes in MBC,35 we hypothesized that supplementing the highly active neoadjuvant docetaxel and vinorelbine regimen with trastuzumab may lead to higher response rates among patients with HER2-overexpressing tumors. This study demonstrated a 39% pCR rate (T0, Tis, N0) to neoadjuvant docetaxel, vinorelbine, and trastuzumab (45% pCR for T0, Tis, NX) in patients with HER2-overexpressing LABC. Contrary to our earlier observation that neoadjuvant docetaxel and vinorelbine resulted in pCR in a greater proportion of HR-negative patients, comparable proportions of HR-positive (33%) and HR-negative (41%) patients achieved pCR (T0, Tis, N0). Although the small sample size precludes any definitive conclusions, this observation may reflect a different impact of HR status in patients with HER2-overexpressing breast cancer that could be investigated in future studies. Whether anthracyclines may ultimately be omitted from HER2-overexpressing early-stage breast cancer treatment is unknown, but determining efficacy for nonanthracycline-containing regimens in these patients provides the basis for phase III evaluations. Of note, recent Breast Cancer International Research Group communications suggest that a nonanthracycline-containing regimen plus trastuzumab as adjuvant treatment of early-stage breast cancer is associated with improved disease-free survival.36 The current study enrolled patients with HER2-overexpressing tumors, which are associated with more aggressive breast cancer, increased likelihood of chemotherapy-resistant disease, and particularly poor prognosis.20-23,35,37 Moreover, 90% were clinically node positive, and 68% had T3/T4 tumors. Despite advanced tumor staging and other poor prognostic factors, the pCR (T0, Tis, N0) rate was 39% (45% for T0, Tis, NX). The observed pCR rate for this nonanthracycline regimen compares favorably with the pCR rates of 11.6% to 26% observed in National Surgical Adjuvant Breast and Bowel Project (NSABP) –B18, NSABP-B27, GEPARDUO, and GEPARTRIO—phase III trials in which anthracycline-containing regimens were administered alone, before, after, or in combination with docetaxel.3,38-41 Buzdar et al37 recently reported a significantly higher pCR rate (no residual invasive disease in the breast and axilla) with neoadjuvant paclitaxel, epirubicin, and trastuzumab versus paclitaxel and epirubicin (65.2% v 26%; P = .016) in stage II to IIIA breast cancer. Although epirubicin has better cardiac safety than doxorubicin, seven of 23 patients randomly assigned to trastuzumab had more than 10% decrease in cardiac ejection fraction. In another recent publication, an 8% incidence of grade 3 cardiac dysfunction was reported for paclitaxel and trastuzumab in patients with MBC, supporting cardiac monitoring during this nonanthracycline regimen.42 The particularly high pCR rate achieved by Buzdar et al37 potentially could be attributed to several factors, such as use of an anthracycline, longer duration of preoperative treatment, and evaluation in earlier disease stages (stage II to IIIA) relative to our study. Nevertheless, it is conceivable that adding AC presurgery, but after docetaxel and vinorelbine and trastuzumab, could improve pCR rates; a study to evaluate this hypothesis is ongoing. A number of studies published since 2000 evaluated trastuzumab with agents having well-established activity against MBC (including anthracyclines, taxanes, and vinorelbine), reporting clinical response rates in the range of 50% to 75%.26,28-31,35,37,42-48 Concurrent trastuzumab plus AC, albeit effective (50% objective response rate), was associated with severe cardiac dysfunction in 27% of patients with MBC.35 A recent joint analysis of two North American phase III trials (NSABP-B31 and N9831) and results of the European Herceptin Adjuvant trial of adjuvant chemotherapy with or without trastuzumab in HER2-overexpressing early-stage breast cancer revealed significant disease-free survival benefits for trastuzumab (with significantly improved overall survival in NSABP-B31/N9831), resulting in early closure of these trials.49,50 Docetaxel, vinorelbine, and trastuzumab was reasonably well tolerated, with mostly manageable toxicities and no deaths, significant cardiac toxicity, or predominant nonhematologic toxicity. However, despite routine G-CSF, the febrile neutropenia incidence was still high at 22%; unfortunately, this outcome mitigates against phase III evaluation. The question remains whether the dosing used for these three agents is necessary for combination use considering their synergistic interactions in vitro. It remains possible that lower dose docetaxel, vinorelbine, and trastuzumab regimens might produce less febrile neutropenia while maintaining efficacy. In fact, recent observations using a lower dose of vinorelbine (30 mg/m2) with the same docetaxel dose and growth factor support suggest that febrile neutropenia is ameliorated to a clinically acceptable range (unpublished observations). Lastly, based on our prior neoadjuvant docetaxel/vinorelbine experience in a similar population, adding trastuzumab did not appear to influence the toxicity profile negatively. Neoadjuvant docetaxel, vinorelbine, and trastuzumab was well tolerated and highly active in HER2-overexpressing LABC, with encouraging clinical response and pCR rates. Additional studies of reduced docetaxel and/or vinorelbine doses to lower the incidence of febrile neutropenia are needed.
Although all authors completed the disclosure declaration, the following authors or their immediate family members indicated a financial interest. No conflict exists for drugs or devices used in a study if they are not being evaluated as part of the investigation. For a detailed description of the disclosure categories, or for more information about ASCO's conflict of interest policy, please refer to the Author Disclosure Declaration and the Disclosures of Potential Conflicts of Interest section in Information for Contributors. Employment: N/A Leadership: N/A Consultant: Steven A. Limentani, Sanofi-aventis; Adam M. Brufsky, Sanofi-aventis, Genentech; Mohammed Jahanzeb, Genentech, Sanofi-aventis, GlaxoSmithKline Stock: N/A Honoraria: Steven A. Limentani, Sanofi-aventis, Amgen; Adam M. Brufsky, Sanofi-aventis, Genentech; Mohammed Jahanzeb, Sanofi-aventis, Genentech, Eli Lilly & Co Research Funds: Steven A. Limentani, Sanofi-aventis, Amgen; Adam M. Brufsky, Sanofi-aventis, Genentech; John K. Erban, Sanofi-aventis; Mohammed Jahanzeb, Genentech Testimony: N/A Other: N/A
Conception and design: Steven A. Limentani, Adam M. Brufsky Administrative support: Steven A. Limentani, Adam M. Brufsky Provision of study materials or patients: Steven A. Limentani, Adam M. Brufsky, John K. Erban, Mohammed Jahanzeb Collection and assembly of data: Steven A. Limentani, Adam M. Brufsky, John K. Erban, Mohammed Jahanzeb, Deborah Lewis Data analysis and interpretation: Steven A. Limentani, Adam M. Brufsky, John K. Erban, Mohammed Jahanzeb Manuscript writing: Steven A. Limentani, Adam M. Brufsky Final approval of manuscript: Steven A. Limentani, Adam M. Brufsky, John K. Erban, Mohammed Jahanzeb, Deborah Lewis Other: John K. Erban
published online ahead of print at www.jco.org on February 12, 2007. Supported by grants from Aventis Pharmaceuticals Inc. Presented in part at the 39th Annual Meeting of the American Society of Clinical Oncology, May 31-June 3, 2003, Chicago, IL. Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.
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Marty M, Cognetti F, Maraninchi D, et al: Randomized phase II trial of the efficacy and safety of trastuzumab combined with docetaxel in patients with human epidermal growth factor receptor 2-positive metastatic breast cancer administered as first-line treatment: The M77001 Study Group. J Clin Oncol 23:4265-4274, 2005 46. Montemurro F, Choa G, Faggiuolo R, et al: A phase II study of three-weekly docetaxel and weekly trastuzumab in HER2-overexpressing advanced breast cancer. Oncology 66:38-45, 2004[Medline] 47. Pegram MD, Pienkowski T, Northfelt DW, et al: Results of two open-label, multicenter phase II studies of docetaxel, platinum salts, and trastuzumab in HER2-positive advanced breast cancer. J Natl Cancer Inst 96:759-769, 2004 48. Raff JP, Rajdev L, Malik U, et al: Phase II study of weekly docetaxel alone or in combination with trastuzumab in patients with metastatic breast cancer. Clin Breast Cancer 4:420-427, 2004[Medline] 49. Piccart-Gebhart MJ, Procter M, Leyland-Jones B, et al: Trastuzumab after adjuvant chemotherapy in HER2-positive breast cancer. N Engl J Med 353:1659-1672, 2005 50. Romond EH, Perez EA, Bryant J, et al: Trastuzumab plus adjuvant chemotherapy for operable HER2-positive breast cancer. N Engl J Med 353:1673-1684, 2005 Submitted December 15, 2005; accepted January 2, 2007.
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Copyright © 2007 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
An antiestrogen was administered with or after radiation therapy in patients with hormone receptor–positive tumors. IV, intravenously; G-CSF, granulocyte colony-stimulating factor.
T) with doxorubicin and cyclophosphamide followed by docetaxel and trastuzumab (AC
