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Journal of Clinical Oncology, Vol 22, No 9 (May 1), 2004: pp. 1621-1629 © 2004 American Society of Clinical Oncology. DOI: 10.1200/JCO.2004.08.065
Phase II Trial of Trastuzumab Followed by Weekly Paclitaxel/Carboplatin As First-Line Treatment for Patients With Metastatic Breast CancerFrom The Sarah Cannon Cancer Center/Tennessee Oncology, Nashville, TN; Jackson Oncology Associates, Jackson, MS; and Northern Virginia Oncology Group, Fairfax, VA Address reprint requests to Howard A. Burris III, MD, The Sarah Cannon Cancer Center, 250 25th Avenue N, Suite 110, Nashville, TN 37203; e-mail: hburris{at}tnonc.com
PURPOSE: To determine the response rate of trastuzumab as first-line therapy in patients with HER-2 overexpressing metastatic breast cancer. To assess the feasibility and toxicity of weekly paclitaxel/carboplatin with or without trastuzumab following initial treatment with trastuzumab. PATIENTS AND METHODS: Sixty-one patients received trastuzumab (8 mg/kg followed by 4 mg/kg/wk) for 8 weeks. Responding patients received 8 additional weeks of trastuzumab (4 mg/kg/wk), and then proceeded to receive trastuzumab (2 mg/kg) in combination with paclitaxel 70 mg/m2 and carboplatin (area under the curve, 2) weekly for 6 weeks followed by 2 weeks rest. Stable patients after the initial 8 weeks of trastuzumab proceeded to treatment with trastuzumab, paclitaxel, and carboplatin. Patients with disease progression during the initial 8 weeks had the trastuzumab discontinued and were treated with weekly paclitaxel/carboplatin. RESULTS: Weekly paclitaxel/carboplatin with or without trastuzumab was well tolerated. Fifty-two patients were assessable for response and all 61 patients were assessable for survival. Seventeen (33%) of 52 patients experienced a minor/partial response to single-agent trastuzumab and received 8 additional weeks of single-agent trastuzumab. Fifteen (29%) of 52 patients had stable disease and proceeded to receive paclitaxel/carboplatin/trastuzumab. Thirty-one patients with measurable disease were assessable for response after initial single-agent trastuzumab followed by paclitaxel/carboplatin/trastuzumab. An overall response rate of 84% (eight complete responses/18 partial responses), median time to progression of 14.2 months, and median overall survival of 32.2 months was reported with the triplet combination. In the patients treated with paclitaxel/carboplatin alone after disease progression on initial single-agent trastuzumab, an overall response rate of 69% (one complete response/10 partial responses), median time to progression of 8.3 months, and median overall survival of 22.2 months was reported. Median time to progression for all 61 patients is 10 months and the median overall survival is 26.7 months. CONCLUSION: This trial confirms the activity and tolerability of weekly paclitaxel/carboplatin alone or in combination with trastuzumab in women with HER-2 overexpressing metastatic breast cancer.
Overexpression of HER-2 is observed in 20% to 30% of patients with breast cancer and is correlated with a poor clinical outcome.1-3 Trastuzumab (Herceptin) is a humanized monoclonal antibody that targets the extracellular domain of the HER-2 receptor and inhibits the proliferation of human tumor cells overexpressing the HER-2 protein. Trastuzumab (Herceptin, Genentech, South San Francisco, CA) has demonstrated antitumor activity as first-line therapy in women with metastatic breast cancer (26% response rate) as well as in women who have tumor progression after chemotherapy for metastatic disease (12% to 15% response rate).4-6 Preclinical studies suggested additive or synergistic activity of trastuzumab when combined with cyclophosphamide, vinorelbine, and platinum and taxane agents, warranting combination studies.7-9 A phase II trial of trastuzumab and cisplatin in patients with previously treated metastatic breast cancer produced an overall response rate of 24%, which is higher than previously reported with either agent alone.10 A large randomized study comparing trastuzumab plus chemotherapy (paclitaxel or an anthracycline plus cyclophosphamide) with chemotherapy alone demonstrated an improved time to disease progression (7.4 v 4.6 months), objective response rate (50% v 32%), duration of response (9.1 v 6.1 months), and survival (25.1 v 20.3 months) for patients who received chemotherapy plus trastuzumab.11 The most serious adverse event reported in clinical trials was cardiac dysfunction. A review of the phase II/III trastuzumab trials demonstrated that patients receiving an anthracycline and cyclophosphamide in combination with trastuzumab experienced the greatest incidence of cardiac dysfunction (27%).12 In comparison, the incidence of cardiac dysfunction was significantly lower in patients receiving trastuzumab plus paclitaxel (13%) or trastuzumab alone (3% to 5%). Taxane/platinum combination regimens are highly active and are used in a variety of treatment settings, including non–small-cell lung, ovarian, bladder, head and neck, and esophageal cancer. A multicenter phase II study evaluated the efficacy and safety of every 3-week paclitaxel (200 mg/m2) and carboplatin (area under the curve [AUC], 6) as first-line treatment for women with metastatic breast cancer.13 The overall response rate was 62%, with a median time to progression of 7.3 months and an estimated 12-month survival of 72%. A similar response rate was reported in a multicenter phase II trial of weekly paclitaxel (100 mg/m2) and carboplatin (AUC, 2) as first-line therapy in women with metastatic breast cancer.14 An overall response rate of 62%, with a median time to progression of 4.8 months and median survival of 16 months, was reported among 95 assessable patients when both drugs were administered weekly for 3 out of every 4 weeks. This phase II trial was designed to explore several questions that remained unanswered at the time of study initiation as a result of the very recent approval of trastuzumab by the Food and Drug Administration. Because of the uncertainty regarding a dose response relationship with trastuzumab, larger doses of trastuzumab were used to assess feasibility and to attempt to achieve more rapid therapeutic trastuzumab concentrations. All patients received a higher dose (8 mg/kg load followed by 4 mg/kg weekly) of trastuzumab in order to determine the response rate and better understand the activity of single-agent trastuzumab as first-line therapy in patients with metastatic breast cancer. Patients who experienced obvious disease progression during the initial 8 weeks had the trastuzumab discontinued and were treated with weekly paclitaxel/carboplatin. Patients with a response or stable disease to trastuzumab were treated with the triple combination of weekly paclitaxel/carboplatin/trastuzumab to assess the feasibility, activity, and toxicity of the regimen. This regimen was selected based on the documented preclinical synergism, activity, and tolerability of the agents when administered weekly, compared with every 3 weeks. Furthermore, treatment-related cardiac dysfunction might be avoided or minimized with a platinum/taxane/trastuzumab regimen.
All patients had pathologically confirmed metastatic breast cancer with 2+ or 3+ HER-2/proto-oncogene overexpression by immunohistochemical staining. Measurable (  1 cm) or assessable disease detectable by radiologic studies or physical examination was required. Patients with bone-only disease had measurable lytic disease on plain x-ray, magnetic resonance imaging (MRI), or computed tomography (CT) scan. Lesions on bone scan, osteoblastic metastases, pleural effusions, and ascites were not considered measurable or assessable. An Eastern Cooperative Oncology Group performance status of  2 was required. The following laboratory parameters were required: WBC count > 3,000/µL, platelets > 100,000/µL, bilirubin < 2.0 mg/dL, and serum creatinine < 2.0 mg/dL. No previous chemotherapy for metastatic disease was allowed. Patients were allowed to have received one prior adjuvant or neoadjuvant chemotherapy regimen, completed more than 3 months before disease recurrence. Adjuvant taxane therapy was allowed if administered every 3 weeks; prior weekly taxane therapy was not allowed. Prior trastuzumab and adjuvant doxorubicin doses more than 360 mg/m2 were not allowed. Prior hormonal and radiation therapy were allowed, but patients had to discontinue either at least 2 weeks before enrollment. Patients were required to have a normal ejection fraction by echocardiogram or multiple gated acquisition scan (MUGA). Patients with meningeal involvement were ineligible. Patients with brain metastases were eligible only if one of the following applied: 1) a single brain metastasis was resected, with no evidence of residual on follow-up CT or MRI; or 2) the patient underwent radiation therapy for brain metastases and the follow-up CT or MRI was normal and there was no residual neurologic dysfunction. Pregnant or lactating women were ineligible, and women of childbearing potential were required to use adequate contraception for the duration of the study. The study was approved by the local institutional review board at all institutions, and written informed consent was obtained before enrollment.
Treatment Plan
All patients had a complete blood count, serum chemistry, MUGA scan, and CT scans pretreatment. The complete blood count was repeated weekly, while the serum chemistry was repeated at the beginning of each cycle. The MUGA scan was repeated every 12 weeks and disease assessments were repeated every 8 weeks. The National Cancer Institute Common Toxicity Criteria (Version 2.0) was used to grade treatment-related toxicities and the standard Southwest Oncology Group criteria were used for disease response assessment.15 Complete response (CR) was defined as total disappearance of clinically and radiologically detectable disease for at least 4 weeks. Partial response (PR) was defined as a 50% reduction in all measurable lesions as measured by the product of the perpendicular diameters of the greatest dimensions of tumor size, with no new lesions appearing for at least 4 weeks. A minor response was defined as a decrease of 25% to 49% in the products of diameters of measurable lesions for at least 4 weeks with no new lesions appearing. All responses required confirmation with subsequent scans 4 weeks after the scans demonstrating the initial response. Stable disease was defined as a decrease of less than 50% or an increase of less than 25% in the size of the measurable lesions, with no new lesions appearing. Disease progression was defined as the appearance of any new lesion or an increase of 25% in the size of the existing lesions. Duration of response was defined as the interval between the date of onset of a PR or CR and the date of disease progression. Time to progression was defined as the interval between the date of the start of treatment and the date of disease progression. Survival was defined as the interval between the date of the start of treatment and the date of death. If a patient was lost to follow-up, that patient was censored at the last date of contact.
Dose Modifications Trastuzumab was given at full dose regardless of blood counts and was not reduced secondary to febrile neutropenia. Any patient who developed signs or symptoms of congestive heart failure or experienced a decrease in their cardiac ejection fraction below the lower limit of normal would have the trastuzumab discontinued; paclitaxel/carboplatin could be continued at the investigator's discretion.
A total of 61 patients were enrolled between October 1998 and April 2001 at 19 network sites. Follow-up data are available through January 2004. The patient characteristics are described in Table 1. Six patients did not meet the definitions for measurable disease and were considered to have assessable disease only. These patients are not included in the response data, but are included in the time to progression and overall survival analyses. Three additional patients were not assessable as a result of premature study discontinuation: one patient requested to be removed after a single dose of trastuzumab; one patient was unable to continue study treatment as a result of moving after week 4 of trastuzumab; and one patient died from a nontreatment related myocardial infarction 3 weeks after starting trastuzumab. As a result, 52 patients with measurable disease are assessable for disease response, and all 61 patients are assessable for survival and safety.
Eighteen (30%) of the 61 patients enrolled completed the planned single-agent trastuzumab followed by six cycles of either paclitaxel/carboplatin or paclitaxel/carboplatin/trastuzumab. At the completion of six cycles of combination chemotherapy, nine of 18 patients were followed until disease progression with no subsequent treatment, six of 18 patients were continued on single-agent trastuzumab, two of 18 received oral tamoxifen, and one patient continued to receive weekly paclitaxel/carboplatin/trastuzumab at the discretion of her physician. Twenty-two patients (36%) discontinued treatment before completing the planned six cycles of chemotherapy because of progressive disease. Seven patients (11%) were removed from study as a result of physician discretion for the following reasons: underwent surgery for residual disease (three patients); determined to be fluorescent in situ hybridization negative (one patient); physician substituted cisplatin for carboplatin because of hypersensitivity reaction (one patient); physician opted to treat with doxorubicin/docetaxel rather than paclitaxel/carboplatin (one patient); and physician opted to treat with radiation therapy and letrozole subsequent to carboplatin hypersensitivity reaction (one patient). Six patients (10%) were removed from the study at the request of the patient. Three of these six patients relocated during the study and were unable to continue study treatment at the new location. Four patients (7%) were removed for intercurrent illnesses consisting of myocardial infarction, cirrhosis of the liver, cerebrovascular accident, and methicillin-resistant Staphylococcal aureus pharyngitis, respectively. Four patients (7%) were also removed for treatment-related toxicities including neuropathy (two patients), myelosuppression (one patient), and diarrhea/stomatitis (one patient). At the time of this report (median follow-up, 49.5 months), seven patients have not demonstrated disease progression and 14 patients remain alive.
Overall Response
Initial Single-Agent Trastuzumab Seventeen of the 52 patients demonstrated a minor or PR after the initial 8 weeks of trastuzumab. Interestingly, seven of nine partial responses and eight of eight minor responses were observed in patients with documented 3+ overexpression. While all of the responding patients should have continued to receive single-agent trastuzumab for 8 additional weeks, one patient received only one additional week (week 9) and was changed to combination therapy with paclitaxel/carboplatin/trastuzumab on week 10 because of questionable disease-related skin changes noted on physical exam on the day of treatment. Eight PRs and four minor responses were reported among the 16 assessable patients at the end of 16 weeks of trastuzumab, and all but one occurred in patients who were 3+ overexpressors.
Paclitaxel/Carboplatin Treatment (without trastuzumab)
Paclitaxel/Carboplatin/Trastuzumab Treatment
Assessable Disease Only
Time to Disease Progression
Overall Survival Fourteen women were alive at the time of data analysis. The median overall survival for all 61 patients was 26.7 months (range, 0.6 to 55.7+ months; Fig 3). Nine of the 41 patients with 3+ overexpression remain alive at the time of analysis. The median overall survival for this group is 29.2 months (range, 0.6 to 55.7+ months). Only five of the 20 patients with 2+ overexpression remain alive at the time of analysis. The median overall survival for this patient subset is 20.8 months (range, 1.5 to 48.7+ months).
Dose Modifications/Reductions The weekly combination chemotherapy regimen with or without trastuzumab was generally well tolerated. Nineteen patients (31%) had 52 doses of weekly chemotherapy held secondary to treatment-related toxicities, primarily myelosuppression. Twenty-eight doses were held because of a WBC 2,000/µL, 15 doses were held because of a platelet count 75,000/µL, and three doses were held for both on the day of treatment. A single dose of chemotherapy was held because of grade 4 anemia (hemoglobin 6.3 g/dL). Five doses were held because of nonhematologic toxicities including neurotoxicity (two patients), fatigue (two patients) and edema of the hand/arm (one patient). Seven patients (11%) required dose reductions secondary to treatment-related toxicities consisting of myelosuppression (three patients), neurotoxicity (two patients), and gastrointestinal toxicities (two patients). Two patients with dose reductions secondary to myelosuppression actually required a second dose reduction (50% of the original dose) in order to be able to tolerate the weekly regimen.
Treatment-Related Hematologic Toxicity
Treatment-Related Nonhematologic Toxicities
Cardiotoxicity Two patients (3%) had trastuzumab discontinued because of declines in their ejection fraction. One patient experienced a 20% decrease in her ejection fraction (51%  41%) associated with mild congestive heart failure symptoms (dyspnea, edema) after 24 months of weekly trastuzumab. The trastuzumab was discontinued and the patient is currently receiving anastrozole to maintain her response. The second patient experienced a 40% decrease in her ejection fraction (63%38%), but was asymptomatic. The patient continued weekly paclitaxel/carboplatin until disease progression and her ejection fraction recovered to 50% on subsequent tests. No other patients experienced an ejection fraction less than 40%. Three additional patients experienced a decline in their ejection fraction that was 20% of the baseline value (71%56%, 74%57%, and 69%50%), but all were asymptomatic and did not discontinue trastuzumab.
One objective of this study was to determine the response rate of trastuzumab as first-line therapy in patients with metastatic breast cancer. Nine partial responses (17%) were reported after eight weeks of trastuzumab (8 mg/kg loading dose followed by 4 mg/kg/wk). This activity is comparable with that previously reported for single-agent trastuzumab. The weekly combination chemotherapy regimen plus or minus trastuzumab was quite active, producing an overall response rate of 69% (9 CR and 27 PRs), median time to progression of 10.0 months, and median survival of 26.7 months. When analyzed by HER-2 overexpression as measured by immunohistochemistry, 34 patients with measurable disease whose tumors overexpressed HER-2 at the 3+ level had a 79% response rate, and the 18 patients with measurable disease whose tumors overexpressed HER-2 at the 2+ level had a 50% overall response rate to paclitaxel/carboplatin with or without trastuzumab. Among the 16 patients who progressed on single-agent trastuzumab, the combination of paclitaxel/carboplatin produced an overall response rate of 69% (one CR, 10 PRs). In the patients continuing on trastuzumab, the triplet combination resulted in an overall response rate of 84% (eight CR, 18 PRs) among 31 assessable patients. This compares favorably to data obtained with weekly paclitaxel/carboplatin (62% overall response, 4.8-month median time to progression, and 16-month median survival), every 3 week paclitaxel/carboplatin (62% overall response, 7.3-month median time to progression, and 19-month median survival), and weekly paclitaxel/trastuzumab (61% overall response).13,14,16 Data from Robert et al17 demonstrated the additive benefit of carboplatin to the paclitaxel/trastuzumab combination in a randomized phase III trial with an improved response rate and time to progression. Perez et al18 confirmed the toxicity advantage of weekly paclitaxel/carboplatin/trastuzumab in an 84 patient randomized study comparing weekly and every 3-week dosing of the chemotherapy regimens. As expected, the weekly administration schedule ameliorated many of the toxicities associated with paclitaxel/carboplatin. No febrile neutropenia was reported, and grade 3/4 neutropenia was reported in 28% of patients. Perez et al13 reported grade 3/4 neutropenia in 82% of patients with the every 3-week paclitaxel/carboplatin regimen. The incidence of grade 3/4 neutropenia was lower in our study compared with the study by Loesch et al,14 but the weekly dose of paclitaxel in our study was 70 mg/m2 compared to 100 mg/m2. The lower dose of paclitaxel also resulted in less peripheral neuropathy (11% grade 3/4 v 5% grade 3). Interestingly, only 11% of the patients enrolled in our study required dose reductions compared to 61% of patients receiving paclitaxel 100 mg/m2 and carboplatin (AUC, 2) in the Loesch study, despite the use of a 6/8 versus 3/4 schedule. This data suggests that slightly lower, more tolerable doses of paclitaxel can be used in combination with weekly carboplatin without compromising antitumor activity. This trial confirms the activity of weekly paclitaxel/carboplatin alone or in combination with trastuzumab in women with metastatic breast cancer. The weekly dosing schedule (paclitaxel 70 mg/m2 plus carboplatin AUC 2) is well-tolerated and does not appear to compromise antitumor activity when compared to similar phase II studies with weekly or every 3-week dosing schedules. Although the weekly regimen is associated with increased clinic visits compared to the every 3-week administration schedule, the improved toxicity profile may result in improved quality of life and should be considered in the palliative treatment of metastatic disease. In summary, this pilot phase II study supplies interesting information for further evaluations of trastuzumab in combination with the taxanes and the platinums. Utilization of single-agent trastuzumab as initial therapy is safe and feasible, and antitumor responses can be obtained. The addition of paclitaxel and carboplatin to the trastuzumab weekly regimen greatly increases the response rate, with encouraging improvements in time to progression compared to historic data. Interestingly, paclitaxel and carboplatin remain highly active and well tolerated as a weekly regimen in patients with metastatic breast cancer. Lack of response to initial single-agent trastuzumab did not interfere with the sensitivity to weekly paclitaxel and carboplatin. While current data would certainly suggest trastuzumab was still present at the time the doublet of paclitaxel and carboplatin was initiated, the response rates noted are consistent with those previously reported by other institutions. The three-drug regimen of weekly paclitaxel, carboplatin, and trastuzumab deserves continued study, and ongoing randomized trials will help verify both the benefits of adding carboplatin, as well as the improved toxicity profile for weekly chemotherapy.
Minnie Pearl Research Network Participating Sites include the following: Tennessee Oncology, Nashville, TN; Montgomery Cancer Center, Montgomery, AL; Oncology/Hematology Group of South Florida, Miami, FL; Atlanta Cancer Care, Atlanta, GA; Graves Gilbert Clinic, Bowling Green, KY; Mary Bird Perkins Cancer Center, Baton Rouge, LA; Louisiana Oncology Associates, Lafayette, LA; Grand Rapids Community Clinical Oncology Program, Grand Rapids, MI; Upstate Carolina Community Clinical Oncology Program, Spartanburg, SC; McLeod Cancer and Blood Center, Johnson City, TN; Greenview Regional Hospital, Bowling Green, KY; Jackson Oncology Associates, Jackson, MS; Northeast Alabama Regional Medical Center, Anniston, AL; Oncology/Hematology Associates of Southwest Virginia, Roanoke, VA; Associates in Oncology and Hematology, Chattanooga, TN; Northern Virginia Oncology Group, Fairfax, VA; Northeast Arkansas Clinic, Jonesboro, AK; Emerywood Internal Medicine and Oncology, Highpoint, NC; South Texas Hematology/Oncology, San Antonio, TX.
The following authors or their immediate family members have 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. Acted as a consultant within the last 2 years: Howard Burris III, BMS, Genentech; Suzanne Jones, BMS, Genentech; F. Anthony Greco, BMS, Genentech; John Hainsworth, BMS, Genentech. Performed contract work within the last 2 years: Howard Burris III, BMS, Genentech; Suzanne Jones, BMS, Genentech; F. Anthony Greco, BMS, Genentech; John Hainsworth, BMS, Genentech; Denise Yardley, BMS, Genentech. Received more than $2,000 a year from a company for either of the last 2 years: Howard Burris III, BMS, Genentech; Suzanne Jones, BMS, Genentech; F. Anthony Greco, BMS, Genentech; John Hainsworth, BMS, Genentech; Denise Yardley, BMS, Genentech.
We thank Dr James R. Gray at The Sarah Cannon Cancer Center for performing the statistical analyses for this study. We would also like to thank Shawn Hess for her assistance with manuscript preparation.
Supported by a grant from Bristol-Myers Squibb and Genentech. Presented in part at the 24th and 25th Annual San Antonio Breast Cancer Symposium, San Antonio, TX, December 10-13, 2001 and December 11-14, 2002; and the 38th Annual Meeting of the American Society of Clinical Oncology, Orlando, FL, May 18-21, 2002. Authors' disclosures of potential conflicts of interest are found at the end of this article.
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6. Baselga J, Tripathy D, Mendelsohn J, et al: Phase II study of weekly intravenous recombinant humanized anti-p185HER2 monoclonal antibody in patients with HER2/neu-overexpressing metastatic breast cancer. J Clin Oncol 14:737-744, 1996 7. Pegram MD, Lopez A, Konecny G, Slamon DJ: Trastuzumab and chemotherapeutics: Drug interactions and synergies. Semin Oncol 27:21-25, 2000 (6 suppl 11)[Medline] 8. Pegram MD, Finn RS, Arzoo K, et al: The effect of HER-2/neu overexpression on chemotherapeutic drug sensitivity in human breast and ovarian cancer cells. Oncogene 15:537-547, 1997[CrossRef][Medline] 9. Baselga J, Seidman AD, Rosen PP, et al: HER2 overexpression and paclitaxel sensitivity in breast cancer: Therapeutic implications. Oncology 11:43-48, 1997 (3 suppl 2) 10. Pegram MD, Lipton A, Hayes DF, et al: Phase II study of receptor-enhanced chemosensitivity using recombinant humanized anti-p185 HER2/neu monoclonal antibody plus cisplatin in patients with HER2/neu-overexpressing metastatic breast cancer refractory to chemotherapy treatment. J Clin Oncol 16:2659-2671, 1998[Abstract]
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14. Loesch D, Robert N, Asmar L, et al: Phase II multicenter trial of a weekly paclitaxel and carboplatin regimen in patients with advanced breast cancer. J Clin Oncol 20:3857-3864, 2002 15. Green S, Weiss GR: Southwest Oncology Group standard response criteria, endpoint definitions, and toxicity criteria. Invest New Drugs 10:239-253, 1992[CrossRef][Medline]
16. Seidman AD, Fornier MN, Esteva FJ, et al: Weekly trastuzumab and paclitaxel therapy for metastatic breast cancer with analysis of efficacy by HER2 immunophenotype and gene amplification. J Clin Oncol 19:2587-2595, 2001 17. Robert N, Leyland-Jones B, Asmar L, et al: Phase III comparative study of trastuzumab and paclitaxel with and without carboplatin in patients with HER-2/neu positive advanced breast cancer. Breast Cancer Res Treat 76:S37, 2002 (suppl 1; abstr 35)[CrossRef] 18. Perez EA, Rowland KM, Suman VJ, et al: N98-32-52: efficacy and tolerability of two schedules of paclitaxel, carboplatin, and trastuzumab in women with HER2 positive metastatic breast cancer: A North Central Cancer Treatment Group randomized phase II trial. Breast Cancer Res Treat 82: S47, 2003 (suppl 1; abstr 216) Submitted August 11, 2003; accepted February 24, 2004.
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Copyright © 2004 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
