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Journal of Clinical Oncology, Vol 26, No 10 (April 1), 2008: pp. 1642-1649 © 2008 American Society of Clinical Oncology. DOI: 10.1200/JCO.2007.11.6699 Randomized Phase III Trial of Weekly Compared With Every-3-Weeks Paclitaxel for Metastatic Breast Cancer, With Trastuzumab for all HER-2 Overexpressors and Random Assignment to Trastuzumab or Not in HER-2 Nonoverexpressors: Final Results of Cancer and Leukemia Group B Protocol 9840
From the Memorial Sloan-Kettering Cancer Center, New York, NY; Cancer and Leukemia Group B Statistical Center, Duke University Medical Center, Durham; University of North Carolina at Chapel Hill, Chapel Hill, NC; Dana-Farber Cancer Institute, Boston, MA; Vermont Cancer Center, Burlington, VT; and The Ohio State University Medical Center, Columbus, OH Corresponding author: Andrew D. Seidman, MD, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, NY 10021; e-mail: seidmana{at}mskcc.org
Purpose Phase II trials suggested that weekly paclitaxel might be more effective and less toxic than every-3-weeks administration for metastatic breast cancer (MBC). Cancer and Leukemia Group B (CALGB) protocol 9840 was initiated to address this question. Subsequently trastuzumab was demonstrated to improve outcomes of paclitaxel therapy for human epidermal growth factor receptor-2 (HER-2)–positive patients, and was therefore incorporated. Because inhibition of HER-family signaling had potential efficacy even without HER-2 overexpression, we randomly assigned for trastuzumab in this population. Patients and Methods Patients were randomly assigned to paclitaxel 175 mg/m2 every 3 weeks or 80 mg/m2 weekly. After the first 171 patients, all HER-2–positive patients received trastuzumab; HER-2 nonoverexpressors were randomly assigned for trastuzumab, in addition to paclitaxel schedule. A total of 577 patients were treated on 9840. An additional 158 patients were included in analyses, for combined sample of 735. The primary end point was response rate (RR); secondary end points were time to progression (TTP), overall survival, and toxicity. Primary comparisons were between weekly versus every-3-weeks paclitaxel, and trastuzumab versus no trastuzumab in HER-2 nonoverexpressors. Results In the combined sample, weekly paclitaxel was superior to every-3-weeks administration: RR (42% v 29%, unadjusted odds ratio [OR] = 1.75; P = .0004), TTP (median, 9 v 5 months; adjusted HR = 1.43; P < .0001), and survival (median, 24 v 12 months; adjusted HR = 1.28; P = .0092). For HER-2 nonoverexpressors, trastuzumab did not improve efficacy. Grade 3 neuropathy was more common with weekly dosing (24% v 12%; P = .0003). Conclusion Weekly paclitaxel is more effective than every-3-weeks administration for MBC. Trastuzumab did not improve efficacy for HER-2 nonoverexpressors. Neurotoxicity is a treatment-limiting toxicity for weekly paclitaxel.
Few single chemotherapeutic agents have been studied as rigorously as the taxanes regarding dose and schedule for breast cancer. Three-hour infusions were found to be similarly effective and more convenient than 241 and 96-hour2 infusions. Dose escalation of paclitaxel from 175 to 210 and 250 mg/m2 offered no improvement in efficacy, but increased neurotoxicity.3 Phase II clinical trials of weekly 1-hour paclitaxel in metastatic breast cancer (MBC) have demonstrated promising efficacy and favorable tolerability, including with trastuzumab.4-10 In 1998, Cancer and Leukemia Group B (CALGB) protocol 9840 began as a prospective randomized comparison of weekly and every-3-weeks (3-weekly) paclitaxel. This trial began in the pretrastuzumab era,13 and the first 171 patients enrolled had tumors of unknown human epidermal growth factor receptor 2 (HER-2) status. The protocol was subsequently revised, and all patients with HER-2–overexpressing breast cancer received trastuzumab. Recognizing that no assessment of HER-2 status is perfect and that there were many unanswered questions about the role of trastuzumab in breast cancer,14-16 we also tested the potential value of trastuzumab in patients with HER-2–nonoverexpressing tumors.
Patients The CALGB 9840 study population consisted of women with measurable, histologically confirmed MBC. Up to one line of prior chemotherapy for locally advanced or metastatic disease was allowed. Bone-only, CNS, lymphangitic pulmonary metastases, and previously irradiated tumors without subsequent progression were considered nonmeasurable. As per the protocol stipulated design, data from MBC patients who received paclitaxel at 175 mg/m2 on CALGB 9342 were incorporated into the analysis.3 Random assignment was weighted (60:40), favoring weekly paclitaxel. A total of 585 patients were accrued to CALGB 9840; 577 patients began protocol therapy and 158 patients from the 175 mg/m2 arm of CALGB 9342 are included in this analysis, for a total of 735 patients (Fig 1).
Prior taxane was allowed as adjuvant therapy, provided that 1 year had transpired from its completion to protocol entry. Adequate renal, hepatic, and hematologic parameters were required (Appendix, online only). After trastuzumab was added to protocol therapy, a normal baseline left ventricular ejection fraction (LVEF) was required. Patients with CNS metastases were eligible if asymptomatic, not receiving corticosteroids, and more than 6 months from cranial irradiation.
Methods Patients were stratified by prior chemotherapy: (1) no chemotherapy in the metastatic setting or recurrence more than 6 months of completion of adjuvant therapy and (2) one prior regimen in the metastatic setting, or no prior chemotherapy for metastases but recurred less than 6 months from completing adjuvant therapy. Subsequent to the amendment requiring HER-2 testing, patients were also stratified by HER-2 status. The first 171 patients were not required to have HER-2 testing and were randomly assigned to paclitaxel 80 mg/m2 weekly via 1-hour infusion, or to paclitaxel 175 mg/m2 every 3 weeks via 3-hour infusion. For the first six infusions, weekly paclitaxel was dosed at 100 mg/m2 but subsequently continued at 80 mg/m2. A 30% incidence of grade 3 peripheral sensory neuropathy resulted in an amended starting dose of 80 mg/m2 weekly. Paclitaxel was to be continued until disease progression or limiting toxicity. CBC was obtained every 3 weeks. Prophylactic hematopoietic growth factor support could be used as required for treatment-limiting neutropenia or anemia. A 21-day cycle of therapy could be initiated in weekly paclitaxel patients provided that the absolute granulocyte count (AGC) was at least 1,000/µL; for 3-weekly paclitaxel, the AGC was to be at least 1,500/µL. Platelets had to be at least 100,000/µL for both schedules on day 1 of each cycle. Standard premedication with dexamethasone 10 mg, diphenhydramine 50 mg, and either cimetidine 300 mg or ranitidine 50 mg intravenously 30 to 60 minutes before paclitaxel infusion was required.17 The protocol was amended on March 15, 2000, to require HER-2 status assessment by immunohistochemistry (IHC) or fluorescence in situ hybridization (FISH). Those patients with HER-2–positive disease (IHC 3+ or FISH+) received weekly trastuzumab 2 mg/kg via 30-minute infusion following a 4-mg/kg loading dose administered over 90 minutes. HER-2–normal patients were randomly assigned 50:50 to receive or not receive trastuzumab. Patients were to receive a minimum of two cycles of therapy unless there was rapid disease progression. Prior trastuzumab became an exclusion criterion, and patients were stratified by HER-2-status for paclitaxel schedule.
Treatment Schedule and Dose Modification
Nonhematologic toxicity. Dosing guidelines for nonhematologic toxicity are described in detail in the Appendix (online only).
Statistical Methods
Power was based on the two primary study objectives: (1) to determine whether weekly paclitaxel results in a significantly higher response rate (RR) than 3-weekly paclitaxel, regardless of HER-2 status and assignment to trastuzumab, and (2) to determine whether trastuzumab significantly increases RR among HER-2 nonoverexpressors, regardless of paclitaxel schedule. Regarding Peretz et al, 1 95% power to test a 50% increase in response incidence from 25% on standard paclitaxel to 37.5% on weekly paclitaxel required 700 patients randomly assigned equally to standard or weekly schedule. Regarding Holmes et al,2 85% power to detect a 50% increase in response incidence from 25% to 37.5% with trastuzumab required 490 patients randomly assigned to receive or not receive trastuzumab. Both calculations assumed a two-sided
Data Analyses CALGB 9840 was monitored biannually by an independent data safety monitoring board beginning within 6 months of activation and continuing until November 2003. Formal interim analyses on tumor response used two-sided bounds constructed from the O'Brien-Fleming approach18 and the Lan-DeMets19 spending function. As part of CALGB's quality-assurance program, study data were reviewed by the study chair and randomly selected patient charts were audited on site at least once every 3 years. CALGB study statisticians performed statistical analyses using SAS 9.0 (SAS Institute, Cary, NC) on data extracted from the CALGB database in February 2006.
Patient Characteristics Table 2 presents patient characteristics in the combined sample by stratification factors (HER-2 status and line of therapy), demographics (age, race), and pretreatment clinical characteristics.
Efficacy Primary end point and tumor response. Table 3 summarizes the RR for the combined and limited samples. For the combined sample, the RR of weekly paclitaxel is 42% versus 29% for 3-weekly paclitaxel, with an unadjusted odds ratio (OR) of 1.75 (P = .0004). In the limited sample, trastuzumab in HER-2–nonoverexpressing tumors did not significantly improve RR (38% v 32%; P = .28).
TTP. Figure 2A shows TTP by paclitaxel schedule (combined sample) and by trastuzumab use in HER-2 nonoverexpressors (limited sample). An early and persistent advantage for weekly paclitaxel over standard paclitaxel was observed. Median TTP for patients receiving weekly paclitaxel was prolonged by 4 months (9 v 5 months; adjusted hazard ratio [HR] = 1.43; P < .0001). Because patients enrolled onto CALGB 9342 were more likely to have been in the second-line setting compared with CALGB 9840, we adjusted for line of therapy. Treatment outcomes were similar in the two studies. Figures 3A and 3B demonstrate the comparability of the CALGB 9342 and CALGB 9840 populations when adjusting for line of therapy. The addition of trastuzumab to paclitaxel in patients with HER-2–normal breast cancer was not associated with significantly longer TTP (7 v 6 months; P = .28; Figure 2B).
Overall survival. Appendix Figure A1A (online only) shows overall survival (OS) by paclitaxel schedule in the combined sample. After adjusting for line of therapy, HER-2 status, trastuzumab, tumoral estrogen-receptor status, and performance score, the HR of 3-weekly to weekly paclitaxel was 1.28 (95% CI, 1.06 to 1.54; P = .0092); in the limited sample, the HR was 1.17 (95% CI, 0.95 to 1.44; P = .14). The addition of trastuzumab in HER-2 nonoverexpressors did not have a significant impact on OS (Fig A1B, online only). Toxicity. Adverse event data are presented for the limited sample only. Hematologic toxicity was generally mild, and is summarized in Tables 4 and 5. Although grade 3 or worse granulocytopenia was more frequent with standard versus weekly paclitaxel (15% v 9%; P = .017), febrile neutropenia requiring hospitalization was infrequent with either schedule (4% v 3%). Trastuzumab did not contribute to hematologic toxicity.
Nonhematologic toxicities occurring with at least 5% incidence are summarized in Tables 6 and 7. Grade 2 and 3 sensory neuropathy was encountered in 21% and 24% of patients receiving weekly paclitaxel versus 21% and 12% receiving standard paclitaxel, respectively (comparison of grades 2 and worse; P = .0046). Grade 2 and 3 motor neuropathy was noted in 8% and 9% of weekly versus 5% and 4% of conventionally dosed patients, resepctively (comparison of grades 2 and worse; P = .013). The incidence of neurosensory toxicity with weekly paclitaxel is inflated as a result of the excess neuropathy encountered in the first 116 patients who received 100 mg/m2 dosing for the first six infusions; for these patients, the incidence of grade 3 neuropathy was 30%, compared with 21% for the subsequent 232 patients who received constant dosing of paclitaxel at 80 mg/m2. Slightly more patients receiving 3-weekly paclitaxel experienced grade 3 or worse myalgia and arthralgia, whereas slightly more weekly paclitaxel patients experienced grade 3 or worse dyspnea. Other grade 3 and 4 nonhematologic toxicities were rare, including serious hypersensitivity reactions, as a result of the all-parenteral premedication regimen employed.17
The use of trastuzumab was associated with a 2.7% incidence of National Cancer Institute Common Toxicity Criteria grade 3 cardiac dysfunction, versus 0% among patients not receiving trastuzumab. Clinically significant cardiac events prompting serious adverse event reporting and hospitalization occurred in four patients receiving trastuzumab and in one patient not receiving trastuzumab; there were no deaths attributable to cardiac toxicity. Two treatment-related deaths occurred, attributable to pneumonia, in patients randomly assigned to weekly paclitaxel alone. Two secondary malignancies occurred, both renal cell carcinomas, one in each paclitaxel schedule, both without trastuzumab.
Weekly paclitaxel was superior to 3-weekly paclitaxel as treatment of MBC in RR and TTP. Importantly, this study also demonstrated a lack of therapeutic effect for trastuzumab in HER-2–nonoverexpressing breast cancer. Weekly paclitaxel improved RR over standard paclitaxel (42% v 29%), and nearly doubled TTP, from 5 to 9 months. This improved efficacy was accompanied by increased neurotoxicity, but did not influence overall quality-of-life scores (assessed prospectively and reported previously).18 Strategies to prevent cumulative neurotoxicity with weekly paclitaxel administration are needed and might include the "intermittent weekly" approach used in other studies (ie, Eastern Cooperative Oncology Group [ECOG] protocol 2100).28 Five previously reported randomized trials (1-3, 21,22) have used paclitaxel at 175 mg/m2 via 3-hour infusion 3-weekly in more than 1,000 MBC patients. The primary analysis in this trial is unique in that it uses historical controls in addition to concurrently randomized controls. As a result, we were able to conduct the trial with fewer patients and less expense, and in less time. A disadvantage is the possibility that patients in the concurrent and historical settings could have fundamentally different characteristics. As part of "borrowing" from historical controls, we demonstrated that that they had outcomes similar to those in concurrent controls, once we adjusted for line of therapy. When trastuzumab was approved for the treatment of HER-2–positive MBC, we faced a critical choice that ultimately made the study more complex. We could either exclude HER-2–positive patients from the trial or treat them with trastuzumab in addition to paclitaxel, recognizing that they would likely have better outcomes than the previous patients with HER-2–positive disease who were treated with paclitaxel alone, generally without knowledge of the HER-2 status. We chose to include trastuzumab for patients with HER-2–positive tumors. At the same time, we took advantage of the opportunity to assess the benefit of trastuzumab in tumors assessed to be HER-2 normal. In effect, this decision created a subtrial with a factorial design. There was the possibility of an interaction between trastuzumab and paclitaxel schedule in the patients with HER-2–normal tumors. Without increasing the sample size, we also had limited ability to assess whether the benefit of weekly paclitaxel was in HER-2–positive tumors than in HER-2–normal or HER-2–unknown tumors. However, in the interest of obtaining timely answers, we deliberately did not increase the sample size and accepted our limited ability to look for interactions or address subsets. All of the historical controls (3-weekly paclitaxel) and the first 55 concurrent controls had unknown HER-2 status. These patients also differed from the remainder of the population in terms of the proportion of patients treated in the first- versus the second-line setting (25% and 76%, respectively). After adjusting for line of therapy, RR, TTP, and OS were similar among these two groups of patients. In addition, after adjusting for other relevant covariates in multivariate analysis, there were no major differences in our conclusions whether we used the combined sample or just the patients randomly assigned on this study. Other studies have demonstrated similar results. Weekly paclitaxel yielded more pathologic complete responses in the neoadjuvant setting compared with 3-weekly scheduling.23 In the adjuvant setting (ECOG 1199), weekly paclitaxel improved disease-free survival over 3-weekly (HR = 1.27; 95% CI, 1.07 to 1.51; P = .006) after four cycles of doxorubicin and cyclophosphamide,24 although this was not a planned, protocol-specified analysis. Recently, the Anglo-Celtic IV trial comparing weekly with 3-weekly paclitaxel reported 42% and 27% RRs (P = .002), respectively, in 560 randomly assigned patients with advanced disease.25 As opposed to CALGB 9840, where treatment lasted until disease progression, in the Anglo-Celtic IV trial, treatment lasted for 6 cycles (18 weeks) in the standard paclitaxel arm and 12 weeks in the weekly arm. It is possible that this asymmetry explains the lack of advantage in TTP observed in the latter trial, despite the higher RR for weekly paclitaxel. Our study showed no benefit for the addition of trastuzumab in patients whose tumors lacked HER-2 overexpression or gene amplification. Although this result was expected, we know of no other prospective demonstration of this observation. Further, this observation addresses the concern that substantial numbers of patients with HER-2–dependent breast cancers might have been mislabeled as "negative" for this receptor. In our study, HER-2 assessment was performed locally. Patients with either IHC 3+ or IHC 2+ and FISH-amplified tumors were considered HER-2 positive and assigned to trastuzumab; all others were considered HER-2 normal and randomly assigned to trastuzumab versus no trastuzumab. Our findings provide a counterbalance to the recently reported results from National Surgical Adjuvant Breast and Bowel Project (NSABP) protocol B-31 suggesting an apparent benefit for adjuvant trastuzumab in patients whose tumors tested negative at a central laboratory by both immunohistochemistry and FISH.29 Weekly paclitaxel served as a foundation for the North Central Cancer Treatment Group (NCCTG)/US Intergroup trial N9831 examining the role of adjuvant trastuzumab.26 Our study confirms the appropriateness of this approach. Weekly therapy may be preferable for other taxanes as well as for paclitaxel. A recently reported randomized trial comparing weekly nanoparticle albumin-bound paclitaxel with 3-weekly dosing demonstrated a higher RR and longer TTP in favor of weekly dosing.27 For paclitaxel, our study establishes the appropriateness of basing future studies, and standard practice, on weekly administration. Comparisons with other schedules, such as every-2-weeks full-dose (dose-dense) paclitaxel, as well as with newer taxanes and formulations, are appropriate.
Although all authors completed the disclosure declaration, the following author(s) indicated a financial or other interest that is relevant to the subject matter under consideration in this article. Certain relationships marked with a "U" are those for which no compensation was received; those relationships marked with a "C" were compensated. 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 or Leadership Position: None Consultant or Advisory Role: Andrew D. Seidman, Bristol-Myers Squibb (C), Genentech (C); Donald A Berry, Bristol-Myers Squibb (C); Lyndsay Harris, Genentech (C); Hyman Muss, Genentech (C); Diana Lake, Genentech (C); Shapiro M Charles, Genentech (C); Larry Norton, Genentech (C), Bristol-Myers Squibb (C); Eric S Winer, Genentech (C); Clifford Hudis, Genentech (C), Bristol-Myers Squibb (C) Stock Ownership: None Honoraria: Andrew D. Seidman, Genentech; P. Kelly Marcom, Genentech; Harold J Burstein, Genentech; Larry Norton, Genentech, Bristol-Myers Squibb Research Funding: P. Kelly Marcom, Bristol-Myers Squibb, Genentech Expert Testimony: None Other Remuneration: None
Conception and design: Andrew D. Seidman, Donald Berry, Larry Norton Administrative support: Andrew D. Seidman, Constance Cirrincione, Grandella Gipson, Larry Norton, Eric Winer, Clifford Hudis Provision of study materials or patients: Andrew D. Seidman, Lyndsay Harris, Hyman Muss, P. Kelly Marcom, Harold Burstein, Diana Lake, Charles L. Shapiro, Peter Ungaro, Larry Norton, Clifford Hudis Collection and assembly of data: Andrew D. Seidman, Donald Berry, Constance Cirrincione, Grandella Gipson, Charles L. Shapiro, Peter Ungaro Data analysis and interpretation: Andrew D. Seidman, Donald Berry, Constance Cirrincione, Larry Norton, Eric Winer, Clifford Hudis Manuscript writing: Andrew D. Seidman, Donald Berry, Eric Winer, Clifford Hudis Final approval of manuscript: Andrew D. Seidman, Donald Berry, Constance Cirrincione, Lyndsay Harris, Hyman Muss, P. Kelly Marcom, Grandella Gipson, Harold Burstein, Diana Lake, Charles L. Shapiro, Peter Ungaro, Larry Norton, Eric Winer, Clifford Hudis
Dosing Guidelines for Nonhematologic Toxicity GI. Patients experiencing grade 3 GI toxicity (other than nausea and vomiting) could be re-treated at a one-level dose reduction. Recurrent grade 3 GI toxicity could result in additional dose reductions. Patients with grade 4 GI toxicity other than nausea and vomiting could be re-treated (using the same dose-reduction schema) only after discussion with the study chair. Patients must have recovered completely from the toxicity before being re-treated. If necessary, a delay of the next infusion for up to 2 weeks was permissible to allow for full recovery. Delays longer than 2 weeks required removing the patient from protocol therapy, with any exceptions requiring documentation and approval by the principal investigator. Neurologic. If the patient experienced significant distress from grade 2 neurotoxicity and/or the physician was uncomfortable with continuing the same doses, a one-level dose reduction was allowed. Patients who developed grade 3 neurotoxicity had paclitaxel withheld until the toxicity resolved to grade 2 or better. The next infusion could be delayed up to 2 weeks to allow for neurologic toxicity to improve. If it did not improve by that time, the patient was to be removed from the study. Grade 3 neurotoxicity warranted a one–dose-level reduction. If grade 3 neurotoxicity developed with additional infusions, further dose reductions could be made to a maximum of four dose reductions, per the schema described in the body of the article (vide supra). Patients whose toxicity persisted after four dose-level reductions were removed from the protocol. Other grade 3 or 4 nonhematologic toxicity. Grade 4 toxicity other than GI or neurologic would result in terminating protocol therapy, unless extenuating circumstances existed, and with the approval of the study chair, and then with the specified dose reduction. Other grade 3 non-GI, non-neurologic toxicities were to follow the same plan for dose reduction as for neurologic and GI toxicity. Allergic reactions. Patients with grade 3 or 4 allergic reactions who were responding to treatment could remain on protocol after discussion with the study chair. Re-treatment after premedication with oral dexamethasone 20 mg at 12 and 6 hours before administration of paclitaxel, along with intravenous H1- and H2-receptor antagonists was recommended. If necessary, infusion-rate adjustment could occur and additional premedication could be administered. Patients had to be informed of the potential risks of recurrent allergic reactions and had to be carefully monitored if rechallenged. Cardiac. After trastuzumab was incorporated into the trial, patients had to have baseline left ventricular ejection fraction (LVEF) of at least 45%. For patients receiving trastuzumab, a follow-up LVEF was required after five cycles (15 weeks) of therapy. If the LVEF declined 15% or more (relative to baseline, not an absolute 15% decline; eg, 50% to 42.5%), even in the absence of signs or symptoms of cardiac dysfunction, assessment of LVEF was to continue every three cycles coinciding with the assessment of tumor response, and continuation of trastuzumab was allowed, with appropriate discussion of risks and benefits. If the LVEF had not declined by 15% after five cycles of therapy, further radiographic assessment of LVEF was not required. In the event of symptomatic cardiac dysfunction, trastuzumab was withhheld. If therapy for cardiac symptoms was required and the symptoms did not resolve, trastuzumab was to be permanently discontinued. If therapy for cardiac symptoms was required and the symptoms resolved, or if no specific therapy was required, trastuzumab could be continued at the discretion of the treating physician.
Participating Institutions and Support Information
Supported in part by National Cancer Institute Grants No. CA77651, CA33601, CA32291, CA77406, CA47577, CA77658, and CA47559. Presented at the 40th Annual Meeting of the American Society of Clinical Oncology, June 5-8, 2004, New Orleans, LA. The content of this manuscript is solely the responsibility of the authors and does not necessarily represent the official views of the National Cancer Institute. Authors’ disclosures of potential conflicts of interest and author contributions are found at the end of this article.
1. Peretz T, Sulkes A, Challet R, et al: A multicenter, randomized study of two schedules of paclitaxel in patients with metastatic breast cancer. Eur J Cancer 31A:S75, 1995 (abstract 426) 2. Holmes FA, Valero V, Buzdar AU, et al: Final results: Randomized phase III trial of paclitaxel by 3-hr versus 96-hr infusion in patients with metastatic breast cancer—The long and short of it. Proc Am Soc Clin Oncol 16:110a, 1998 (abstr 426) 3. Winer E, Berry DA, Woolf S, et al: Failure of higher-dose paclitaxel to improve outcome in patients with metastatic breast cancer: Cancer and Leukemia Group B trial 9342. J Clin Oncol 22:2061-2068, 2004 4. Seidman AD, Hudis CA, Albanel J, et al: Dose-dense therapy with weekly 1-hour paclitaxel infusions in the treatment of metastatic breast cancer. J Clin Oncol 16:3353-3361, 1998[Abstract] 5. Perez EA, Vogel CL, Irwin DH, et al: Multicenter phase II trial of weekly paclitaxel in women with metastatic breast cancer. J Clin Oncol 19:4216-4223, 2001 6. Gori S, Mosconi AM, Basurtol C, et al: Weekly paclitaxel in metastatic breast cancer patients. Tumori 88:470-473, 2002[Medline] 7. Sato K, Inoue K, Saito T, et al: Multicenter phase II trial of weekly paclitaxel for advanced or metastatic breast cancer: The Saitama Breast Cancer Clinical Study Group (SBCCSG-01). Jpn J Clin Oncol 33:371-376, 2003 8. Lombardi D, Crivellari D, Scuderi D, et al: Long-term, weekly one-hour infusion of paclitaxel in patients with metastatic breast cancer: A phase II monoinstitutional study. Tumori 90:285-288, 2004[Medline] 9. ten Tije AJ, Smorenburg CH, Seynaeve C, et al: Weekly paclitaxel as first-line chemotherapy for elderly patients with metastatic breast cancer: A multicentre phase II trial. Eur J Cancer 40:352-357, 2004[CrossRef][Medline] 10. 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 13. Slamon D, Leyland-Jones B, Shak S, et al: Use of chemotherapy plus a monoclonal antibody against HER2 for metastatic breast cancer that overexpresses HER2. N Engl J Med 344:783-792, 2001 14. Brandt BH, Roetger A, Dittmar T, et al: C-erbB2/EGFR as dominant heterodimerization partners determine a motogenic phenotype in human breast cancer cells. FASEB J 13:1939-1949, 1999 15. DiGiovanna MP, Stern DF, Edgerton SM, et al: Relationship of epidermal growth factor receptor expression to ERbB-2 signaling activity and prognosis in breast cancer patients. J Clin Oncol 23:1152-1160, 2005 16. Longva KE, Pederson NM, Haslekas C, et al: Herceptin-induced inhibition of ErbB2 signaling involves reduced phosphorylation of Akt but not endocytic down-regulation of ErbB2. Int J Cancer 116:359-367, 2005[CrossRef][Medline] 17. Micha JP, Rettenmaier MA, Dillman R, et al: Single-dose dexamethasone paclitaxel premedication. Gynecol Oncol 69:122-124, 1998[CrossRef][Medline] 18. O'Brien PC, Fleming TR: A multiple testing procedure for clinical trials. Biometrics 35:549-556, 1979[CrossRef][Medline] 19. Lan GKK, Demets DL: Discrete sequential boundaries for clinical trials. Biometrika 70:659-663, 1983 20. Naughton MJ, Gu L, Wang XF, et al: Quality of life companion to CALGB 9840: A phase III study of paclitaxel via weekly 1 hour versus standard 3 hour infusion every 3 weeks with trastuzumab in the treatment of patients with/without HER2/neu overexpressing metastatic breast cancer. J Clin Oncol 24:46s, 2006 (suppl; abstr 674)[CrossRef] 21. Nabholtz JM, Gelmon K, Bontenbal M, et al: Multicenter, randomized comparative study of two doses of paclitaxel in patients with metastatic breast cancer. J Clin Oncol 14:1858-1867, 1996 22. Smith RE, Brown AM, Mamounas EP, et al: Randomized trial of 3-hour versus 24-hour infusion of high-dose paclitaxel in patients with metastatic or locally advanced breast cancer: National Surgical Adjuvant Breast and Bowel Project Protocol B-26. J Clin Oncol 17:3403-3411, 1999 23. Green MC, Buzdar AU, Smith T, et al: Weekly paclitaxel improves pathologic complete remission in operable breast cancer when compared with paclitaxel once every 3 weeks. J Clin Oncol 23:5983-5992, 2005 24. Sparano JA, Wang M, Martino S, et al: Phase III study of doxorubicin-cyclophosphamide followed by paclitaxel or docetaxel given every 3 weeks or weekly in patients with axillary node-positive or high-risk node-negative breast cancer: Results of North American Breast Cancer Intergroup Trial E1199. J Clin Oncol 25:6s, 2007 (suppl; abstr 516)[CrossRef] 25. Verrill MW, Lee J, Cameron DA, et al: Anglo-Celtic IV: First results of a UK National Cancer Research Network randomized phase III pharmacogenetic trial of weekly compared to 3 weekly paclitaxel in patients with locally advanced or metastatic breast cancer. J Clin Oncol 25:33s, 2007 (suppl; abstr LBA1005) 26. 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 27. Gradishar W, Krasnokjon D, Cheporov S, et al: Randomized comparison of weekly or every -3-week (q3w) nab-paclitaxel compared to q3w docetaxel as first-line therapy in patients (pts) with metastatic breast cancer (MBC). J Clin Oncol:40s, 2007 (suppl; abstr 1032) 28. Miller K, Wang M, Gralow J, et al: A randomized phase III trial of paclitaxel versus paclitaxel plus bevacizumab as first-line therapy for locally recurrent or metastatic breast cancer: A trial coordinated by the Eastern Cooperative Oncology Group (E2100). Breast Cancer Res Treat 94:S6, 2005 (suppl; abstr 3) 29. Paik S, Kim C, Jeong J, et al: Benefit from adjuvant trastuzumab may not be confined to patients with IHC 3+ and/or FISH-positive tumors: Central testing results from NSABP B-31. J Clin Oncol 25:5s, 2007 (suppl; abstr 511) Submitted May 23, 2007; accepted November 27, 2007.
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Copyright © 2008 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
7 days) as a 5-µg/kg injection daily beginning on day 2, continuing until the ANC was more than 10,000/mm3 (3-weekly arm) or subcutaneously daily from day 2 to 5, or until the ANC was more than 10,000/mm3, whichever came first (weekly arm). Filgrastim was continued in subsequent cycles. A paclitaxel dose reduction with the next course of therapy was to occur if grade 4 thrombocytopenia (platelets < 25,000/mm3) occurred, with further dose reductions possible (
of .05. Because protocol therapy for the standard arm of CALGB 9342, a precursor to the current study, was identical to the standard arm of the current study, the former group of patients was included in the current study analysis to conserve patient resources, reducing accrual from 700 to 580. Inclusion of the CALGB 9342 patients necessitated a 60:40 weighted random assignment of treatment assignment (weekly:3-weekly). The CALGB Statistical Center performed all random assignment using a permuted block scheme. 
2 tests to model and assess the relationship of treatment with OS and TTP. Multivariate models for each end point were built using variables of known prognostic importance in MBC: number of metastatic sites, ER status, performance status, prior adjuvant chemotherapy, and prior radiotherapy. Also included were line of therapy, HER-2 status, and trastuzumab use. Two or more proportions were compared using contingency table analysis; their 95% CIs used exact binomial methods. OS and TTP distributions were plotted using the Kaplan-Meier method. Estimates of treatment effect and their corresponding significance levels were derived using multivariate models that adjust for prognostic variables were labeled "adjusted"; those derived from univariate models were labeled "unadjusted." All P values are two-sided. Because the study was not powered to address therapeutic effect within subsets of patients, comparisons within HER-2 subsets are exploratory only; P values are provided as descriptive measures only. 
