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Originally published as JCO Early Release 10.1200/JCO.2005.05.031 on August 8 2005 © 2005 American Society of Clinical Oncology.
"Will Weekly Work"? Seems to Be So...Memorial Sloan-Kettering Cancer Center, New York, NY Weekly administration of paclitaxel proved superior to once-every-3-weeks administration for metastatic breast cancer in Cancer and Leukemia Group B Trial 9840, the large randomized trial reported in 2004.1 In this trial of more than 700 patients assessable for efficacy by preplanned analysis, weekly scheduling improved response rate (40% v 28%; P = .0017) and median time to disease progression (9 months v 5 months; P = .0008). The report by Green et al2 in this issue of the Journal of Clinical Oncology demonstrates that weekly paclitaxel administration, compared with once-every-3–weeks dose administration, improves the likelihood of pathologic complete remission in the breast and axillary lymph nodes (28.2% v 15.7%; P = .02), as well as the opportunity for breast-conserving surgery (P = .02). These observations lend further support for the use of more frequent paclitaxel dosing in breast cancer, regardless of stage. The authors employed a once-every-3-weeks regimen of paclitaxel that is currently atypical (225 mg/m2 over 24 hours), which was more toxic than weekly paclitaxel dosing at 80 mg/m2/wk due to increased neutropenia, myalgia, and neuropathy. In this regard, two previous large randomized trials failed to show benefit for a dose escalation of paclitaxel of over 175 mg/m2 when given every 3 weeks3 or for prolongation of the infusion duration from 3 to 24 hours.4 Also, the weekly regimen developed by Sikov et al5 that was described as both dose-dense and dose-intense is clearly more toxic than lower sustained and uninterrupted weekly paclitaxel dosing, as evidenced by midstream changes in dose and schedule of administration during this trial due to prohibitive neurotoxicity and myelosuppression. Indeed, even weekly paclitaxel dosing at 80 mg/m2 cannot be described as simply "dose-dense therapy" relative to the historical once-every-3-weeks dosing regimen of 175 mg/m2—it is also a more dose-intense mode of paclitaxel delivery (80 mg/m2/wk v 58.3 mg/m2/wk). These distinctions notwithstanding, it is notable that the delivered paclitaxel dose intensities in the once-every-3-weeks and weekly arms of the Green trial are actually quite similar, as listed in Table 3 of their article. This further substantiates that the advantage in pathologic complete response (pCR) rate observed in this trial can be attributable to the shorter dose-dense intertreatment interval of the weekly schedule. Although a purely kinetic model would show that the benefits of dose-dense therapy derive from a smaller temporal window of opportunity for the emergence and the expansion of drug-resistant cell clones, the authors also point out the pro-apoptotic effects of weekly paclitaxel administration, as well as its effect in reducing tumoral interstitial fluid pressure and alteration of vascular endothelial cells. Indeed, exposure to lower, more frequent doses of paclitaxel, also known as "metronomic" dosing, could potentially exploit antiangiogenic effects. The recent demonstration6 that antiangiogenic concentrations of paclitaxel have differential microtubule effects on endothelial cells as compared with tumor cells provides further rationale for this strategy. Much reason for optimism regarding this therapeutic approach comes from the recent report of the Eastern Cooperative Oncology Group (ECOG) 2100 trial by Miller and Sledge,7 in which the addition of the anti–vascular endothelial growth factor monoclonal antibody bevacizumab significantly prolonged time to disease progression in women with metastatic breast cancer when added to weekly paclitaxel. Perhaps the greatest benefit of this combined antiangiogenic approach will be observed in earlier-stage disease, such as the neoadjuvant or adjuvant setting. Weekly paclitaxel is compared with once-every-3-weeks paclitaxel in the large, randomized adjuvant trial ECOG 1199, in which weekly docetaxel is compared with an every-3-weeks regimen. In analyzing this trial's results, it will be important to critically assess differences in safety, feasibility, and tolerability, particularly if there is no obvious superior treatment in terms of efficacy. Weekly paclitaxel is currently being compared with once-every-2-weeks paclitaxel in the Intergroup adjuvant trial, SWOG 0221. Weekly paclitaxel has served as a component of the control arm of the large Intergroup adjuvant randomized trial NCCTG 9831, examining the impact of trastuzumab, with either sequential or concurrent and sequential administration of trastuzumab. The current report by Green et al, taken together with the benefits for weekly paclitaxel observed in Cancer and Leukemia Group B (CALGB) 9840, and for the benefit of adding bevacizumab to weekly paclitaxel in advanced breast cancer, all suggest a promising future for weekly paclitaxel in the management of earlier-stage disease. Author's Disclosures of Potential Conflicts of Interest
The author or 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.
Dollar Amount Codes (A) < $10,000 (B) $10,000-99,999 (C)
REFERENCES 1. Seidman AD, Berry D, Cirrincione C, et al: Phase II study of weekly paclitaxel via 1-hour infusion versus standard 3h infusion every third week in the treatment of metastatic breast cancer, with trastuzumab for HER2 positive MBC and randomized for trastuzumab in HER2 normal MBC. Proc Am Soc Clin Oncol 22:6s, 2004 (suppl; abstr 512)
2. Green MC, Buzdar AU, Smith T, et al: Weekly paclitaxel improves pathologic complete remission in operable breast cancer when compared with once-every-3-weeks paclitaxel. J Clin Oncol 23:5983-5992, 2005
3. Winer EP, 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. Peretz T, Sulkes A, Challet R, et al: A multicenter, randomized phase III study of two schedules of paclitaxel in patients with advanced breast cancer. Eur J Cancer 31A:S75, 1995 (abstr 345) 5. Sikov WM, Akerly W, Kahanic S, et al: Multicenter, 3-arm randomized study of high-dose weekly paciltaxel (HDWP) versus standard-dose weekly paclitaxel (SDWP) for metastatic breast cancer (MBC). Proc Am Soc Clin Oncol 21:34a, 2002 (abstr 134)
6. Pasquir E, Honore S, Pourroy B, et al: Anti-angiogenic concentrations of paclitaxel induce an increase in microtubule dynamics in endothelial cells but not in cancer cells. Cancer Res 65:2433-2440, 2005 7. Sledge G, Miller K, Perez E, et al: Advances in monoclonal antibody therapy for breast cancer. Presented at the 41st Annual Meeting of the American Society of Clinical Oncology, Orlando, FL, May 13-17, 2005
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Copyright © 2005 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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$100,000 (N/R) Not Required
