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Journal of Clinical Oncology, Vol 26, No 21 (July 20), 2008: pp. 3655-3656 © 2008 American Society of Clinical Oncology. DOI: 10.1200/JCO.2008.17.5281
Dose-Dense Chemotherapy With Trastuzumab Is an Appropriate OptionDepartment of Medicine, Memorial Sloan-Kettering Cancer Center, New York, NY To the Editor: We agree with the editorial comment by Drs Mayer and Burstein regarding the use of dose-dense chemotherapy combined with trastuzumab as adjuvant treatment for HER-2–positive breast cancer—large phase III trials are indeed preferred in providing the basis for making treatment recommendations. However, we disagree with their conclusion that this principle precludes the adoption of our regimen in clinical practice. Two successive Cancer and Leukemia Group B/Intergroup phase III trials (C9344 and C9741) established first the benefit of adding a taxane and then the principle of dose density.1,2 Subsequently, N9831, National Surgical Adjuvant Breast and Bowel Projecty B-31, and Breast Cancer International Research Group 006 established the principle that trastuzumab can be safely combined with the sequential doxorubicin plus cyclophosphamide (AC)–taxane regimen (regardless of the taxane, dose, or schedule).3,4 All that was needed was a study melding these observations with a focus on feasibility and safety, which is what our trial accomplished successfully. Moreover, as we note in our paper, a phase III trial for schedule (dose density) or for the use of trastuzumab is not likely to successfully accrue being that these questions have already been answered.5 Therefore, we respectfully disagree with the editorial conclusion that patients with HER-2–positive disease who would have been eligible for our trial should be denied this regimen. With regard to cardiac safety, it was the intention of our study design to demonstrate that this toxicity, assessed exactly as it was in the larger phase III trials, was not likely to be increased through the use of the therapeutically superior dose-dense (dd) regimen. Hence, we purposely designed this study to accrue just enough patients (70) to provide evidence that the cardiac risk of dd AC followed by paclitaxel with trastuzumab is unlikely to be increased. With a median follow-up of 28 months, we saw no concerning cardiac signals and observed a congestive heart failure rate of one in 70 (1.4%).5 Most cardiac events are expected to occur during treatment, so we anticipate that the total cardiac event rate will remain low with continued follow-up. Furthermore, and in stark distinction to the multicenter phase III trials, we saw no patients with significant drops in the left ventricular ejection fraction (LVEF) after dd AC. This further strengthens the argument that dd AC may be safer than conventional every third week administration. Indeed, in C9741, a 50% reduction in cardiac events was seen with every-second-week treatment compared with the conventional schedule.6
The 4% rate of patient drop-out during the trastuzumab treatment due to asymptomatic LVEF decline was lower in our study5 than in B-31/N9831 (14%).3 We again note that the patients we enrolled were nearly identical in age to those enrolled on B-31 and N9831, and we therefore cannot attribute our favorable results due to age differences. We also note that with the dd regimen, 91% of the patients successfully completed the full year of trastuzumab, which is in distinction to the mere 68% patient completion rate in B-31 and N9831.3 Hence, our patients had greater trastuzumab exposure with no apparent increase in cardiac toxicity. We do agree that by specifying an entry LVEF of It is important to also note that the dd regimen reported in C9741 was less likely to require inpatient treatment for neutropenia and fever, and was, of course, completed more quickly, which is advantageous regarding quality of life.2 Controlling for dose size and number of cycles, there are no examples in which the dd approach compromises therapeutic efficacy. Nor are there any reasons to suspect that the simultaneous use of trastuzumab would abrogate the therapeutic advantages of dose density. Hence, we are puzzled by the editorialists’ concern that a shorter duration of simultaneous exposure could somehow compromise treatment benefit. As was true in NSABP B31 and the BCIRG 006, patients on our trial received four administrations of full-dose taxane while simultaneously receiving weekly trastuzumab. The fact that the patients in our trial received their taxane doses in an accelerated fashion should only increase the therapeutic benefit in combination with trastuzumab as it does in the absence of trastuzumab. Furthermore, while it is likely that the simultaneous use of a taxane plus trastuzumab is more effective than either alone, the results of the HERA trial do demonstrate that trastuzumab is active without simultaneous chemotherapy, and the prolonged (1 year) use of this agent is included in our regimen.7 Based on phase III trials, trastuzumab is indicated for the adjuvant therapy of HER-2–over-expressing, gene-amplified breast cancer. Based on a large Intergroup phase III trial, dose density increases the therapeutic efficacy of AC-paclitaxel adjuvant chemotherapy without increasing toxicity.2 Based on our prospective study, dd chemotherapy is not a contraindication to the use of trastuzumab. Hence, we assert that dd AC followed by a taxane combined with trastuzumab is an appropriate regimen for treating patients with HER-2–positive early stage breast cancer. AUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST 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: Chau Dang, Genentech (C), Amgen (C); Clifford Hudis, Genentech (C), Amgen (C) Stock Ownership: None Honoraria: Chau Dang, Genentech, Amgen; Clifford Hudis, Genentech, Amgen Research Funding: Chau Dang, Genentech, Amgen; Clifford Hudis, Genentech, Amgen Does your study have any NIH funding? No Expert Testimony: None Other Remuneration: None REFERENCES
1. Henderson IC, Berry DA, Demetri GD, et al: Improved outcomes from adding sequential paclitaxel but not from escalating doxorubicin dose in an adjuvant chemotherapy regimen for patients with node-positive primary breast cancer. J Clin Oncol 21:976-983, 2003 2. Citron ML, Berry DA, Cirrincione C, et al: Randomized trial of dose-dense versus conventionally scheduled and sequential versus concurrent combination chemotherapy as postoperative adjuvant treatment of node-positive primary breast cancer: First report of Intergroup trial C9741/Cancer and Leukemia Group B Trial 9741. J Clin Oncol 21:1431-1439, 2003 3. 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 4. Slamon DJ, Eiermann W, Robert NJ, et al: Phase III randomized trial comparing doxorubicin and cyclophosphamide followed by docetaxel with doxorubicin and cyclophosphamide followed by docetaxel and trastuzumab with docetaxel, carboplatin and trastuzumab in HER2 positive early breast cancer patients: BCIRG 006 study. Presented at the San Antonio Breast Cancer Symposium, San Antonio, TX, December 13-16, 2007 5. Dang C, Fornier M, Sugarman S, et al: The safety of dose-dense doxorubicin and cyclphosphamide followed by paclitaxel with trastuzumab in HER-2/neu overexpressing/amplified breast cancer. J Clin Oncol 26:1216-1222, 2008 6. Hudis C, Citron ML, Berry D, et al: Five year follow-up of INT C9741: Dose dense (DD) chemotherapy (CRx) is safe and effective. Breast Cancer Res 94:S20, 2005 (suppl 1) 7. Smith I, Proctor M, Gelber RD, et al: 2-year follow-up of trastuzumab after adjuvant chemotherapy in HER2-positive breast cancer: A randomised controlled trial. Lancet 369:29-36, 2007[CrossRef][Medline]
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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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55% for our study, we may have selected a somewhat healthier group of patients. However, this does not challenge the above arguments that our regimen is at least as safe as conventionally-timed, trastuzumab-containing treatments. Indeed, our regimen may be especially well tolerated by patients at low risk for cardiac toxicity. 
