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Journal of Clinical Oncology, Vol 26, No 10 (April 1), 2008: pp. 1585-1587 © 2008 American Society of Clinical Oncology. DOI: 10.1200/JCO.2007.15.7651
Optimal Schedule of Paclitaxel: Weekly Is BetterDepartments of Breast Medical Oncology and Systems Biology, The University of Texas M.D. Anderson Cancer Center, Houston, TX Chemotherapy for cancer has been studied since 1942, when the first trials of nitrogen mustard in humans were initiated. Identifying a compound with antitumor activity does not necessarily complete the development of a new useful drug because the optimal dose and schedule of administration must also be found. Norton, using Gompertzian growth kinetics, developed a model to predict why a very active agent may produce only a modest clinical benefit.1,2 This, and other findings, has encouraged a reevaluation of both the dose and schedule of cancer therapy as crucial factors in treatment outcomes.3 More than 30 years ago, researchers at the Southern Research Institute (Birmingham, AL) explored optimal dosing and scheduling of cancer chemotherapy in a preclinical leukemia model. Some of their conclusions are still valid today: "the optimal schedule can make the difference between a good response and a poor response or even between success and failure," "the optimal schedules for cytotoxic agents differ," and "therapy should be cycled at a higher rate than that of the regrowth of the tumor."4,5 However, there is evidence that many patients may not be receiving optimal doses of currently available agents.5-7 The initial studies of paclitaxel, one of the most thoroughly studied drugs for breast cancer, used a 24-hour intravenous infusion repeated every 21 days. Subsequent studies determined that a 3-hour infusion was more convenient than—and as effective as—24 to 96 hour infusions.8,9 Dose escalation from 175 to 250 mg/m2 did not improve efficacy, but increased toxicities; more recently,10 increasing the frequency of infusions showed improved outcomes.11 In this issue of the Journal of Clinical Oncology, Seidman et al12 report that weekly paclitaxel administration is superior to every-3-weeks (3-weekly) paclitaxel for metastatic breast cancer, with a significant increment in response rate and an important advantage in time to progression. In addition, the authors did not see any benefit from the addition of trastuzumab to chemotherapy in patients whose tumors lacked human epidermal growth factor-2 (HER-2) overexpression or gene amplification. These are important conclusions, although the study has limitations that should be considered. The first, most controversial, issue relates to the trial design. To complete the total number of patients in the control arm of the study, 158 patients from a previous study (CALGB 9342) were "borrowed" as historical controls. Because of this, one can not call this a pure randomized study, given that the historical controls may be different from the random controls not only by the number of previous therapies received, but by other unmeasured characteristics and by trial effect. Saving patients and time in clinical trial design may not be the wrong direction to explore, especially in an era when the number of clinically important questions to be asked and the number of new and exciting drugs to be tested in a timely matter far exceeds patient, investigator, and financial resources. However, novel statistical methods and trial designs should be prospectively tested and validated before they are integrated into trials that ask critically important questions. In that manner, potential problems with data analysis can be minimized without jeopardizing the credibility of results. Another, less controversial, issue was the decision to add trastuzumab to chemotherapy in all patients, instead of excluding patients with HER-2–positive disease. The investigators were able to examine the benefit of trastuzumab in HER-2–negative disease through a subtrial factorial design. This definitely made the study more complex, with nine groups of patients evaluated. Because the response rates in the historical controls without trastuzumab therapy were lower, this could inflate the difference between the main treatment arms, although the overall conclusion did not change. Despite these limitations, Seidman's trial adds to the growing literature about proper scheduling of anticancer agents, specifically taxanes. Weekly paclitaxel was superior to 3-weekly paclitaxel for the treatment of metastatic breast cancer. It almost doubled the time to progression and increased the response rate from 29% to 42%, without affecting patient quality of life. The activity of paclitaxel is directly related to the cell cycle; for this reason, it has been hypothesized that its more frequent administration might improve efficacy. In addition, paclitaxel administered in a more continuous manner exhibits proapoptotic and antiangiogenic properties, increasing its antineoplastic effects.13-15 Symmans et al16 performed serial fine-needle aspirates after paclitaxel infusions in patients undergoing neoadjuvant therapy, and found that the apoptotic response to paclitaxel was subsided within 4 days, suggesting that more frequent dosing might be beneficial to maintain apoptotic response. Preclinical studies also demonstrated that tumor apoptotic response after paclitaxel treatment was associated with decreased interstitial pressure, vasodilatation, and increased endothelial surface area. Tumor "decompression" continues for several days after the apoptotic response, which means that in humans, by day 7, there is a period of improved intratumoral perfusion and drug delivery to cancer cells.13,17,18 Several phase II studies in metastatic breast cancer showed that weekly paclitaxel produced significant response rates.19-23 The largest of these, by Perez et al,20 reported a 21.5% response rate and a 41.8% overall clinical benefit. Other important studies in early breast cancer have demonstrated the superiority of weekly paclitaxel compared to every 3-week administration. The neoadjuvant study by Green et al.11 randomly assigned 258 patients to either weekly (total of 12 doses) or 3-weekly (four cycles) administration of paclitaxel followed by four cycles of fluorouracil/doxorubicin/cyclophosphamide (FAC) in standard doses 3-weekly. Patients receiving weekly paclitaxel had a higher pathologic complete response rate (28.8%) than did patients treated with the 3-weekly schedule (15.7%; P = .02). The Intergroup E-1199 adjuvant study that compared weekly to 3-weekly paclitaxel (and docetaxel) after four cycles of doxorubicin and cyclophosphamide showed a significant improvement in disease-free survival favoring the weekly schedule of paclitaxel (hazard ratio [HR] = 1.27; 95% CI, 1.07 to 1.51; P = .006).24 Data using new formulations of paclitaxel (nanoparticle albumin-bound) in metastatic breast cancer also confirmed the superiority of the weekly schedule.25 This conglomerate of preclinical and clinical evidence makes weekly paclitaxel the optimal way of administering this drug, on and off clinical trials. Today, systemic therapy is tailored to the expression of a few genes in the tumor such as estrogen receptor, progesterone receptor, and HER-2/neu. When trastuzumab was approved for treating metastatic breast cancer, the authors decided to add this agent to taxane therapy, utilizing a factorial design. Although the study was not powered to address the therapeutic effect in the different HER-2 subsets, exploratory findings showed that the addition of trastuzumab in patients with HER-2–negative breast cancer did not improve time to progression or overall survival. This is the only prospective study to our knowledge to date to examine this question. In this trial, tumors that had gene amplification or 2+ or 3+ immunohistochemistry staining were considered HER-2 positive; thus, only tumors with 0 or 1+ staining were considered HER-2 negative. These findings are in contrast to the recently presented National Surgical Adjuvant Breast and Bowel Project (NSABP) B-31 retrospective analysis, in which there appeared to be benefit of adjuvant trastuzumab even in patients with HER-2–negative tumors tested in a central laboratory, although these tumors had been designated HER-2–positive at trial entry.26 Trastuzumab is a monoclonal antibody that binds to the extracellular domain of the HER-2 receptor. Phosphorylation of the tyrosine kinase domain of this receptor and other members of the epithelial growth factor receptor family by homodimerization or heterodimerization through phosphorylated p95 induces both cell proliferation and survival signaling through the mitogen-activated protein kinase (MAPK) and the phosphoinositide 3-kinase (PI3K) pathways, respectively. Potential mechanisms of action of trastuzumab include cleavage of the extracellular domain of HER-2, leaving a membrane-bound phosphorylated p95, reduced shedding of the extracellular domain resulting in reduction of p95, reduced signaling as a result of physical inhibition of dimerization, and antibody-dependent, cell-mediated cytotoxicity.27 The level of HER-2 in breast cancer cells is normally measured by immunohistochemistry and/or fluorescence in situ hybridization (FISH). Data suggest that HER-2 protein concentrations in breast cancer cells increase before immunohistochemical and FISH analyses turn positive,28 so trastuzumab may block cell proliferation and apoptosis before there is evidence of HER-2 positivity. Whether these apparently conflicting results are a result of either the vagaries of HER-2 testing or the optimal definition of HER-2 positivity is uncertain at this time. However, the question about the benefit of trastuzumab in patients with HER-2–negative disease is one that needs further evaluation. The dose and schedule of chemotherapy both play an important role in the outcomes of breast cancer, in early and in metastatic stages of the disease. The importance of dose density and intensity have been well established in the curative setting, in which the delivery of full-dose chemotherapy, administered on schedule, has a beneficial effect on survival.24,29 Current methods of dosing anticancer agents will change as a result of advances in genomics and proteomics, which continue to provide specific information about individual tumors. These technologies will make it possible to better predict sensitivity or resistance to treatment and treatment-related adverse events, leading to truly personalized therapy. Optimization of dose and determination of best schedules and combinations of cancer drugs should have a high priority in new drug development. Because there are many potential schedules and possible combinations with other drugs, and only a few of them can be tested clinically, preclinical models will continue to be useful. At present, the treatment of breast cancer remains largely empirical; in the not too distant future, we may genotype and phenotype both tumor and patient to more rationally treat the malignancy and to minimize adverse effects. AUTHORS' DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST The author(s) indicated no potential conflicts of interest. AUTHOR CONTRIBUTIONS Conception and design: Ana Maria Gonzalez-Angulo, Gabriel N. Hortobagyi Manuscript writing: Ana Maria Gonzalez-Angulo, Gabriel N. Hortobagyi Final approval of manuscript: Ana Maria Gonzalez-Angulo, Gabriel N. Hortobagyi REFERENCES
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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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