Capecitabine dosing is not yet optimized for breast cancer
Authors: C. Hudis, T. Traina, L. Norton
Journal: Annals of Oncology (2010)

We read with interest the review by Zielinski et al. [1.Zielinski C. Gralow J. Martin M. Optimising the dose of capecitabine in metastatic breast cancer: confused, clarified or confirmed?.Ann Oncol. 2010; 21: 2145-2152Abstract Full Text Full Text PDF PubMed Scopus (38) Google Scholar]regarding the optimal use of capecitabine and we agree that the dosing recommended on the package insert is not ideal for most patients. However, we are not satisfied that the existing studies have been designed to properly address the question and we do not believe that starting at a lower dose and using the 14/7 schedule should constitute the last word on this topic. For example, while noting our team's development of the 7/7 schedule, a critical distinction was overlooked: this schedule was not empiric but was instead developed using a mouse model and mathematical methods of experimental design and analysis. Based on these data, we conducted a phase I study followed by phase II studies demonstrating the feasibility and safety of adding bevacizumab or lapatinib depending on human epithelial growth factor 2 status [2.Traina T.A. Theodoulou Feigin K. et al.Phase I study of a novel capecitabine schedule based on the Norton-Simon mathematical model in patients with metastatic breast cancer.J Clin Oncol. 2008; 26: 1797-1802Crossref PubMed Scopus (59) Google Scholar, 3.Traina T.A. Theodoulou M. Dugan U. et al.A novel capecitabine dosing schedule combined with bevacizumab is safe and active in patients with metastatic breast cancer: a phase II study.J Clin Oncol (Meeting Abstracts). 2008; 26: 1101Crossref Google Scholar, 4.Traina T.A. Theodoulou M. Feigin K. et al.Safety of a novel capecitabine dosing schedule when combined with lapatinib in patients with HER2-positive metastatic breast cancer refractory to trastuzumab.J Clin Oncol (Meeting Abstracts). 2009; 27: 1131Crossref Google Scholar]. In addition, we demonstrated that body surface area-based dosing for capecitabine may not be necessary, as has been long recognized across the spectrum of cytotoxic agents [5.Ratain M. Body-surface area as a basis for dosing of anticancer agents: science, myth, or habit?.J Clin Oncol. 1998; 16: 2297-2298Crossref PubMed Scopus (157) Google Scholar]. This is of more than academic concern as the lower starting dose of capecitabine that the authors advocate using has been found, despite modest evidence of superiority in the metastatic setting, to be clearly inferior to either cyclophosphamide, methotrexate and 5-fluouracil or adriamycin (doxorubicin) and cyclophosphamide as adjuvant treatment [6.Muss H.B. Berry D.A. Cirrincionne C.T. et al.Adjuvant chemotherapy in older women with early-stage breast cancer.N Engl J Med. 2009; 360: 2055-2065Crossref PubMed Scopus (423) Google Scholar]. Capecitabine dosing is particularly important given the potential utility of this agent in low- and middle-income countries where palliation of hormone-non-responsive breast cancer can be challenging and properly dosed capecitabine can offer the advantage of low risks of neutropenia, alopecia, and other troublesome or dangerous toxic effects. However, the only way for us to truly optimize the use of capecitabine and other important agents is to conduct scientifically designed, prospective, definitive phase III trials.disclosureRoche provided funding for some of the preclinical and clinical data to which we refer. We read with interest the review by Zielinski et al. [1.Zielinski C. Gralow J. Martin M. Optimising the dose of capecitabine in metastatic breast cancer: confused, clarified or confirmed?.Ann Oncol. 2010; 21: 2145-2152Abstract Full Text Full Text PDF PubMed Scopus (38) Google Scholar]regarding the optimal use of capecitabine and we agree that the dosing recommended on the package insert is not ideal for most patients. However, we are not satisfied that the existing studies have been designed to properly address the question and we do not believe that starting at a lower dose and using the 14/7 schedule should constitute the last word on this topic. For example, while noting our team's development of the 7/7 schedule, a critical distinction was overlooked: this schedule was not empiric but was instead developed using a mouse model and mathematical methods of experimental design and analysis. Based on these data, we conducted a phase I study followed by phase II studies demonstrating the feasibility and safety of adding bevacizumab or lapatinib depending on human epithelial growth factor 2 status [2.Traina T.A. Theodoulou Feigin K. et al.Phase I study of a novel capecitabine schedule based on the Norton-Simon mathematical model in patients with metastatic breast cancer.J Clin Oncol. 2008; 26: 1797-1802Crossref PubMed Scopus (59) Google Scholar, 3.Traina T.A. Theodoulou M. Dugan U. et al.A novel capecitabine dosing schedule combined with bevacizumab is safe and active in patients with metastatic breast cancer: a phase II study.J Clin Oncol (Meeting Abstracts). 2008; 26: 1101Crossref Google Scholar, 4.Traina T.A. Theodoulou M. Feigin K. et al.Safety of a novel capecitabine dosing schedule when combined with lapatinib in patients with HER2-positive metastatic breast cancer refractory to trastuzumab.J Clin Oncol (Meeting Abstracts). 2009; 27: 1131Crossref Google Scholar]. In addition, we demonstrated that body surface area-based dosing for capecitabine may not be necessary, as has been long recognized across the spectrum of cytotoxic agents [5.Ratain M. Body-surface area as a basis for dosing of anticancer agents: science, myth, or habit?.J Clin Oncol. 1998; 16: 2297-2298Crossref PubMed Scopus (157) Google Scholar]. This is of more than academic concern as the lower starting dose of capecitabine that the authors advocate using has been found, despite modest evidence of superiority in the metastatic setting, to be clearly inferior to either cyclophosphamide, methotrexate and 5-fluouracil or adriamycin (doxorubicin) and cyclophosphamide as adjuvant treatment [6.Muss H.B. Berry D.A. Cirrincionne C.T. et al.Adjuvant chemotherapy in older women with early-stage breast cancer.N Engl J Med. 2009; 360: 2055-2065Crossref PubMed Scopus (423) Google Scholar]. Capecitabine dosing is particularly important given the potential utility of this agent in low- and middle-income countries where palliation of hormone-non-responsive breast cancer can be challenging and properly dosed capecitabine can offer the advantage of low risks of neutropenia, alopecia, and other troublesome or dangerous toxic effects. However, the only way for us to truly optimize the use of capecitabine and other important agents is to conduct scientifically designed, prospective, definitive phase III trials. disclosureRoche provided funding for some of the preclinical and clinical data to which we refer. Roche provided funding for some of the preclinical and clinical data to which we refer.