Modulations of dose intensity of doxorubicin and cyclophosphamide in association with G-CSF and peripheral blood stem cells in adjuvant chemotherapy for breast cancer: comparative evaluation of completion and safety of three intensive regimens

Abstract

Summary:The aim of this study was to evaluate and to compare in terms of toxicity the modulations of dose intensity of cyclophosphamide and doxorubicin in adjuvant chemotherapy for high-risk breast cancer. Four cycles of sequential high-dose chemotherapy with doxorubicin and cyclophosphamide (AC), supported with G-CSF and peripheral blood stem cells (PBSC) were administered to 81 women. Three successive cohorts were studied: doxorubicin (75 mg/m 2 ) + cyclophosphamide (3000 mg/m 2 ) every 21 days (group 1), doxorubicin (75 mg/m 2 ) + cyclophosphamide (3000 mg/m 2 ) every 15 days (group 2), and doxorubicin (75 mg/m 2 ) + cyclophosphamide (6000 mg/m 2 ) every 21 days (group 3). Seventy-five patients received four cycles of treatment with a total of 310 cycles administered. The received dose intensity of doxorubicin was higher in group 2 and that of cyclophosphamide was lower in group 1 than in the other two groups. Hematological and extra-hematological toxicities, as well as the number and duration of hospitalizations for toxicity, were significantly higher in group 3. We conclude that the group 3 regimen is associated with toxicities comparable to autologous transplantation. Increasing dose intensity of doxorubicin and cyclophosphamide is feasible in an outpatient setting and safe in groups 1 and 2 with the support of hematopoietic factor and PBSC. The efficacy of adjuvant chemotherapy for patients with node positive breast cancer is now clearly demonstrated and widely used in standard clinical practice. In this situation, anthracyclines and cyclophosphamide are validated as effective and are part of the most active regimens without taxanes. Since the 1990s, following the work of the National Surgical Adjuvant Breast and Bowel Project (NSABBP), four cycles of doxorubicin (60 mg/m 2 ) and cyclophosphamide (600 mg/m 2 ), every 21 days, are considered as the minimum requirement for effective adjuvant chemotherapy in breast cancer (AC regimen). 1 With these two drugs, the importance of dose intensity has been clearly established in experimental models. 2 Furthermore, clinical data have suggested and frequently demonstrated the relevance of dose and dose intensity in the breast cancer setting. 3,4 Relatively modest dose variations of these drugs have been tested without the use of hematopoietic growth factors, resulting in benefits in dose escalation of anthracyclines but not clearly for cyclophosphamide.We and others 5-9 were able to develop much larger dose escalation of anthracyclines and cyclophosphamide in breast cancer when hematopoietic growth factors and/or peripheral blood stem cells (PBSC) were added to cycles of chemotherapy. In a previous report, 10 we demonstrated that, when compared to the standard dose intensity of the AC regimen of the NSABBP, we could safely increase the relative dose intensity (RDI) of doxorubicin (ϫ1.25) and cyclophosphamide (ϫ5) (group 1) in intensive outpatient chemotherapy designed for poor risk patients.We designed the present study to further increase relative dose intensity of...

Molecular Imaging of Stem Cells

“…Regenerative medicine has been used to repair different organs/systems: endocrine (i.e., pancreas) [5], musculoskeleton (i.e., bone, joints) [6,7], and cardiovascular system (i.e. myocardium) [8][9][10], as well as adjuvant treatment for malignancies [11]. While much has been learned on how stem cells function in cell culture, several questions remain regarding the biology of stem cells in living subjects.…”