Breast cancer cytotoxic chemotherapy

Cytotoxic chemotherapy is eventually required in most patients with metastatic breast cancer. Patients with hormone-receptor-negative tumors require chemotherapy as initial therapy of symptomatic metastases. Patients who respond initially to hormonal manipulations eventually cease to respond and go on to require chemotherapy. The median duration of response is 5 to 12 months, but some patients will have an excellent response to an initial course of chemotherapy and may live 5 to 10 years or longer without evidence of disease. In general, median survival of patients after treatment with commonly used drug combinations for metastatic breast cancer is 14 to 33 months. The median time to response has ranged from 2 to 3 months in most studies, but this period depends in large part on the site of measurable disease. The median time to appearance of response is between 3 and 6 weeks in patients whose disease is primarily in the skin and lymph nodes, 6 to 9 weeks in patients with metastatic lung involvement, 15 weeks in patients with hepatic involvement, and nearly 18 weeks in patients with bone involvement. Thus it is often the case that an immediate response to therapy is not... 

Finally, therapeutic sequencing of different hormonal agents is fast becoming a common clinical practice, and fulvestrant is a good treatment choice to extend the opportunity for using endocrine therapies before reliance upon cytotoxic chemotherapy is necessary. Further research is required in order to evaluate the optimal sequence, both in clinical practice as well as in the laboratory, to choose the correct treatment of breast cancer in each person after the appearance of tamoxifen-induced drug resistance (Robertson 2004 Osipo et al. 2004 Johnston 2004 Robertson et al. 2005). 

A. Bielawska, K. Bielawski, K. Chrzanowski, S. Wolczynski, Prolinase-Activated Prodrug for Cancer Chemotherapy. Cytotoxic Activity of Proline Analogue of Chlorambucil in Breast Cancer MCF-7 Cells , Farmaco 2000, 55, 736-741. 

Bielawska, A., Bielawska, K., Chrzanowski, K., and Wolczynski, S. Prolidase-activated prodrug for cancer chemotherapy cytotoxic activity of praline analogue of chlorambucil in breast cancer MCF-7 cells. II Farmaco 55 736-741, 2000. 

Tamoxifen is beneficial in postmenopausal women when used alone or when combined with cytotoxic chemotherapy. The present recommendation is to administer tamoxifen for 5 years of continuous therapy after surgical resection. Longer durations of tamoxifen therapy do not appear to add additional clinical benefit. Results from several randomized trials for breast cancer have established that adjuvant chemotherapy for premenopausal women and adjuvant tamoxifen for postmenopausal women are of benefit to women with stage I (node-negative) breast cancer. While this group of patients has the lowest overall risk of recurrence after surgery alone (about 35-50% over 15 years), this risk can be further reduced with adjuvant therapy. 

Cytotoxic drags that have been used alone and in combination as adjuvant therapy in breast cancer include doxorubicin, epirubicin, cyclophosphamide, methotrexate, fluorouracil, paclitaxel, docetaxel, melphalan, prednisone, vinorelbine, and vincristine. The most common combination chemotherapy regimens employed in the adjuvant and metastatic setting are listed in Table 125-11. 

ERP status was studied in pre- and postmenopausal women with advanced breast cancer and correlated with clinical response to cytotoxic chemotherapy in a retrospective study (K5). These patients were treated with CAP (cyclophosphamide, adriamycin, 5-fiuorouracil) or CMF (cyclophosphamide, methotrexate, 5-fluorouracil) CMFV (CMF, vincristine) or CAFVP or CMFVP (CAFV or CMFV, prednisone). The data suggested that ERP+ tumors responded better to cytotoxic chemotherapy than ERP- tumors. However, within the ERP+ group, the premenopausal women appear to have a better chance of responding to chemotherapy than postmenopausal ones. 

The prognostic usefulness of ERP in predicting response to cytotoxic chemotherapy was studied (H7) in pre- and postmenopausal women with advanced disseminated breast cancer and in patients receiving postsurgical adjuvant therapy. In both sets of patients, the response or failure to respond to chemotherapy was independent of ERP status. 

Adjuvant chemotherapy with CMF administered to premenopausal women with axillary node positive breast cancer (B3) induced permanent ovarian suppression in 47 of 77 (61%) patients. After a median observation time of 37 months, the relapse-free and overall survival times were significantly longer for patients with permanent amenorrhoea. A strongly positive correlation between CMF-induced amenorrhoea and age of the patients, as well as between age and tumor PRP status, was found. The induction of ovarian suppression predominantly occurs in patients with PRP positive tumors and may add an endocrine effect to the cytotoxic action of adjuvant chemotherapy in this particular group of older premenopausal women. 

In a clinical study the change in the status and the concentration of ERP and PRP under cytotoxic chemotherapy was studied (J7). A total of 38 patients with locally advanced breast cancer were treated with cytotoxic chemotherapy, including adriamycin, cyclophosphamide, 5-fluorouracil, and prednisone. The concentrations of ERP and PRP in the tumor were studied before starting the chemotherapy and after one to nine courses of chemotherapy. This therapeutic response rate was not related to the initial level of ERP and PRP. After chemotherapy, there... 

Jouve, M., Palangie, T., Dorval, T., Garcia-Giralt, E., Merle, S., Zajdela, A., Magdelenat, H., Coutant, M and Pouillart, P Breast cancer. Development of the concentration of hormonal receptors under cytotoxic chemotherapy. Bull. Cancer 73(3), 271-278 (1986). 

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