Breast cancer combination therapy

Topotecan (TPT) is a molecule discovered in a HIF-1-targeted high-throughput screen of the NCI Diversity Set and is a topoisomerase I inhibitor. TPT acts by inhibiting the hypoxic induction of HIF-la protein and interferes with its ability to bind DNA [202]. However, in a phase I/II clinical study of patients with metastatic breast cancer, TPT therapy was found to have limited efficacy and deemed not appropriate as a first-line therapy for breast can-cer[203]. Several clinical trials are currently recruiting women with locally advanced or metastatic breast cancer to test efficacy of these types of inhibitors in combination therapy [195]. 

Hodgkin s disease, lymphocytic lymphoma, histiocytic lymphoma, mycosis fungoides, testicular cancer, Kaposi s sarcoma, breast cancer Acute leukemia, combination therapy for various cancers... 

Although the incidence of breast cancer has been increasing in the United States, the mortality rate has been decreasing over the past two decades. This trend reflects the success of early detection and the development of effective treatment regimens. Treatment for most breast cancer patients includes a combination of pharmacologic and nonpharmacologic therapy. 

Cytotoxic drugs that have been used alone and in combination as adjuvant therapy in breast cancer include doxorubicin, epirubicin, cyclophosphamide, methotrexate, fluorouracil,... 

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... 

For women whose breast cancer has metastasized to bone, bisphosphonates are recommended, in addition to chemotherapy or endocrine therapy, to reduce bone pain and fractures.28,64 Pamidronate (90 mg) and zoledronate (4 mg) can be given intravenously once each month. These bisphosphonates are given in combination with calcium and vitamin D. 

A subsequent large epidemiologic study found a greater risk for breast cancer with combined estrogen-progestogen use, as well as increased risk for estrogen-only therapy and tibolone, but selection bias was found in the study population. 

In a reanalysis of 51 studies, less than 5 years of therapy with combined estrogen and progestogen was associated with a 15% increase in risk for breast cancer, and the risk increased with greater duration of treatment. Five years after discontinuation of hormone replacement therapy, the risk of breast cancer was no longer increased. 

Santen RJ, Pinkerton J, McCartney C (2001) Clinical review 121 Risk of breast cancer with progestins in combination with estrogen as hormone replacement therapy. J Clin Endocrinol Metab 86(l) 16-23... 

Finally, one of fhe most recent and most interesting approvals of a new formulation of paclifaxel was fhe approval of the agent ABl-007 (Abraxane ) (Abraxis Oncology, Schaumburg, IL, U.S.A.) (paclifaxel protein-bound particles for injectable suspension [albumin-bmmd]). It is indicated for treatment of breast cancer after failure of combination chemotherapy for metastatic disease or relapse within 6 months of adjuvant chemotherapy. Prior therapy should have included an anthracycline unless clinically contraindicated. The endpoint for that pivotal trial of Abraxane vs. paclitaxel was a... 

O Shaughnessy, J. et al., Superior survival with capecitabine plus docetaxel combination therapy in anthracycline-pretreated paEents with advanced breast cancer phase III trial results, J. Clin. Oncol, 20, 2812-2823, 2002. 

Eulvestrant has been evaluated in two randomised phase III trials in postmenopausal women with advanced disease after progression on prior antiestrogen therapy. In both trials, fulvestrant was at least as effective as anas-trozole. In a prospectively designed combined analysis of the results from both trials, median time to progression (TTP) was 5.5 months for fulvestrant versus 4.1 months for anastrozole [172]. Eulvestrant and tamoxifen have been compared as first-line treatments in a trial including post-menopausal women with advanced breast cancer. In this study, the between-treatment difference was non-significant (median TTP 6.8 versus 8.3 months) [173]. 

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