Combination Chemotherapy for Advanced Disease

Standard approaches to the systemic management of breast cancer have probably reached a plateau. Endocrine therapy leads to responses in only 1/3 of patients, probably even less if no clinical preselection is applied, and the median benefit probably does not exceed one year. Although three-drug chemotherapeutic combinations yield responses in 55-65% of patients, the median duration of response is at best only 10 months, and addition of more drugs does not seem to offer much additional benefit. Although combining these approaches seems attractive initially, the theoretical improvement would be modest even if the effects were additive, and in fact the endocrine component may well perturb the cell cycle kinetics to reduce sensitivity to the cytotoxic component so that results would be less than additive. Clinical trials of combined chemo-endocrine regimens have tended to evaluate only the initial response rate, whereas a valid comparison must consider the total response duration and survival given either combined or the usual sequential approaches. Combining endocrine and cytotoxic chemotherapies may have a greater effect when a more rational means for their amalgamation is employed. Early trials using endocrine manipulation to synchronize cell sensitivity to cytotoxic treatment have been promising. Increasing attention needs to be directed towards more innovative trial design which is respectful of the biological realities of cancer.

Section: Systemic Chemotherapy /Or Advanced Breast Cancermentioning

confidence: 98%

Efforts to combine endocrine and chemotherapy in the management of breast cancer: Do two and two equal three?

Lippman¹

1983

“…Since that observation, innumerable studies have appeared in the literature demonstrating that a variety of drug combinations can all be expected to result in fairly high initial response rates in patients with metastatic breast cancer (15,16). While there is considerable variability in overall response rates between one study and another, several conclusions may be drawn with confidence.…”

Section: Cytotoxic Chemotherapy For Systemic Breast Cancermentioning

confidence: 96%

“…If, for the sake of discussion, these relatively high initial response rates are accepted, there are many disconcerting features of response data in patients with metastatic breast cancer that remain. First, the median duration of response to therapy in virtually all reported studies of any substantial size is less than a year (15,17). What this means is that even allowing for an initial response rate of two out of every three patients, if the median duration response is less than a year, than less than a third of patients with metastatic breast cancer benefit from their initial combination chemotherapy for more than a year.…”

Section: Cytotoxic Chemotherapy For Systemic Breast Cancermentioning

confidence: 98%

An assessment of current achievements in the systemic management of breast cancer

Lippman

1984

Over the past twenty years, breast cancer has come to be much more commonly regarded and treated as a systemic disease. Conventional chemotherapy and endocrine therapy used according to schedules that are tolerable to patients are generally effective and often induce worthwhile responses; nevertheless, the responses in general have a median duration of less than a year, and these therapies are rarely if ever curative. Continued efforts to use available agents with mere modifications of schedule and intensity seem unlikely to substantially improve upon the modest success already achieved. Rather, we desperately need radically new schedules, new agents (especially non-myelosuppressive agents), and new approaches (e.g. monoclonal antibody targeting of drugs, toxins, or radionuclides, perhaps combined with tumor sensitizing agents such as heat). It is our hope that consideration of some of these issues will encourage others to be bolder in devising the next generation of clinical trials.

“…The regimen of cyclophosphamide-methotrexate-5-fluorouracil (CMF) appeared in 1976 as efficacious as most reported chemotherapeutic programs (10). A low-dose CMF regimen had been observed to achieve equivalent response rates with minimal toxicity (11).…”

Section: Introductionmentioning

confidence: 98%

“…Combination chemotherapy in metastatic breast cancer yields objective response rates of 40 to 703/o (10). The regimen of cyclophosphamide-methotrexate-5-fluorouracil (CMF) appeared in 1976 as efficacious as most reported chemotherapeutic programs (10).…”

Section: Introductionmentioning

confidence: 99%

Randomized clinical trial of tamoxifen plus sequential CMF chemotherapy versus tamoxifen alone in postmenopausal women with advanced breast cancer

Glick

Creech²,

Torri

et al. 1981

Eighty-eight postmenopausal women with metastatic breast cancer, in whom estrogen receptors (ER) were positive or unknown, were treated on a controlled trial to determine the effectiveness of tamoxifen and to assess the therapeutic advantage of sequentially adding low-dose cyclophosphamide-methotrexate-5-fluorouracil (CMF) chemotherapy in tamoxifen responders. Patients with known ER negative status were not studied. After the initial 12-week treatment with tamoxifen alone, 60% of ER positive patients achieved complete or partial response as did 35% in whom ER were unknown. Response status further improved in 18% randomized to continue tamoxifen alone vs 31% in whom CMF was added to tamoxifen. There were no statistically significant differences in time to the development of progressive disease or survival between the ER positive and ER unknown patients or between the tamoxifen and tamoxifen plus CMF groups. We conclude that inability to determine ER status should not prejudice against the use of tamoxifen in postmenopausal patients with advanced breast cancer. No benefit has been demonstrated from the addition of CMF chemotherapy in tamoxifen responders.