Operable Breast Cancer

HAMBURG—The benefits of tamoxifen are modest at best in patients with operable breast cancer who receive postoperative chemotherapy, according to a study presented here at the European Breast Cancer Conference. “The overall survival for [treated and untreated] groups was 8%,” reported Robert Paridaens, MD, a medical oncologist at University Hospital Gasthuisberg in Leuven, Belgium. He stressed, however, that other factors can influence the value of tamoxifen. For example, among patients with both estrogen- and progesterone receptor-positive tumors, 88% are alive five years after diagnosis. “Even so, that rate was the same between those who did and those who did not use tamoxifen,” he said. Tamoxifen was associated more with relapse-free survival, though. Among those treated with tamoxifen, 72% were relapse-free at five years, compared with 66% of those who did not use tamoxifen. Among the 1,863 study participants, the current median follow-up is 6.3 years. At the time the ongoing study was reported, investigators had recorded 359 deaths and 551 events, defined as relapse, death, or both. Ambivalent Results in Chemotherapy-Treated Patients Dr. Paridaens explained that he and his co-investigators were interested in assessing tamoxifen's other benefits because, although the drug had been shown to reduce recurrence and mortality in patients with hormone receptor-positive operable disease, less clear benefits had been seen in patients receiving adjuvant chemotherapy. Earlier studies have also suggested that tamoxifen and chemotherapy may in fact be partially antagonistic, and that concomitant use of tamoxifen with chemotherapy was less effective than chemotherapy alone, he noted. From March 1991 through May 1999, a study under the auspices of the European Organization for Research and Treatment of Cancer (EORTC) recruited pre- and postmenopausal women who had operable breast cancer in Stages I to IIIA. Among these, half received tamoxifen therapy for three years following combination chemotherapy; the other half had no tamoxifen. All patients had received six cycles of any one of several regimens of adjuvant combination chemotherapy. The chemotherapy treatment options consisted of cyclophosphamide, methotrexate, and fluorouracil (CMF); cyclophosphamide, doxorubicin, and fluorouracil (CAF); or cyclophosphamide, epirubicin, and fluorouracil (CEF). The study protocol did not exclude patients by their menopausal status or by the primary tumor's hormone-receptor status. Patients were excluded if they had other forms of cancer, such as contralateral breast cancer. Exceptions consisted of adequately treated cervical carcinoma or basal cell skin carcinoma. The investigators analyzed the patients' treatment centers, chemotherapy regimens, and age. At the start of the last chemotherapy cycle, patients were randomized to receive 20 mg of tamoxifen daily for three years or no further treatment. The goal was to determine whether treatment resulted in at least a 5% increase in the five-year survival rate, from the current rate of 80% to 85% or more. This endpoint required at least 159 deaths in each treatment arm.Figure: The findings reported by Robert Paridaens, MD, showed that tamoxifen-treated patients are less likely to have a recurrence, but that there is no overall survival benefit for tamoxifen in patients receiving postoperative chemotherapy.The study also sought to assess relapse-free survival, local control, and the incidence of second primary breast cancer, as well as to correlate the results with the tumors' hormone-receptor status. The findings show that tamoxifen-treated patients are less likely to have a recurrence, but that there is no overall survival benefit to tamoxifen in patients receiving postoperative chemotherapy, Dr. Paridaens reported. Inconsistent Findings Several breast oncology experts noted in telephone interviews, however, that the findings differed from other research showing a clear benefit to tamoxifen. Robert W. Carlson, MD, Chair of the Breast Cancer Guidelines Committee of the National Comprehensive Cancer Network (NCCN) and Professor of Oncology at Stanford University School of Medicine, said, “This is an interesting large study. The results are surprising and not consistent with other studies of tamoxifen in early breast cancer. “The results are disappointing, and one reason might be that the study included women with estrogen receptor-negative disease. Also, the patients were treated with tamoxifen for three years, when we have data showing that there are more benefits when tamoxifen is taken for up to five years. The short course and the number of estrogen receptor-negative women may explain these findings. As we practice breast oncology in the United States, we always know the hormone-receptor status of every breast cancer patient.” Julia Smith, MD, a medical oncologist and Clinical Assistant Professor at New York University School of Medicine, noted that some used anthracycline and some did not. “That's very important,” she said. “These drugs can interact differentially with tamoxifen. “In addition, the investigators did not mention whether they stratified by HER-2/neu. That is important because we know that anthracycline, tamoxifen, and HER-2/neu can all have differing effects on outcome. “I think this study is food for thought because with postmenopausal women with early-stage, small, receptor-positive tumors, we know you may not add a benefit with tamoxifen if you also add adjuvant chemotherapy,” she continued.Figure: George Somlo, MD: “If you ask me if I'm going to stop prescribing tamoxifen after chemotherapy, the answer is no.”“We may be talking about very small increases in benefit. For some women, the small percentage gain is enough. This study doesn't yet give clear indication of what to do at this time.” Like Dr. Carlson, Dr. Smith pointed out that the three-year treatment duration was short, and that “five years is optimal.” “If you ask me if I'm going to stop prescribing tamoxifen after chemotherapy, the answer is no,” said another member of the NCCN Breast Cancer Guideline Committee, George Somlo, MD, Associate Director of High-Dose Chemotherapy in the Division of Medical Oncology and Therapeutics Research at City of Hope National Medical Center. “This is one of several studies that have been recently presented looking at whether there is a role for tamoxifen in delaying recurrence or extending survival for patients with operable breast cancer, particularly when you provide it in combination with chemotherapy. The findings show no difference in outcome, which is a contradiction to other studies. The various chemotherapeutic regimens give the study a bit of heterogeneity.” He also agreed that the three-year duration of treatment may not have been long enough for the patients to derive full benefit from tamoxifen. “The variety of chemotherapeutic regimens and the duration of tamoxifen may explain why the investigators found only modest benefit to tamoxifen,” Dr. Somlo said. “One additional difference is that studies in the United States were conducted in postmenopausal women, and this study included pre- and postmenopausal women.” Weekend Admission to Hospitals & Possible Health Risks Most hospitals have reduced staff on weekends. Does this affect patient mortality or the quality of care? Two articles in the Aug. 1 issue of The American Journal of Medicine studied mortality rates and delays in receiving urgent procedures as a function of weekend-vs-weekday hospital admission. The first, a study of some 500,000 admissions to 441 hospitals in California found a 3% increase in mortality in patients admitted on weekends. Three problems—cancer of the ovary/uterus, duodenal ulcer, and cardiovascular symptoms—showed larger weekend effects. The researchers were also surprised, they said, to find that large teaching hospitals had greater variation in their weekend-vs-weekday mortality rates when compared with minor teaching and non-teaching hospitals. “In light of prior research, our findings confirm the presence of the weekend effect but suggest that it may be smaller than previously determined,” said lead author Peter Cram, MD, MBA, of the University of Iowa Roy J. and Lucille A. Carver College of Medicine. “The finding that the weekend effect may be larger in major teaching hospitals is cause for concern and requires confirmation.” In the second article, all acute care admissions from all 190 emergency departments in Ontario from 1988 to 1997 were analyzed to determine how long patients had to wait for six urgent procedures, as a function of day of admission. In more than 125,000 patients, only 5% of all urgent procedures were done on weekends, with coronary angioplasty the lowest at 1.5%. Patients admitted on Fridays or Saturdays had the longest waits for procedures. Further, patients with longer waits had longer total hospital stays. “Our findings of increased lengths of hospital stay for patients with longer procedure waits suggest opportunities for cost savings and more efficient care,” said lead author Chaim M. Bell, MD, PhD, of St. Michael's Hospital and the Institute for Clinical Evaluative Sciences in Toronto. “Reducing any delays that contribute to prolonged lengths of stay might allow hospitals to realize some savings in operating costs.” In an accompanying editorial in the same issue, Joel S. Weissman, PhD, of the Department of Medicine & Institute for Health Policy at Massachusetts General Hospital writes, “People can surf the Web, trade stocks, go to restaurants, and buy a carton of milk 24-hours a day; but, as currently structured, our nation's hospitals are not fully operational on weekends and holidays.” If more research shows that patients are at higher risk of injury or death on weekends, or that overall costs can be lowered by going to full 24/7 operation, then hospitals will be forced to change, he said.

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