Estrogen receptor status and adjuvant polychemotherapy or antiestrogen therapy in patients with high-risk breast cancer

Summary This pilot study includes 115 consecutive patients admitted in the period from 1978 to 1981. Patients eligible for this study were at high risk according to the TNM classification with stages pT1-pT3 and pN+, MO. Primary therapy included modified radical mastectomy and axillary-node clearance, one or more ipsilateral nodes being involved in routine histology. All tumors were assayed for estrogen and progesterone receptors. According to the result of the estrogen receptor assay, estrogen-receptor-positive patients were treated with Tamoxifen 30 mg/day for a period of 2 years. Estrogen-receptor-negative patients were treated with cytoxan, methotrexate, and 5-fluorouracil or adriblastin, cytoxan. After a median observation time of 36 months, overall there have been 31 recurrences: 9=17.3% in the estrogen-receptor-positive group and 22=34.9% in the estrogen-receptor-negative group. The analysis of different subgroups showed no significant differences, either in relation to axillary lymph-node status or in relation to menopausal status in the endocrine-treated compared with the polychemotherapy group. This result suggests, especially in the subgroup of patients with involvement of one to three axillary nodes, that estrogen-receptor-positive and estrogen-receptor-negative patients should be considered as separate groups when adjuvant therapy is indicated. Possibly hormone-receptor-positive patients may benefit from endocrine therapy and do not need polychemotherapy.     

A peptide derived from alpha-fetoprotein prevents the growth of estrogen-dependent human breast cancers sensitive and resistant to tamoxifen

An 8-mer peptide (EMTOVNOG) derived from alpha-fetoprotein was compared with tamoxifen for activity against growth of human breast cancer xenografts implanted in immune-deficient mice. Both peptide and tamoxifen prevented growth of estrogen-receptor-positive MCF-7 and T47D human breast cancer xenografts. A subline of MCF-7, made resistant to tamoxifen by a 6-month exposure to this drug in culture, was found to be resistant to tamoxifen in vivo. Peptide completely prevented the xenograft growth of this tamoxifen-resistant subline of MCF-7. Neither peptide nor tamoxifen was effective in slowing the xenograft growth of the estrogen-receptor-negative MDA-MB-231 human breast cancer. A worrisome side effect of tamoxifen is its hypertrophic effect on the uterus. In this study, tamoxifen was shown to stimulate the growth of the immature mouse uterus in vivo, and the peptide significantly inhibited tamoxifen's uterotrophic effect. The mechanism of action of peptide is different from that of tamoxifen in that the peptide does not interfere with the binding of [(3)H]estradiol to the estrogen receptor. In conclusion, alpha-fetoprotein-derived peptide appears to be a novel agent that interferes with the growth of tamoxifen-sensitive as well as tamoxifen-resistant estrogen-receptor-positive human breast cancers; it inhibits the uterotrophic side effect of tamoxifen and, thus, it may be useful in combination with or in place of tamoxifen for treatment of estrogen-receptor-positive human breast cancers.     

Combination chemotherapy compared to tamoxifen as initial therapy for stage IV breast cancer in elderly women

In a randomized crossover study, 181 patients over the age of 65 with recurrent breast cancer received either tamoxifen or cyclophosphamide, methotrexate, and fluorouracil (CMF). After progression on tamoxifen, a hormone withdrawal period was required. Because of altered pharmacokinetics with aging, creatinine clearance was used in calculating the dose of CMF. Response rates were 45% on tamoxifen and 38% on CMF, with median durations of 10.4 and 7.9 months, respectively. Survival rates tended to favor tamoxifen as the initial treatment even in estrogen-receptor-negative patients. Additional disease control with hormone withdrawal occurred in 23% of patients, and this benefit was highly correlated with prior hormone response. We conclude that initiation of hormone therapy rather than CMF chemotherapy is justified in almost all situations in elderly patients, and combination chemotherapy, is safe and useful after hormone failure if modified on the basis of renal dysfunction.     

Tamoxifen in the treatment of breast cancer

Tamoxifen, an antiestrogen, is a competitive inhibitor of estradiol, blocking its effects on the target organs. During the 10 years it has been used in the United States it has become preferred over estrogens for treating postmenopausal women with metastatic breast cancer. Recently, tamoxifen has been used in treating premenopausal women with recurrent breast cancer, and its efficacy has been proved equal to that of ovarian ablation. In comparative trials, tamoxifen has been as effective as alternative endocrine treatments, and has greatly reduced toxicity and no irreversible side effects. Because of the high risk for systemic relapse in patients with breast cancer with regional lymph node metastases, (stage II), tamoxifen has been evaluated as adjuvant therapy after local treatment of the tumor. The results of these trials have shown a significant increase in the disease-free survival of postmenopausal women treated with tamoxifen, particularly in patients with hormone-receptor-positive tumors. Tamoxifen has not been as useful as adjuvant treatment in premenopausal women, for whom combination chemotherapy is the treatment of choice.     

Increasing protection after tamoxifen: insights from the extended adjuvant aromatase inhibitor trials

For disease-free postmenopausal women with hormone-responsive breast cancer, a risk for relapse remains following 5 years of adjuvant therapy with tamoxifen. Additional therapy with tamoxifen beyond 5 years is not indicated due to a demonstrated lack of efficacy beyond this time frame. Thus, there is a need for other endocrine therapy options in the period beyond 5 years. The third-generation aromatase inhibitors (anastrozole, letrozole, and exemestane) have emerged as at least as effective and somewhat better tolerated alternatives to tamoxifen. Three trials were initiated to evaluate the efficacy and tolerability of aromatase inhibitors in the extended adjuvant setting. Among these, the large, double-blind, randomized, placebo-controlled MA.17 trial has already demonstrated a significant benefit of letrozole when compared with placebo on disease-free survival in postmenopausal women previously treated for 4.5–6 years with tamoxifen. A smaller open-label trial, the Austrian Breast and Colorectal Cancer Study Group 6a has reported a significant benefit for anastrozole on recurrence when used as extended adjuvant therapy when compared with no treatment, and similar results have been seen with extended adjuvant exemestane in the National Surgical Adjuvant Breast and Bowel Project B-33 trial. The results of these trials have important clinical implications for the future of extended adjuvant hormonal therapy for breast cancer. Dr. Rose has served on advisory boards for Roche, AstraZeneca, Novartis, Eli Lilly, and Bristol Meyers Squibb and has participated in Speaker’s Bureau for AstraZeneca and Novartis.     

Trends in endocrine therapy and chemotherapy for early breast cancer: a focus on the premenopausal patient

Purpose: The majority of breast cancers are diagnosed at an early stage, and treatment is focused on cure and prolonging disease-free survival. Local therapy (surgery and/or radiation treatment) is standard, along with systemic adjuvant therapy that may effectively prevent or delay relapse and death in early-stage disease. In premenopausal women, adjuvant therapeutic approaches include combination cytotoxic chemotherapy and endocrine therapy. Cyclophosphamide, methotrexate and 5-fluorouracil (CMF) was the established chemotherapy regimen; however, newer regimens have more recently been introduced that may offer some benefit over CMF including anthracycline-containing regimens [e.g. cyclophosphamide, epirubicin and 5-fluorouracil (CEF)], and taxane-containing regimens. For women with oestrogen receptor (ER)-positive disease, a second option is endocrine therapy that aims to suppress mitogenic oestrogen signalling. Until recently, 5 years of tamoxifen was regarded as the standard adjuvant endocrine treatment in ER-positive disease. Ovarian ablation is also effective in premenopausal women, and can be achieved by surgery, radiotherapy, or via the use of a luteinising hormone-releasing hormone analogue such as goserelin. Combining tamoxifen and goserelin treatment provides more effective oestrogen blockade than either drug alone. However, as the third-generation aromatase inhibitors (AIs) have demonstrated improved efficacy over tamoxifen in postmenopausal women with early and advanced disease, combination treatment with goserelin plus an AI may provide optimal oestrogen blockade in premenopausal patients. Conclusions: This review assesses the relative merits of chemotherapeutic and endocrine approaches for the treatment of early breast cancer, and summarises relevant ongoing clinical trials, with an emphasis on the premenopausal setting.     

Prolonging tamoxifen therapy for primary breast cancer. Findings from the National Surgical Adjuvant Breast and Bowel Project clinical trial

Objective: To determine whether prolonging the duration of tamoxifen administration beyond the cessation of a combined chemotherapy regimen benefits patients with primary breast cancer with positive findings in axillary nodes who benefit initially from the combined regimen. Design: Nonrandomized, nonconcurrent cohort study. Setting: National Surgical Adjuvant Breast and Bowel Project, conducted in 68 institutions in North America. Patients: Women were included if they had breast cancer with positive nodes and were aged 49 years or less with both estrogen and progesterone receptor levels of 10 fmol or more, aged 50 to 59 years with progesterone receptor levels of 10 fmol or more, or aged 60 to 69 years. Two cohorts were compared: patients who were randomly assigned to the tamoxifen arm of the adjuvant chemotherapy trial (randomized patients) and women who were added to this arm after randomization had ceased (registered patients). Three hundred seventy-seven women in each group who were disease free at the end of the initial 2-year treatment period were followed for an additional 3 years. Interventions: All received melphalan, fluorouracil, and tamoxifen (10 mg twice daily by mouth) for 2 years. Registered patients (but not randomized patients) were offered tamoxifen for a third year after the initial 2-year treatment period, and 273 (72%) agreed. Measurements and Main Results: Women receiving a third year of tamoxifen had a better disease-free survival rate (odds ratio, 1.54; 95% confidence interval, 1.14 to 2.07; p = 0.004) and survival rate (odds ratio, 1.56; 95% Cl, 1.02 to 2.37; p = 0.04) through their fifth postoperative year. Women aged 50 years or more benefited, but those aged 49 years or less did not. Conclusions: The benefit of tamoxifen given to tamoxifen-responsive patients in conjunction with melphalan and fluorouracil appears to be enhanced when the tamoxifen treatment is continued beyond cessation of treatment with these agents.     

Role of carbonic anhydrase IX expression in prediction of the efficacy and outcome of primary epirubicin/tamoxifen therapy for breast cancer

The purpose of this study is to investigate the role of carbonic anhydrase IX (CAIX) expression in predicting the response to epirubicin and disease-free survival (DFS) in breast cancer patients enrolled in a single institution trial of primary anthracycline and tamoxifen therapy. CAIX expression was assessed in 183 patients with T2-4 N0-1 breast cancer enrolled in a randomized trial comparing four cycles of single agent epirubicin versus epirubicin+tamoxifen as primary systemic treatment. All patients received postoperatively four cycles of the four weekly i.v. cyclophosphamide, methotrexate, 5-fluorouracil regimen. Patients with estrogen receptor (ER)-positive primary tumors received 5 years of adjuvant tamoxifen. Pretreatment, p53 (P=0.007), c-erbB2 (P<0.01), and Ki67 (P=0.02) were directly associated with CAIX expression, while bcl2 (P<0.000) and ER (P=0.000) and progesterone receptor (PgR; P<0.01) were inversely correlated. In multivariate analysis, only high p53 and low bcl2 were independently associated with CAIX positivity. CAIX immunostaining was significantly associated with poor outcome for DFS (P<0.002) and overall survival (P=0.001). In multivariate analysis, a significant interaction was found between CAIX and markers of hormone sensitivity, bcl2 (P=0.01), ER (P=0.02), PgR (P=0.02), and lymph node involvement (P=0.04), in predicting DFS. Presently, there are few clinical markers of resistance to tamoxifen treatment in ER-positive tumors. CAIX expression in breast cancer patients shows a negative predictive role of treatment efficacy in ER-positive patients on the adjuvant tamoxifen after primary chemo-endocrine therapy. Studies investigating the effects of pH on tamoxifen uptake and the effects of therapy with CA inhibitors are planned.     

Controlled clinical trial of doxorubicin and tamoxifen versus tamoxifen monotherapy in hepatocellular carcinoma

OBJECTIVES: Treatment results of advanced hepatocellular carcinoma have remained unsatisfactory; the response rates to intravenous doxorubicin are no better than 20%. Oral tamoxifen has been proposed on the basis of beneficial results in some trials. The aim of this study was to evaluate whether the addition of doxorubicin to oral tamoxifen improves survival compared to oral tamoxifen alone. METHODS: Thirty-two consecutive patients with a priori defined contra-indications against surgery (transplantation, resection) or chemo-embolization were evaluated to receive chemotherapy. All patients received oral tamoxifen 30 mg bid; 16 also received intravenous doxorubicin 50 mg/m2 every 4 weeks. The control group consisted of the remaining 16 patients who either were considered unfit for doxorubicin because of a Karnofsky index < 50% (n = 5), cardiac disease (n = 6) or who refused to have cytotoxic drug therapy (n = 5). RESULTS: Median survival time was 148 days (95% CI 89.2-206.8) in the doxorubicin group and 96 days (95% CI 49.0-143.0) in the control group, and this was not significantly different (P= 0.408), regardless of the presence or absence of cirrhosis. CONCLUSIONS: In conclusion, the results of our study indicate that combination therapy using doxorubicin and tamoxifen is unlikely to considerably improve survival compared to tamoxifen alone in patients with advanced hepatocellular carcinoma.     

Long-term risk of breast cancer recurrence: the need for extended adjuvant therapy

Background: All women with early breast cancer, even those with small tumors and negative nodes, remain at appreciable risk of recurrence after surgery over the subsequent 10–15 years. In women with tumors expressing estrogen receptors and/or progesterone receptors, standard systemic adjuvant therapy is 5 years of tamoxifen, which substantially reduces the risk of recurrence and breast cancer-related death. Tamoxifen efficacy benefits are limited to 5 years of treatment, presumably a consequence of acquired tamoxifen resistance. The third-generation aromatase inhibitors, which are highly selective and potent in suppressing whole-body estrogen synthesis in postmenopausal women, are being investigated as alternative or complementary treatments to tamoxifen. For treatment beyond adjuvant tamoxifen for 5 years, letrozole is the only aromatase inhibitor for which clinical trial data were reported. That trial, MA.17, evaluated letrozole as extended adjuvant treatment following standard adjuvant tamoxifen in postmenopausal women with predominantly estrogen receptor—and/or progesterone receptor—positive early breast cancer. Results: Compared with placebo, letrozole markedly reduced the residual risk of recurrence, by 42%, and the improvement in disease-free survival was irrespective of patient nodal status. A significant improvement in overall survival has already been seen in the patients at highest risk, those with positive nodes. Conclusion: On the basis of these results, extended adjuvant letrozole is recommended for all patients completing 5 years of adjuvant tamoxifen, including women generally considered at minimal risk.     

Effects of tamoxifen on cardiovascular risk factors in postmenopausal women

OBJECTIVE: To determine the effects of tamoxifen on risk factors for cardiovascular disease in disease-free postmenopausal women. DESIGN: Double-blind, placebo-controlled, randomized 2-year clinical trial. SETTING: University health sciences center. PATIENTS: Clinically postmenopausal women (140) with a diagnosis of axillary node-negative breast cancer, who were disease-free by laboratory and clinical evaluations. MEASUREMENTS: Levels of total cholesterol, high-density lipoprotein (HDL) cholesterol, triglycerides, apolipoprotein A-I, apolipoprotein B, glucose, weight, blood pressure, and reported exercise and work activity were measured. MAIN RESULTS: Postmenopausal women receiving tamoxifen were evaluated at 3- or 6-month intervals during a 2-year assessment period and showed a mean decrease of 12% in total cholesterol levels (at 24 months -0.672 mmol/L; 95% CI, -0.839 to -0.505 mmol/L) and a mean decrease of 20% in calculated low-density lipoprotein (LDL) cholesterol levels (at 24 months, -0.725 mmol/L; 95% CI, -0.868 to -0.583 mmol/L) (P less than 0.001). Women with greater baseline cholesterol levels had greater decreases with tamoxifen treatment. Levels of HDL cholesterol decreased in patients treated with tamoxifen, but this decrease was only statistically significant at one of five measurement times. Apolipoprotein A-I levels increased significantly at the two time points at which it was measured (P = 0.02), and apolipoprotein B levels decreased significantly at these times (P less than 0.01) in patients treated with tamoxifen. Plasma glucose levels, reported exercise and work activity, reported smoking, weight, and systolic and diastolic blood pressures did not change with treatment. CONCLUSION: During 2 years of treatment, tamoxifen showed generally favorable effects on the lipid and lipoprotein profile of treated postmenopausal women. These effects may partially explain the decrease in adverse events and in mortality related to coronary heart disease seen in patients receiving adjuvant tamoxifen treatment.     

Combined effects of epirubicin and tamoxifen on the cell-cycle phases in estrogen-receptor-negative Ehrlich ascites tumor cells

Laboratory and clinical data suggest some interactions between cytotoxic agents and tamoxifen. The mechanisms of these interactions differ in estrogen-receptor-negative cell lines. The ability of tamoxifen to modify the effects of epirubicin on the cell-cycle phases of estrogen-receptor-negative Ehrlich's carcinoma ascitic cells (EATC) was studied in mice. The results showed that combination of tamoxifen with epirubicin decreased the thymidine labelling index more effectively than did either drug alone. Adding tamoxifen to epirubicin treatment induced both an early S-phase and G2-M-phase arrest and a later G0-G1-phase arrest in EATC. An increase of S0 cells in the quiescent fraction could play a role in these changes, and some of these quiescent cells may not be viable, causing them to die later. In conclusion, the data suggest that continuous exposure to tamoxifen might modify the effects of epirubicin via cell-cycle perturbations.Abbreviations ER estrogen receptor - EATC Ehrlich ascites tumor cells - TLI thymidine labelling index     

Deleted in Colorectal Cancer Protein Expression as a Possible Predictor of Response to Adjuvant Chemotherapy in Colorectal Cancer Patients

PURPOSE: The deleted in colorectal cancer (DCC) gene predicts a poor outcome for patients with colorectal carcinoma. This study was designed to investigate whether the expression of the DCC protein also can predict response to adjuvant chemotherapy.METHODS: The expression of DCC was evaluated immunohistochemically in 74 paraffin-embedded tumor samples from patients with Stage II (n = 41) and Stage III (n = 33) colorectal carcinomas. Follow-up time was at least 60 (median, 64) months. Follow-up was at least five years for all patients who are alive. End points of the study were recurrence of disease and death. Forty-eight patients received adjuvant therapy of 5-fluorouracil + levamisole; 28 were not treated.RESULTS: Fifty percent of tumors were deleted in colorectal cancer-positive (DCC+). Proportion of survival and disease-free survival were higher in the DCC+ patients (83 percent) than in deleted in colorectal cancer-negative (DCC–; 54 percent). In the DCC+ group, adjuvant treatment was a strong positive predictive factor for survival and disease-free survival. All DCC+ patients who received adjuvant chemotherapy (CHEMO+) are alive with no evidence of disease, whereas without chemotherapy (CHEMO–) only 54 percent are alive (P = 0.0001). When stratification was performed by stage, patients in Stage II who were DCC+/CHEMO+ had survival and disease-free survival of 100 percent, whereas in DCC+/CHEMO– survival rate was 75 percent and disease-free survival rate 62 percent (P = 0.042). Patients in Stage III who were DCC+/ CHEMO+ had survival and disease-free survival of 100 percent, whereas in DCC+/CHEMO– both dropped to zero (P = 0.0002). On the other hand, in the DCC– tumors, there was no statistical significant relationship between chemotherapy and survival or disease-free survival (DCC–/CHEMO– had 57 percent survival; DCC–/CHEMO+ had 52 percent survival).CONCLUSIONS: DCC is a prognostic factor for colorectal cancer. Positive expression of DCC identifies a subgroup of patients who respond favorably to adjuvant chemotherapy, which resulted in our cases, in 100 percent survival and disease-free survival rates. Without treatment, the survival rate of DCC+ patients dropped significantly. We suggest that DCC immunostaining should be performed routinely. All DCC+ patients should receive adjuvant chemotherapy. For DCC– tumors, a larger cohort of patients should be studied before definitive conclusions can be drawn; however, clinical trials of new drug combinations should focus on DCC– patients.Reprints are not available.Supported in part by a grant from the Medical Research Fund of the Rabin Medical Center.Presented in part at the 4th World Congress on Advances in Oncology and 2nd International Symposium on Molecular Medicine, Vouliagmeni, Athens, Greece, October 7 to 9, 1999.     

Chemoprevention of breast cancer and the trials of the National Surgical Adjuvant Breast and Bowel Project and others

The idea of breast cancer prevention by hormonal means stemmed from the results of treatment trials, many of them carried out by the National Surgical Adjuvant Breast and Bowel Project (NSABP). Over the years, a number of NSABP treatment studies demonstrated that breast cancer recurrence was reduced in women with the disease who were given tamoxifen, a selective estrogen receptor (ER) modulator (SERM). Five subsequent tamoxifen prevention trials with this agent have shown a 48% reduction in ER-positive cancers, but no effect for ER-negative cancers, and an increase in endometrial cancer and thromboembolic events. The drug raloxifene, another SERM, originally examined as an osteoporosis agent, has also shown promise for the prevention of breast cancer, although, as with tamoxifen, the drug carries a risk for thromboembolic events. There is recent evidence in a large treatment trial that the aromastase inhibitor anastrazole, a 'pure anti-estrogen', holds promise as a breast cancer preventive agent. Longer follow-up and the testing of additional agents is required before these drugs can be used widely for prevention. In addition, future research should focus on the identification of at-risk women who can perhaps be targeted for specific prevention agents.     

Effective adjuvant treatments. A brief review of U.S. clinical trials.

A variety of adjuvant trials performed in the United States for osteogenic sarcoma, breast, lung, and colon cancer have achieved encouraging results and are briefly summarized. Trials in osteogenic sarcoma are reporting 2-year disease-free survival rates of 50%. However, they have only been evaluated against historical controls and there is some evidence that other factors might have greatly improved the disease-free survival in the absence of adjuvant therapy. The NSABP breast cancer trial only shows significant improvement for women under 50 years of age with 1 to 3 positive axillary nodes. A very promising trial using intrapleural BCG immunotherapy for squamous cell lung cancer is described. Also, two trials of 5-fluorouracil for colo-rectal cancer, both showing trends suggesting slight improvement among treated patients, are presented. Proper care in the design of adjuvant trials with sufficient attention paid to prognostic variables is urged.     

Prognostic indicators in node-negative early stage breast cancer.

With the increasing availability of screening mammography, more women are diagnosed as having breast cancers at an early, node-negative stage. The majority of these patients would be cured with total mastectomy or breast conservation treatment. However, about 30% of the patients would have recurrence of disease in distant sites. In recent randomized clinical trials, adjuvant systemic therapy has been shown to reduce the rate of recurrence in these patients. Proper selection of patients for adjuvant therapy is necessary to avoid exposing many patients with low risk of recurrence to treatments for whom the benefit is not justified by the toxicity and the cost. In this article, we review the clinical and pathologic prognostic factors in early stage, node-negative breast cancer patients, including tumor size, nuclear and histologic grades, estrogen and progesterone receptors, menopausal status, proliferative rate, HER-2/neu oncogene amplification, and cathepsin D level. Favorable prognostic factors include tumor size less than or equal to 2 cm, low nuclear and histologic grades, low S-phase fraction, diploid state, low cathepsin-D level, and positive estrogen and progesterone receptor status. The value of HER-2/neu oncogene overexpression is controversial, and further studies are needed to define its role as a prognostic factor in patients with node-negative breast cancer. Based on these prognostic factors, it is possible to identify subsets of patients who have a low risk of recurrence and would not benefit significantly from adjuvant systemic therapy.     

Advanced ovarian cancer: long-term results of treatment with intensive cisplatin-based chemotherapy of brief duration

Study Objective: To determine the efficacy of a 6-month course of combination chemotherapy with hexamethylmelamine, cyclophosphamide, doxorubicin, and cisplatin (H-CAP) in the treatment of advanced ovarian carcinoma. Design: Prospective, non-randomized, single-institution trial with a 6-month course of chemotherapy, followed by second-look laparotomy for restaging. Minimum follow-up after completion of therapy is 83 months. Patients: Fifty-five patients with advanced (stage III or IV), intermediate- or high-grade epithelial carcinoma of the ovary. Twenty patients had limited residual tumor (3 cm or less maximal tumor diameter) after initial cytoreductive surgery; 35 had extensive residual disease. Interventions: All patients received chemotherapy with hexamethylmelamine (150 mg/m2 body surface area orally on days 1 to 14), cyclophosphamide (350 mg/m2 intravenously on days 1 and 8), doxorubicin (20 mg/m2 intravenously on days 1 and 8), and cisplatin (60 mg/m2 intravenously on day 1). Courses were repeated at 4-week intervals; 41 patients (75%) received six courses; 10 patients received five courses, 3 patients received four courses, and 1 patients received three courses. Forty-seven patients underwent second-look laparotomy after completion of therapy; 8 had their disease restaged clinically. Results: Fifty-three of fifty-five patients (96%) had either partial or complete response to treatment. Nineteen of forty-seven patients who had a second-look laparotomy had a surgically documented complete response; 17 of these 19 patients began chemotherapy with limited residual tumor. Ten patients (18%) remain disease-free 83 to 108 months after therapy, whereas three additional patients died of other diseases without clinical evidence of recurrent ovarian cancer. Nine of twenty patients who began chemotherapy with limited residual tumor remain disease-free, as compared to only 1 of 35 patients with more extensive tumor (P less than 0.001). All long-term, disease-free survivors had surgically documented complete response at second-look laparotomy. Conclusions: Treatment with cisplatin-based combination chemotherapy after aggressive cytoreductive surgery should be considered standard treatment for advanced ovarian carcinoma. Our intensive, 6-month course of treatment produced results comparable to those previously reported with prolonged treatment.     

Effect of prior chemotherapy regimens on the efficacy of endocrine therapy within a German cohort of the TEAM trial

Purpose

Prior chemotherapy may affect the efficacy of endocrine therapy.

Methods

The tamoxifen exemestane adjuvant multinational (TEAM) trial compared 5 years of adjuvant exemestane with the sequence of tamoxifen followed by exemestane in postmenopausal women with hormone-receptor-positive breast cancer. A total of 1,502 patients were enrolled in Germany (739 received tamoxifen followed by exemestan and 610 exemestan alone). A retrospective analysis of the German cohort of TEAM was conducted to determine whether prior chemotherapy affected clinical outcome of endocrine therapy.

Results

Overall survival, disease-free survival and distant recurrence were similar between patients who received sequential therapy and those who received exemestane monotherapy, irrespective of prior chemotherapy. Overall survival was not significantly different between patients who had received prior chemotherapy and those who had not (P = 0.2836). Disease-free survival and distant recurrence were significantly better in patients who had not received prior chemotherapy versus those who had (P = 0.0308 and P = 0.0001). In patients receiving sequential therapy, there were no significant differences in overall survival according to prior chemotherapy use (P = 0.1812). However, disease-free survival and distant recurrence were significantly different dependent on prior chemotherapy (P = 0.0143 and P = 0.0053).

Conclusion

In conclusion, there was no difference in overall survival between breast cancer patients who did receive prior chemotherapy before endocrine therapy and those who had not. Patients who had not received prior chemotherapy had significantly improved disease-free survival and less distant recurrence versus those who had received chemotherapy.     

Severe hypertriglyceridemia induced by tamoxifen

A 71-year-old woman was admitted to our hospital because of severe hypertriglyceridemia. The patient had a 26-year history of non-insulin-dependent diabetes mellitus and hyperlipidemia (T-chol 300 mg/dl, TG 300 mg/dl). She was treated with sulfonylurea and clofibrate. Seven years before admission, she had undergone a radical mastectomy for cancer of the left breast. After the operation, she had received tamoxifen and fluorouracil. One month before admission, she had marked hypertriglyceridemia (triglyceride 2,106 mg/dl). After discontinuation of tamoxifen and fluorouracil, her serum triglyceride level decreased to 372 mg/dl; when tamoxifen was given again, it increased to 581 mg/dl, and her hepatic triglyceride lipase activity decreased from 0.228 to 0.164 mumol FFA/ml/min. Apolipoprotein E phenotype was wild type E3/3. The concentration of sex-hormone-binding globulin increased from 110 to 130 nmol/l. These changes associated with tamoxifen treatment were similar to those seen after administration of estrogen. Tamoxifen, an anti-estrogen, has been used as adjuvant therapy in cases of estrogen-receptor-positive breast cancer. Tamoxifen has some weak estrogenic activity. The tamoxifen-induced hypertriglyceridemia seen in this case was an effect of its estrogenic action.