Mogens Kjaer

Postoperative Radiotherapy in High-Risk Premenopausal Women with Breast Cancer Who Receive Adjuvant Chemotherapy

BACKGROUND Irradiation after mastectomy can reduce locoregional recurrences in women with breast cancer, but whether it prolongs survival remains controversial. We conducted a randomized trial of radiotherapy after mastectomy in high-risk premenopausal women, all of whom also received adjuvant systemic chemotherapy with cyclophosphamide, methotrexate, and fluorouracil (CMF). METHODS A total of 1708 women who had undergone mastectomy for pathological stage II or III breast cancer were randomly assigned to receive eight cycles of CMF plus irradiation of the chest wall and regional lymph nodes (852 women) or nine cycles of CMF alone (856 women). The median length of follow-up was 114 months. The end points were locoregional recurrence, distant metastases, disease-free survival, and overall survival. RESULTS The frequency of locoregional recurrence alone or with distant metastases was 9 percent among the women who received radiotherapy plus CMF and 32 percent among those who received CMF alone (P<0.001). The probability of survival free of disease after 10 years was 48 percent among the women assigned to radiotherapy plus CMF and 34 percent among those treated only with CMF (P<0.001). Overall survival at 10 years was 54 percent among those given radiotherapy and CMF and 45 percent among those who received CMF alone (P<0.001). Multivariate analysis demonstrated that irradiation after mastectomy significantly improved disease-free survival and overall survival, irrespective of tumor size, the number of positive nodes, or the histopathological grade. CONCLUSIONS The addition of postoperative irradiation to mastectomy and adjuvant chemotherapy reduces locoregional recurrences and prolongs survival in high-risk premenopausal women with breast cancer.

Dose-response relationship of epirubicin in the treatment of postmenopausal patients with metastatic breast cancer: a randomized study of epirubicin at four different dose levels performed by the Danish Breast Cancer Cooperative Group.

PURPOSE To test for possible correlations between dose of single-drug epirubicin and efficacy/toxicity in postmenopausal women with metastatic breast cancer. The study also included analysis of a correlation between pharmacokinetic and pharmacodynamic parameters. PATIENTS AND METHODS Two hundred eighty-seven women were randomized to receive either 40, 60, 90, or 135 mg/m2 of epirubicin intravenously (IV) every 3 weeks. Treatment consisted of first-line cytotoxic therapy for metastatic disease. In patients with early progressive disease after either 40 or 60 mg/m2, dose escalation to 135 mg/m2 was performed. A full pharmacokinetic analysis was performed in 78 patients. RESULTS Among 263 eligible patients, an increase in response rate and time to progression was found with an increase in dose from 40 to 90 mg/m2, while no increase in efficacy was found from 90 to 135 mg/m2. Multivariate analysis, using the Cox proportional hazards model with time to progression as the end point, confirmed that epirubicin dose more than 60 mg/m2 was an independent prognostic covariate. Furthermore, a significant association was established between randomized dose and both hematologic and nonhematologic toxicity. No association between pharmacokinetic parameters and efficacy parameters was demonstrated. On the other hand, a significant correlation between pharmacokinetic parameters and both hematologic and nonhematologic toxicity was found. CONCLUSION An increase in dose of epirubicin from 40 to 90 mg/m2 is accompanied by increased efficacy. Further increases in dose do not yield increased efficacy. A positive correlation between epirubicin dose and toxicity, as well as a correlation between pharmacokinetic parameters and toxicity, was also established.

Phase III Study of Intravenous Vinorelbine in Combination With Epirubicin Versus Epirubicin Alone in Patients With Advanced Breast Cancer: A Scandinavian Breast Group Trial (SBG9403)

PURPOSE To determine whether the addition of intravenous (IV) vinorelbine to epirubicin increased the progression-free survival in first-line treatment of metastatic breast cancer. PATIENTS AND METHODS A total of 387 patients were randomly assigned to receive IV epirubicin 90 mg/m(2) on day 1 and vinorelbine 25 mg/m(2) on days 1 and 8, or epirubicin 90 mg/m(2) IV on day 1. Both regimens were given every 3 weeks for a maximum of 1 year but discontinued prematurely in the event of progressive disease or severe toxicity. In addition, epirubicin was discontinued at a cumulative dose of 1000 mg/m(2) (950 mg/m(2) from June 1999). Prior anthracycline-based adjuvant chemotherapy and prior chemotherapy for metastatic breast cancer was not allowed. Reported results were all based on intent-to-treat analyses. RESULTS Overall response rates to vinorelbine and epirubicin, and epirubicin alone, were 50% and 42%, respectively (P =.15). The complete response rate was significantly superior in the combination arm (17% v 10%; P =.048) as was median duration of progression-free survival (10.1 months v 8.2 months; P =.019). Median survival was similar in the two arms (19.1 months v 18.0 months; P =.50). Leukopenia related complications, stomatitis, and peripheral neuropathy were more common in the combination arm. The incidences of cardiotoxicity and constipation were similar in both arms. CONCLUSION Addition of vinorelbine to epirubicin conferred a significant advantage in terms of complete response rate and progression-free survival, but not in terms of survival.

Treatment of advanced breast cancer with tamoxifen: Evaluation of the dose-response relationship at two dose levels

SummaryIn order to establish the optimal dose of tamoxifen in the treatment of advanced breast cancer in postmenopausal women, a randomized trial comparing 90 mg daily with the currently recommended dose of 30 mg daily was conducted. Sixty-eight patients were treated with the high dose and 75 patients with the low dose. The rate of response was 36 and 37% (p = 0.74), respectively. The time to response, duration of response, and the time to treatment failure were also identical at the two dose levels. Only a few side effects were observed, and they were equally distributed among the two treatment groups. It is concluded that a 30 mg daily dose of tamoxifen seems to be as effective as 90 mg.

COMBINING 5-FLUOROURACIL WITH INTERFERON-ALPHA IN THE TREATMENT OF ADVANCED COLORECTAL CANCER : OPTIMISM FOLLOWED BY DISAPPOINTMENT

Pre-clinical data have demonstrated synergy between 5-fluorouracil (5-FU) and interferon (IFN)-alpha in colon cancer cell lines. In 1989 the first small single-institution phase II study with this combination in advanced colorectal cancer showed a response of 81% with substantial toxicity, whereas IFN-alpha alone was virtually inactive. Ten published phase II studies including 175 evaluable patients have demonstrated a response rate of 2.3%. 5-FU alone has been used extensively and is moderately active with response rates of 10-11% in 1148 patients evaluated by the Advanced Colorectal Cancer Meta-analysis Project in 1992 and 1994. Eleven subsequent phase II studies with 5-FU + IFN-alpha published over the period of 1990-1994 on 548 patients showed a response rate of 28% with 2% toxic deaths. Recently, nine phase III clinical trials including 1727 randomized patients have compared 5-FU + IFN-alpha to some standard therapies, most often treatment regimens based on 5-FU + leucovorin. Except for one study involving 105 patients, the rest of the phase III studies have demonstrated either no difference (six studies) or significantly worse results (two studies showing substantial toxicity with IFN-alpha + 5-FU). Several studies are ongoing, but results are not likely to change. In conclusion, after a period of high hopes, the combination of 5-FU + IFN-alpha does not seem to fulfill the original expectations. It is costly, it is toxic and it is not effective. New treatment strategies must be developed if progress is to be obtained.

A Phase II Study of UFT and Leucovorin in Combination with Mitomycin C in Patients with Metastatic Colorectal Cancer

The main objectives of this phase II study were to determine efficacy and safety of the combination of UFT with Leucovorin and mitomycin C in patients with metastatic colorectal cancer. Ninety-seven patients were treated with UFT (91 patients 300 mg/m2, 6 patients 250 mg/m2)+Leucovorin 90 mg days 1–28 q 5 weeks. During the first 4 cycles the patients also received mitomycin C 7 mg/m2 on day 1. At the end of 4 courses patients with benefit from the treatment could receive further courses of UFT and Leucovorin alone. Two patients had a complete response (2%), 20 (21%) had a partial response, 40 (41%) had no change, 19 (20%) had progression, and 16 (17%) were not evaluable for response. The overall response rate by intention to treat was 22/97 (23%). Median time to progression was 5 months and median survival 13 months. Severe (grade 3–4) toxicities included: anorexia 3%, nausea 6%, vomiting 7%, diarrhoea 7%, and fatigue 9%. Febrile neutropenia, renal failure, and thrombocytopenia were seen in 1% of the patients, respectively. The combination of UFT with Leucovorin and mitomycin C shows similar clinical activity with regard to overall response rate (23%) and survival (13 months) to other frontline 5-fluorouracil-based therapies in metastatic colorectal cancer patients. The results indicate that mitomycin C did not increase either efficacy or toxicity. Therefore, phase III trials with this regimen cannot be recommended.

Combined epirubicin and vinorelbine as first-line therapy in metastatic breast cancer: a pilot study performed by the Danish Breast Cancer Cooperative Group

This pilot study investigated the tolerability and efficacy of increasing doses of epirubicin and vinorelbine as first-line chemotherapy for metastatic breast cancer. Acute toxicity was manageable at all dose levels for combinations of epirubicin 60-90 mg/m2 on day 1 and vinorelbine 15-25 mg/m2 on days 1 and 8 repeated every 3 weeks. Myelotoxicity was the most frequent toxic event, with a significant increase in grade 4 leukopenia from 0% at dose level 1 (60+15 mg/m2) to 26% at dose level 6 (90+25 mg/m2). Signs of acute or chronic cardiotoxicity grades 2-4 were seen in 15% of the patients and included arrhythmia and decreased function. No significant association was established between dose and nonhematological toxicity. Objective responses were observed in 49 of the 99 evaluable patients (49.5%, 95% CI 39.9-59.2), 18 being complete and 31 partial responses. Responses were observed at all six dose levels. In conclusion, acute toxicity was manageable at all dose levels for combinations of epirubicin 60-90 mg/m2 on day 1 and vinorelbine 15-25 mg/m2 on days 1 and 8. In the treatment of advanced breast cancer, improvement of the antitumor efficacy by the addition of vinorelbine to epirubicin remains to be demonstrated in a randomized phase III trial.

Bioavailability of a new oral formulation of medroxyprogesterone acetate compared with the standard formulation: a single dose randomized study.

Twenty-six female patients with breast cancer participated in an open, randomized, cross-over study comparing single dose bioavailability of a recently developed oral medroxyprogesterone acetate (MPA) formulation (200 mg sachet where MPA is loaded in a polyvinylpyrrolidone cross-linked polymer, MPA/PVP) with the standard formulation (500 mg tablet). Blood tests were performed under standardized conditions for 120 h in all patients and MPA plasma concentrations determined by means of HPLC. Dose-normalized AUC(0-Tz), AUC (0-∞) and Cmaxwere all significantly higher for the MPA/PVP formulation than for the standard formulation. The relative bioavailability of the MPA/PVP formulation was on average three times superior to that of the standard formulation. This new MPA formulation might have important clinical implications for the treatment of hormone-sensitive cancer.

On-demand antiemetic treatment with the serotonine antagonist tropisetron in cisplatin-treated cancer patients.

Fourteen cancer patients treated with cisplatin received repeated infusions of tropisetron on-demand in conjunction with emesls. In subsequent chemotherapy courses, prophylactic troplsetron was given In a dose Identical to the cumulated dose in study course 1. Troplsetron in study course 1 abolished emesis after 7.5 min (5 mg). Duration of effect was more than 7 h in 50% of the patlents. No relationship between dose and duration of effect was seen. After study course 2, eight of 10 patients preferred prophylactic troplsetron. Two patients with hypertension had a severe Increase in blood pressure probably related to tropisetron. It is concluded that tropisetron has an instant and lasting effect on nausea and vomiting when given on-demand. The majority of patients, however, prefer prophylactic treatment. Hypertension may be a side effect from tropisetron and caution should be displayed in hypertensive patients.