Duration of adjuvant chemotherapy for breast cancer: a joint analysis of two randomised trials investigating three versus six courses of CMF.

Cyclophosphamide, methotrexate and fluorouracil adjuvant combination chemotherapy for breast cancer is currently used for the duration of six monthly courses. We performed a joint analysis of two studies on the duration of adjuvant cyclophosphamide, methotrexate and fluorouracil in patients with node-positive breast cancer to investigate whether three courses of cyclophosphamide, methotrexate and fluorouracil might suffice. The International Breast Cancer Study Group Trial VI randomly assigned 735 pre- and perimenopausal patients to receive 'classical' cyclophosphamide, methotrexate and fluorouracil for three consecutive cycles, or the same chemotherapy for six consecutive cycles. The German Breast Cancer Study Group randomised 289 patients to receive either three or six cycles of i.v. cyclophosphamide, methotrexate and fluorouracil day 1, 8. Treatment effects were estimated using Cox regression analysis stratified by clinical trial without further adjustment for covariates. The 5-year disease-free survival per cents (+/-s.e.) were 54+/-2% for three cycles and 55+/-2% for six cycles (n=1024; risk ratio (risk ratio: CMFx3/CMFx6), 1.00; 95% confidence interval, 0.85 to 1.18; P=0.99). Use of three rather than six cycles was demonstrated to be adequate in both studies for patients at least 40-years-old with oestrogen-receptor-positive tumours (n=594; risk ratio, 0.86; 95% confidence interval, 0.68 to 1.08; P=0.19). In fact, results slightly favoured three cycles over six for this subgroup, and the 95% confidence interval excluded an adverse effect of more than 2% with respect to absolute 5-year survival. In contrast, three cycles appeared to be possibly inferior to six cycles for women less than 40-years-old (n=190; risk ratio, 1.25; 95% confidence interval, 0.87 to 1.80; P=0.22) and for women with oestrogen-receptor-negative tumours (n=302; risk ratio, 1.15; 95% confidence interval, 0.85 to 1.57; P=0.37). Thus, three initial cycles of adjuvant cyclophosphamide, methotrexate and fluorouracil chemotherapy were as effective as six cycles for older patients (40-years-old) with oestrogen-receptor-positive tumours, while six cycles of adjuvant cyclophosphamide, methotrexate and fluorouracil might still be required for other cohorts. Because endocrine therapy with tamoxifen and GnRH analogues is now available for younger women with oestrogen-receptor-positive tumours, the need for six cycles of cyclophosphamide, methotrexate and fluorouracil is unclear and requires further investigation.

Randomized 2 x 2 trial evaluating hormonal treatment and the duration of chemotherapy in node-positive breast cancer patients: an update based on 10 years' follow-up. German Breast Cancer Study Group.

PURPOSE: In 1984, the German Breast Cancer Study Group started a multicenter randomized trial to compare six versus three cycles of cyclophosphamide, methotrexate, and fluorouracil (CMF) starting perioperatively and to investigate the additional effect of tamoxifen as adjuvant treatment in node-positive breast cancer patients treated with mastectomy. PATIENTS AND METHODS: From 1984 to 1989, 473 patients were randomized from 41 institutions. After a median follow-up of approximately 10 years for overall survival (OS) and 9 years for event-free survival (EFS), the treatment groups were compared with respect to OS and EFS. Results based on a median follow-up of 56 months have been published earlier. RESULTS: Estimated cumulative locoregional incidence rate after 10 years was 19.9%; the corresponding rate of distant recurrences was 41.3%. Concerning duration of chemotherapy, we did not find any difference between six and three cycles of CMF (EFS: relative risk [RR] in multivariate analysis = 0.95; 95% confidence interval [CI], 0.74 to 1.21 OS: RR = 0.90; 95% CI, = 0.69 to 1.18). Treatment with tamoxifen resulted in an improvement in outcome (EFS: RR = 0.81; 95% CI, 0.61 to 1.07, OS: RR = 0.74; 95% CI, 0.55 to 1.0) although it proved not significant. Number of positive lymph nodes and progesterone receptor were the dominant prognostic factors. CONCLUSION: In this study, we observed some tendency in favor of hormonal treatment, which is in agreement with the literature. Concerning duration of chemotherapy, the results of this study provide further evidence that a reduction to three cycles of CMF is possible without increasing the risk of recurrence or death. For a definitive conclusion, however, further investigations are required.

Randomized 2 x 2 trial evaluating hormonal treatment and the duration of chemotherapy in node-positive breast cancer patients. German Breast Cancer Study Group.

PURPOSE: In 1984, the German Breast Cancer Study Group (GBSG) started a multicenter randomized clinical trial to compare the effectiveness of three versus six cycles of 500 mg/m2 cyclophosphamide, 40 mg/m2 methotrexate, and 600 mg/m2 fluorouracil (CMF) on day 1 and 8 starting perioperatively with or without tamoxifen (TAM) (3 x 10 mg/d for 2 years). The aim of the trial was to compare recurrence-free and overall survival between the different treatment modalities. PATIENTS AND METHODS: During 5 years, 41 institutions randomized 473 patients (3 x CMF: 145; 3 x CMF + TAM: 93; 6 x CMF 144; 6 x CMF + TAM: 91). Until March 31, 1992, median follow-up time was 56 months with 197 events for disease-free survival and 116 deaths observed. This provides a power of approximately 80% to detect a potential treatment difference corresponding to a relative risk (RR) of 0.67 for recurrence-free survival. Treatment modalities and various patient characteristics were evaluated by means of a multivariate Cox regression analysis. RESULTS: No significant difference in recurrence-free survival was observed with respect to hormonal therapy (RR = 0.75 TAM v no TAM; 95% confidence interval [CI], 0.54 to 1.04; P = .08) as well as duration of chemotherapy (RR = 0.90 of 6 x CMF v 3 x CMF; 95% CI, 0.67 to 1.19; P = .45). Similar results were obtained for overall survival. The multivariate analysis revealed a significant prognostic impact of the number of positive lymph nodes and the progesterone receptor level on recurrence-free survival. Compliance with chemotherapy within the range of 85% to 115% of the target dose was achieved in 94% and 78% of the patients randomized to 3 x CMF and 6 x CMF, respectively. Sufficient compliance with TAM was reported for 141 patients (93%). CONCLUSION: At this stage of follow-up, six courses of CMF are not superior to three courses with respect to recurrence-free survival.

[Treatment of primary therapy refractory choriocarcinoma using the EMA-CO protocol]. / Behandlung eines primär therapieresistenten Chorionkarzinoms nach dem EMA-CO-Schema.

This is a report on a 33 year old patient with a metastatic gestational choriocarcinoma. The patient was hospitalized with the picture of a spontaneous left kidney rupture and nephrectomy was performed. Under primary mono-dose methotrexate chemotherapy, the patient showed rapidly progressive metastases in both lungs, liver, right kidney and soft tissue. With the use of multiple-chemotherapy, according to the EMA-CO scheme, we observed complete remission. To date, there has been no indication of any tumour recurrence.

[Adjuvant chemotherapy in dysgerminoma]. / Adjuvante Chemotherapie beim Dysgerminom.

This is a report on a young patient with dysgerminoma of the right ovary. Right-side adnexectomy and hysterectomy were performed initially. Due to the clearly elevated tumour marker levels, indicating an involvement of other germ cell elements, we opted for postoperative chemotherapy instead of radiotherapy. The follow-up included regular monitoring of the tumour markers. To date, there has been no indication towards tumour recurrence.

[Spindle cell sarcoma of the female breast]. / Das Spindelzellsarkom der weiblichen Brust.

Malignant mesenchymal breast tumors are extremely rare. Without cystosarcoma phylloides, the frequency of primary sarcomas is 0.6% of all neoplasms of the breast. A case is reported of an adolescent girl, and the diagnostic features and treatment are discussed in correlation to the literature data. The pathogenesis of the sarcoma and the possible connection with Epstein-Barr viral infection is analysed. All treatment modalities with surgery, radiation therapy and systemic cytostatic application were carried out. Nevertheless, the patient developed twice a local recurrence. Then we started a high-dose Beta-Interferon treatment. Until today a total disease-free survival is established.

[Arterial regional chemotherapy of advanced breast cancer]. / Arterielle regionale Chemotherapie fortgeschrittener Mammakarzinome.

From October 1985 to November 1987, arterial regional chemotherapy with mitoxantrone was undertaken in 18 patients with primary far advanced carcinoma of the breast, of inflammatory or ulcerating type. Two patients had a bilateral carcinoma. Eight weeks after regional chemotherapy 18 of 20 tumours had become operable. Regression of tumour size by at least 50% (checked by mammography) was achieved in seven patients. Axillary lymphadenectomy gave negative results in 6 of 17 patients. Conversion of the receptor status occurred in only 2 of 12 patients. There were only few side effects: alopecia in 20%, leucopenia less than 2,500/microliters in 18%, thrombocytopenia less than 100,000/microliters in 7% patient. After a follow-up period of up to 28 months local recurrence was noted in two, distant metastases in three cases. A totally disease-free period was achieved in 14 patients.

[HELLP syndrome: a life-threatening form of pre-eclampsia]. / Das HELLP-Syndrom: eine lebensgefährliche Form der Präeklampsie.

A rather unusual but dramatic form of EPH gestosis or pregnancy-induced hypertension is presented via the case of a 30-year old second gravida in the 30th week of pregnancy. This is a case of pre-eclampsia combined with haemolysis, elevated liver function tests and low platelet counts. Diagnostic features, pattern and pathophysiology are discussed with regard to international literature.

Scintigraphic diagnosis of cirrhosis: a receiver operator characteristic analysis of the common interpretative criteria.

Receiver operator characteristic (ROC) techniques were used to determine relative importance of heterogeneity, bone marrow uptake, hepatomegaly, splenomegaly, and focal lesions in the scintigraphic diagnosis of cirrhosis, as well as to determine whether each of the criteria should be used as an identifier (high sensitivity) or as a discriminator (high specificity). Heterogeneity, splenomegaly, and bone marrow uptake were found to be good identifiers of hepatic disease. However, heterogeneity was found to be a poor discriminator for cirrhosis, splenomegaly showed some value as a discriminator, and bone marrow uptake was found to be a reliable discriminator for alcoholic liver disease. The presence of focal lesions was a good discriminator for metastatic disease, and was not specific for cirrhosis. Hepatomegaly also was not specific for cirrhosis. This method of analysis provides a relatively simple method for assembling a hierarchical guide to diagnostic criteria for the interpreting physician.