FEC (5-fluorouracil-epirubicin-cyclophosphamide) monthly versus FEC weekly in metastatic breast cancer. First results of a randomized trial.

Patients (n = 174) with metastatic breast cancer previously untreated with anthracycline cytotoxic agents were randomized into two groups: Group 1 received FEC (5-fluorouracil 500 mg/m2, epirubicin 60 mg/m2 and cyclophosphamide 500 mg/m2) once every fourth week and group 2 received the treatment once weekly in the same monthly dosage. Treatment was recommended to continue until disease progression or to a cumulative epirubicin dose of 1,000 mg/m2, but could be discontinued at any time at the patient's request or at the treating physician's judgement. An interim analysis was made when 131 patients were evaluable for response, and 128 patients for toxicity. Hematological toxicity was significantly more severe in the monthly group, as was nausea and vomiting. Of the monthly treated patients 76% had total alopecia compared to 14% in the weekly group. There were no statistically significant differences in the occurrence of mucositis. Monthly FEC gave significantly higher response rate than weekly treatment (52 vs 34%, p = 0.01). Time to progression was significantly (p = 0.004) longer with monthly FEC. Patients in the monthly treated group lived significantly (p = 0.02) longer than patients in the weekly group. These results indicate that both toxicity and efficacy of epirubicin-containing combination therapy in breast cancer is dependent on the treatment schedule, not merely on dosage. Both efficacy and toxicity increased when the treatment was given once monthly compared to the weekly schedule.     

Postirradiation sarcoma. Analysis of a nationwide cancer registry material

Thirty-three cases of postirradiation sarcoma (PIS) from the files of the Finnish Cancer Registry were analyzed. The most frequent first primary tumors were cancers of the breast (seven cases) and female reproductive organs (13 cases). Five patients had a childhood cancer. The median total radiation dose at the site of the PIS was 3600 cGy (1600 cGy to 11200 cGy). The median interval from start of radiation therapy to detection of PIS was 13.2 years (3.4 to 22.8 years). The PIS was of soft tissue origin in 25 of 33 cases. The most frequent histologic types were osteosarcoma (ten cases, including four extraskeletal tumors), malignant fibrous histiocytoma (ten cases), and fibrosarcoma (six cases). The overall crude 5-year survival rate was 29% (calculated from the start of treatment for PIS), and for patients initially treated with either radical surgery or combined marginal surgery and postoperative irradiation it was 67%. The authors conclude that there is a chance for cure for radically treated patients with postirradiation sarcoma that emphasizes the importance of regular long-term follow-up of cancer patients.     

The response evaluation of bone metastases in mammary carcinoma. The value of radiology, scintigraphy, and biochemical markers of bone metabolism

The correlation between response of metastatic bone lysis and bone pain, various biochemical markers of bone metabolism, and radiological and scintigraphic findings was investigated in 49 women with breast cancer included in a calcitonin supportive therapy trial. All patients had dominant skeletal disease and were on stable systemic treatment (cytotoxic or hormonal) for a least 6 months before the first response evaluation. Bone pain correlated poorly with treatment response. Changes in sclerotic metastases did not show any apparent relation to changes in lytic lesions. A correlation between bone scans and lytic activity on radiographs was found. The absolute level of biochemical bone markers did not correlate with treatment response, but seemed instead to reflect the rate of bone turnover. The relative level of bone markers with respect to baseline showed better correlation to treatment response. The best conventional marker of disease activity was urinary hydroxyproline/creatinine. Propeptide of Type III procollagen (PIIINP), a novel marker reflecting collagen turnover, promises to be at least as sensitive as hydroxyproline. Stable and regressing patients had the same prognosis and significantly longer survival than progressors.     

The possible role of enterohepatic cycling on bioavailability of norethisterone and gestodene in women using combined oral contraceptives

Using steady-state conditions we aimed to test if administration of oral activated charcoal affects the bioavailability of norethisterone acetate (NET Ac) and gestodene (GEST) by inhibiting their enterohepatic recirculation. Thirteen volunteers received, in a randomized order, Minulet (75 microg GEST and 30 microg ethinylestradiol [EE(2)]) and Econ/30 (1 mg NET Ac and 30 microg EE(2)), each for 4 months. Serum GEST and norethisterone (NET) levels were evaluated with respect to C(max,) t(max) and 24-h area under the curve (AUC(0-24h)) in the middle of the control (3rd) cycle and the charcoal treatment (4th) cycle during both pill treatments. No statistically significant difference was seen in any of the aforementioned variables between the control and charcoal treatment cycles of either pill. Neither was a difference seen in the bioavailability of GEST and NET as evaluated by the ratios of two 24-h AUCs calculated in the control and charcoal cycles of each pill treatment (p = 0.29). The results suggest that enterohepatic circulation of GEST and NET is not of clinical importance. We conclude that women on oral contraceptives can take activated charcoal for the treatment of diarrhea when administered 3 h after and at least 12 h before pill intake.     

Use of bisphosphonates in skeletal metastasis

At present, there is sufficient evidence to propose practice guidelines that would include the use of bisphosphonates in the management of hypercalcemia, in breast cancer with bone metastases and multiple myeloma. Future research should concentrate on investigating the adjuvant use of bisphosphonates in breast cancer, particularly in order to find out the adequate target groups. Phase III studies comparing the old and new generation bisphosphonates are important as well as trials comparing the other palliative regimens with bisphosphonates. A widespread use of bisphosphonates would have a major impact on drug budgets. Does the cost of achieved palliation represent the optimal use of resources when compared with other possible options for palliation? This issue has not become easier with the emerging new expensive regimens in oncology. An economical analysis, ideally in the setting of randomized trials, is needed.     

The steady-state pharmacokinetics of tamoxifen and its metabolites in breast cancer patients

The steady-state pharmacokinetics of tamoxifen and its metabolites was studied in sixteen patients with advanced mammary cancer. Patients were randomized to receive tamoxifen given as Tamofen, Leiras, or as Nolvadex, ICI, 20 mg twice daily for 16 weeks in a cross-over study. Plasma and urine samples were analyzed during one dose interval (12 h) after treatment for 8 and 16 weeks. The concentrations of tamoxifen, N-desmethyltamoxifen, N,N-desdimethyltamoxifen, and metabolite Y were determined in plasma and the areas under the plasma level curves were calculated. 4-Hydroxytamoxifen was not found in plasma. In urine samples only tamoxifen and N-desmethyltamoxifen were above the detection limits even though metabolite Y was also analyzed after acid hydrolysis. There were no statistically significant differences in the concentrations of tamoxifen and its metabolites between the two preparations. The results of nonresponders did not differ from those of responders. Liver metastases had no effect on the metabolism of tamoxifen.