Homocysteine, a risk factor for coronary artery disease or not? A meta-analysis.

This meta-analysis suggests that homocysteine may not be as harmful for the heart as it seems. At the same time, however, homocysteine may be an indicator for unhealthy lifestyles, and therefore, an important variable for cardiologists to take into account when assessing coronary artery disease.

Randomized comparison of cisplatin plus epirubicin or doxorubicin for advanced epithelial ovarian carcinoma. A multicenter trial.

Stage III and IV epithelial ovarian cancer patients were prospectively randomized to receive eight courses of 60 mg/m2 of cisplatin plus either 75 mg/m2 of epirubicin (62 patients) or 60 mg/m2 of doxorubicin (54 patients). Clinical response rates for cisplatin/epirubicin of 42% [15% complete response (CR) and 27% partial response (PR)] and for cisplatin/doxorubicin of 55% (24% CR and 31% PR) were not statistically different (p = 0.14). The negative second look rate was 35% (10/29) for cisplatin/doxorubicin and 17% (5/30) for cisplatin/epirubicin (p = 0.12). The progression-free interval for cisplatin/epirubicin (13 months) was not statistically different (p = 0.09) from that for cisplatin/doxorubicin (19 months). The median survivals for cisplatin/epirubicin (756 days) and cisplatin/doxorubicin (739 days) were similar (p = 0.70). Cardiotoxicity was greater for the cisplatin/doxorubicin group (p = 0.0003). With similar survival and less cardiotoxicity, the cisplatin/epirubicin regimen had the more favorable therapeutic index.

Continuous infusion of interleukin-2 and cyclophosphamide as treatment of advanced cancers: a National Biotherapy Study Group Trial.

We have evaluated the effect of Interleukin-2 [IL-2] after Cyclophosphamide (C) chemotherapy in 41 patients with metastatic cancer. IL-2 was given as a continuous infusion priming cycle 36 hours after C at 1 gm/m2 intravenously. In 39 evaluable patients, there were no complete remissions [CR], 2 partial remissions [PR], and 1 had a minor response [MR]. Stable disease for 30 days was seen in 16 patients whereas 20 progressed. The durations of partial and minor responses were brief, ranging from 1-6 months. Grade 3-4 neutropenia was seen in 41%. This was more severe than seen with IL-2 alone or IL-2 combined with lower doses of C. The marrow suppression was due to the chemotherapy. This combination of IL-2 and C appears to be reasonably well tolerated by patients, but toxicity is greater and the response rate is no better than results achieved by IL-2 alone. Responses of 26 patients with renal cancer appear to be inferior to our historical data using IL-2/LAK cells without C. Immune monitoring demonstrated changes expected with C chemotherapy (i.e., a non-selective decline in immune function). C induced no further differences in IL-2 induced changes in immune function.

Adjuvant CMFVP versus melphalan for operable breast cancer with positive axillary nodes: 10-year results of a Southwest Oncology Group Study.

Four hundred forty-one women with operable breast cancer with histologically positive axillary nodes were randomized to receive either combination cyclophosphamide (60 mg/m2 orally everyday for 1 year); fluorouracil (300 mg/m2 intravenously [IV] weekly for 1 year); methotrexate (15 mg/m2 IV weekly for 1 year); vincristine (0.625 mg/m2 IV for 10 weeks); prednisone (30 mg/m2 orally days 1 to 14, 20 mg/m2 days 15 to 28, 10 mg/m2 days 29 to 42) (CMFVP) or single-agent melphalan (L-PAM) (5 mg/m2 orally every day for 5 days every 6 weeks for 2 years) chemotherapy after a modified or radical mastectomy between January 1975 and February 1978. Patients were stratified according to menopausal status and number of positive nodes (one to three, more than three nodes) before randomization. Seventy-eight patients were ineligible, most (56) because they were registered more than 42 days from surgery. Maximum duration of follow-up is 12 years, with a median of 9.8 years. The treatment arms were balanced with respect to age, menopausal status, and number of positive nodes. Among eligible patients, disease-free survival and survival were superior with CMFVP (P = .002, .005, respectively). At 10 years, 48% of patients treated with CMFVP remain alive and disease-free and 56% remain alive, compared with 35% alive and disease-free and 43% alive on the L-PAM arm. Disease-free survival and survival were significantly better with CMFVP compared with L-PAM only in premenopausal patients and patients with four or more positive nodes. Both regimens were well tolerated, although toxicity was more severe and more frequent with CMFVP. We conclude that after 10 years of follow-up, adjuvant combination chemotherapy with CMFVP is superior to single-agent L-PAM in patients with axillary node-positive primary breast cancer. The major advantage is in premenopausal women and in patients with more than three positive axillary nodes.

Phase I evaluation of chlorozotocin (NSC-178248): weekly schedule.

A phase I trial of chlorozotocin was completed for a weekly times four dose schedule repeated every 8 weeks. Thrombocytopenia was the acute dose limiting toxicity. Nausea and vomiting were moderate to severe and dose related. Two cases of possible drug related irreversible nephrotoxicity were seen. Transient elevations of serum creatinine and mild proteinuria were noted. Also, transient elevations in SGOT were observed. One patient with a carcinoid tumor had a 60% reduction in his 5HIAA level after one course of therapy. The recommended dose for phase II clinical studies of chlorozotocin is 40 mg/m2 IV weekly for four weeks, repeated every 8 weeks.

Combined modality therapy for first recurrence of breast cancer. A Southwest Oncology Group study.

The Southwest Oncology Group has completed a study of 213 women with the first recurrence of breast cancer. Eligibility included a radical or modified radical mastectomy for cure and recurrence which had received no other form of therapy. Patients were started on tamoxifen (TAM) 20 mg daily (Phase I). Failures, or responders who subsequently failed, had an oophorectomy if the ovaries were intact, and TAM was continued (Phase II). During Phase III, eligible patients underwent an adrenalectomy, and lastly, in Phase IV, patients received chemotherapy. Responses to TAM were seen in 40% of 56 premenopausal patients, 46% of 95 postmenopausal women, and 44% of 62 patients without intact ovaries. Oophorectomy plus TAM gave responses only in premenopausal women who failed to respond on TAM or in postmenopausal patients who had a prior response to TAM. Adrenalectomy was successful in 7 of 21 patients. Chemotherapy resulted in 13% complete and 47% partial responses. Median overall survival was 108, 155, and 115 weeks, respectively, for the three patient groups. The authors believe that until results with chemotherapy improve significantly, hormonal therapy is the preferred first-line management of recurrent breast cancer.

Phase I evaluation of AT-125 single dose every three weeks.

A Phase I trial of AT-125 was completed for the bolus dose every three week schedule. Dose limiting toxicity was primarily central nervous system (CNS) in the form of ataxia, confusion, hallucinations and dysarthria. Although this was most severe at doses of 150 mg/m2, lesser symptoms were reported at all dose levels. Nausea and vomiting were moderate to severe at higher doses. Myelosuppression did not occur. This schedule is not recommended for Phase II studies until methods are developed to reduce drug-related CNS toxicity.

Phase I trial of Indicine-N-Oxide on two dose schedules.

Indicine-N-Oxide is the water soluble N-oxide of the pyrolizidine alkaloid indicine recently evaluated in Phase I trials. Initially in a weekly times four schedule, twenty-nine patients were treated with a dose range of 1.0 to 7.5 g/m2 per week. Fifteen of 40 of the courses of four doses were interrupted by myelosuppression which prohibited completion of the course. Therefore, an intermittent schedule was evaluated utilizing single doses repeated every 3-4 weeks. Twenty-six patients were treated at doses of 5 to 10 g/m2. Myelosuppression is the dose limiting toxicity of both schedules with thrombocytopenia being more severe than leukopenia. Myelosuppression is predictable and reversible on the intermittent schedule. It is more severe in patients with heavy prior treatment. Partial responses were seen in four patients, one with a mucoepidermoid carcinoma of the salivary gland and three with adenocarcinoma of the colon. Phase II studies are planned at a starting dose of 7.5 g/m2 every 3-4 weeks in patients with no prior treatment and 5 g/m2 in patients with prior treatment.

Effect of mannitol and plasma on the cytotoxicity of cisplatin.

A soft agar cell culture for human granulocyte precursor cells (CFU-c) was used to assess the cytotoxic effect of cisplatin before and after preincubating the drug with either mannitol and/or fresh human plasma. Consistent growth inhibition of CFU-c was found with survival of 87, 64 and 34% at cisplatin concentrations of 10(-7) M, 10(-6) M and 10(-5) M respectively. Dose-related survival was not changed by preincubating cisplatin with mannitol in molar ratios of 1:100 and 1:1000 for 4 and 24 hr. Preincubating 10(-5) M cisplatin with human plasma increased CFU-c survival corresponding to a loss of activity of 92 and 98% after 4- and 24-hr preincubations respectively. No significant difference in survival of CFU-c was noted whether bone marrow cells were exposed to cisplatin in human plasma or in the ultrafiltrate of human plasma. Mannitol did not change the decrease in cisplatin activity due to plasma protein binding. These data indicate that the cytotoxic effect of cisplatin can be reduced by exposure to human plasma but not to mannitol.

Tamoxifen and oophorectomy in the treatment of recurrent breast cancer: a Southwest Oncology Group Study.

The relatively short survival following chemotherapy in patients with metastatic carcinoma of the breast and the introduction of antiestrogens has led to renewed interest in the hormonal therapy of breast cancer. Pritchard et al. (Cancer Treat. Rep., 64: 787-796, 1980) have recently stated that response to the antiestrogen tamoxifen (TAM) strongly predicts a subsequent response to oophorectomy in premenopausal patients. The Southwest Oncology Group administered TAM to pre- and postmenopausal women with first recurrence of breast cancer. Following response and subsequent relapse, or after no response, patients underwent an oophorectomy while continuing on TAM. None of 14 premenopausal patients who responded to TAM had a response to oophorectomy plus TAM, while 5 of 22 had a remission with oophorectomy plus TAM after initially failing with TAM alone. The reverse was seen in postmenopausal women; 4 of 18 responders to TAM subsequently responded to oophorectomy plus TAM, but none of 18 TAM failures responded to oophorectomy plus TAM. These results suggest that in the premenopausal women the TAM dose may be insufficient to block all estrogen action and that oophorectomy, by removing the major source of estrogen, can result in a more effective antiestrogen action of TAM leading to a response. No explanation is readily available for the results in postmenopausal patients.

Combination chemotherapy (CMFVP) versus L-phenylalanine mustard (L-PAM) for operable breast cancer with positive axillary nodes: a Southwest Oncology Group Study.

The Southwest Oncology Group in a prospective randomized study compared one year of adjuvant combination chemotherapy with continuous CMFVP to two years of intermittent L-PAM in women with operable breast cancer with histologically positive axillary lymph nodes. In fully evaluable patients with a 42-month median and 30-month minimum follow-up, treatment failures have occurred in 26% of 145 receiving CMFVP and 47% of 167 women given L-PAM (P = 0.002). Disease-free survival times were significantly longer with CMFVP than with L-PAM in the following subgroups: premenopausal women (P = 0.002), postmenopausal women (P = 0.002), women with 1-3 involved axillary nodes (P = 0.003), and women with four or more involved axillary nodes (P = 0.002). CMFVP was effective in pre- and postmenopausal women. There is a significant difference in survival in favor of CMFVP compared to L-PAM (P = 0.005). The life table estimates of survival at 42 months are 86% for women on the CMFVP treatment arm and 73% for women on the L-PAM treatment arm. There was no correlation between the interval from mastectomy to onset of chemotherapy (between one and six weeks) and recurrence rates. Acute toxicity with both treatment arms was moderate and reversible. These results show that continuous CMFVP is superior to intermittent L-PAM in decreasing recurrences and increasing survival in both pre- and postmenopausal women with operable breast cancer with histologically involved axillary nodes.

Multiple myeloma: a therapeutic enigma.

Multiple myeloma is one of the few malignancies with a distinct tumor marker, the myeloma protein. This marker, as well as other disease manifestations, can be used to follow the progress of the tumor. Myeloma was also one of the first cancers to respond to chemotherapy and well known are the reports in the early 1960s of good results with melphalan and with cyclophosphamide. Since that time many other agents have been introduced and combination chemotherapy with several drugs were tried extensively. The enigma: Despite the tumor marker and despite the many available drugs there has been very little progress made in improving the outcome of multiple myeloma in the last two decades.

Breast cancer in Arabic women.

A case-control study of breast cancer was conducted in Cairo, Egypt and in Kuwait. This is the first such report from Arabic countries and the most significant finding is the animal incidence rate of 7.67 per 100,000 in Kuwaiti women, which ranks amongst the lowest thus far reported in the world. Factors which contribute to this low rate are a short period of active menstruation, low family history, first childbirth at very early age and most likely significant dietary factors. More than 45% of Egyptian women give birth to a child before the age of 20, with 56.5% of controls and 42.3% of patients (p less than 0.01). Many patients already have extensive disease at time of diagnosis as a result of considerable delay. However, this delay did not result in a high incidence of inflammatory breast carcinoma, such as has been reported in Tunisia.

Phase I study on bruceantin administered on a weekly schedule.

Fifteen adult patients with advanced solid tumors received bruceantin at doses of 1.6-6.0 mg/m2 iv for 30 minutes/week X 4, followed by a 2-week rest. The dose-limiting toxic effect was nausea and vomiting, which was more severe in patients with hepatic metastases or liver function abnormalities. Other sporadic toxic effects included fever, chills, malaise, alopecia, hypotension, thrombocytosis, and leukocytosis. Hematologic toxicity was insignificant. The recommended starting dose for phase II studies is 5 mg/m2/week X 4, every 6 weeks, with a reduction to 3 mg/m2 for patients with hepatic metastases.

Phase I evaluation of IMPY in a twice weekly schedule.

IMPY was given to 25 patients with advanced cancer on a twice weekly schedule in escalating doses from 165 to 3000 mg/m2. Nausea, vomiting, fatigue, generalized weakness, and decreases in performance status were dose-limiting. In one patient treated at a dose of 3000 mg/m2 for three doses, hemolytic anemia resulted, with a 6-g/dl decrease in hemoglobin. No tumor regression occurred. A reasonable starting dose for phase II studies is 1200 mg/m2 twice weekly for 3 weeks, with planned rapid escalation to 1800 mg/m2 in patients tolerating the lower dose level.