Hendré C. Falkson

Fluorouracil, imidazole carboxamide dimethyl triazeno, vincristine, and bis‐chloroethyl nitrosourea in colon cancer

A randomized clinical trial was undertaken comparing A) fluorouracil (FU) 15 mg/kg/day I.V. X 5 given monthly; and B) fluorouracil 10 mg/kg/day I.V. on day 1 to 5; imidazole‐4‐carboxamide, 5‐(3,3‐dimethyl‐1‐triazeno) (ICDT) 3 mg/ kg/day I.V. on days 1 and 2; vincristine (VCR) 0.025 mg/kg I.V. on day 1; and 1,3‐bis‐(2‐chloroethyl)‐1‐nitrosourea (BCNU) 1.5 mg/kg I.V. on day 1. Of 24 patients in Group A (FU), the response seen was complete remission in 2, partial remission in 4, improvement in 3, no change in 4, and progressive disease in 11. Of 28 patients randomized to Group B (FU, ICDT, VCR, and BCNU) the response seen was complete remission in 4, partial remission in 8, improvement in 4, no change in 2, and progressive disease in 10. The worthwhile response rate in patients receiving FU was therefore 25%, while that in the group receiving the four‐drug combination was 42.8%. Hemopoietic toxicity was comparable in the two groups. Nausea and vomiting were much more severe in those patients receiving the four‐drug combination. Alopecia occurred in all patients on the four‐drug combination who received more than two courses of treatment.

Long-term survival of patients treated with combination chemotherapy for metastatic breast cancer

Long-term survival of patients with metastatic breast cancer treated on two prospective stratified randomised trials has been analysed. Patients on study B122 received either cyclophosphamide, methotrexate and 5-fluorouracil (CMF) or cyclophosphamide, doxorubicin and 5-fluorouracil (CAF). On study B141 patients received CAF or mitolactol (dibromodulcitol), doxorubicin and vincristine alternating after every three cycles with three cycles of CMF (DAV/CMF). Long-term follow-up of 172 patients showed no significant survival difference (in multivariate regression models) for treatment with either CMF vs. CAF or CAF vs. DAV/CMF. The difference in median survival times between CMF and CAF showed a trend in favour of CAF. Advances in the management of metastatic breast cancer in postmenopausal women obtained by doxorubicin regimens have had a small but measurable impact on survival, but known patient discriminants were not overridden by the treatment regimens investigated in these studies.

Phase II trial of fotemustine in patients with metastatic malignant melanoma

SummaryFotemustine is a novel chloroethylnitrosourea, that readily penetrates the blood brain barrier. Preliminary French studies reported encouraging results with fotemustine in patients with cerebral metastases of malignant melanoma. Thirty-one patients with histologically confirmed metastatic malignant melanoma were entered on a phase II trial. The treatment regimen consisted of fotemustine, administered intravenously as a rapid infusion, at a dose of 100 mg/m2 on day 1, 8 and 15 every 4 to 5 weeks. Objective response (CR+PR) was documented in 3 patients. Median time to treatment failure (TTF) was 44 days and median survival was 164 days. Life threatening toxicity did not occur; hematological toxicity and nausea and vomiting were the most common toxicities. Despite a somewhat disappointing response rate, objective responses were documented in patients with cerebral metastases. Since no other chemotherapeutic agent has shown therapeutic efficacy in cerebral metastases from malignant melanoma fotemustine therefore warrants further study.

Prognostic factors in metastatic malignant melanoma. An analysis of 236 patients treated on clinical research studies at the Department of Medical Oncology, University of Pretoria, South Africa from 1972-1992.

Prognostic factors in 236 patients with metastatic malignant melanoma were analyzed. The patients were all entered on clinical research studies at a single institution. Univariate and multivariate analyses were performed on data which was prospectively collected. Seven independent variables were analyzed for effect on response, time to treatment failure (TTF) and survival. Univariate analysis identified four factors which significantly effected response, TTF and survival: PS, dominant site of disease, number of sites of disease and treatment. In multivariate analyses dominant site of disease and treatment remained significant factors influencing response rates, but performance status (PS) and number of sites of metastases lost statistical significance. Treatment and number of sites were significant for TTF and treatment, PS and disease-free interval were significant for survival. The identification of prognostic factors may lead to identification of subgroups of patients who may benefit from existing treatment programs, and may allow for new treatment programs to be designed with greater insight, logic and rationale.

A phase I/II investigation of trioxifene mesylate in advanced breast cancer: clinical and endocrinologic effects

Tamoxifen and trioxifene are antiestrogens that appear to have different endocrine effects when tested in rats. Whereas tamoxifen has considerable clinical activity, trioxifene is a new antiestrogen with undefined clinical activity. Thirty‐six patients were treated with graded doses of trioxifene. The low‐dose group (0.5 to 12 mg/m2 twice daily) had a 21% response rate in 24 subjects, and the high‐dose group (40 to 100 mg/m2 twice daily) had a 33% response rate in 12 patients (P = 0.13). The time to treatment failure was 67 days and 178 days for the low‐ and high‐dose groups, respectively. Toxicities were non‐dose dependent; those of moderate frequency included leukopenia (41%) and nausea (31%). Tamoxifen reduced both prolactin and inducible growth hormone (GH). Trioxifene, although reducing prolactin, differed from tamoxifen in that an increase in inducible GH occurred. Furthermore, a striking dose‐dependent decrease in luteinizing hormone and lesser decrease in follicle‐stimulating hormone occurred only in the trioxifene‐treated patients. This implies an intrinsic estrogenic action of trioxifene in man. Trioxifene is no more efficacious than tamoxifen and has more toxicity.

Carcinoembryonic antigen as a marker in patients with breast cancer receiving postsurgical adjuvant chemotherapy

Serial plasma CEA levels were determined over a period of 1–3 years in 114 patients receiving adjuvant chemotherapy for T1, 2 or 3a N+ MO breast cancer. CEA values were correlated with clinical status, scintiscans, and other biochemical parameters. CEA values >2.5 ng/ml were considered abnormal. Forty‐one patients had normal values throughout the adjuvant period. In 73 patients where abnormal values occurred, four different patterns were seen: (1) a statistically significant number (30/73) had initial elevations with a decreasing titer; (2) rising titer (10/73); (3) fluctuating titer of transient elevation (25/73); and (4) persistent elevation (8/73). Seventeen patients developed overt metastases, this was associated with a rising CEA in nine patients (P < 0.002). CEA was more sensitive for predicting relapse than alkaline phosphatase or LDH. The correlation between CEA determination and the eventual development of metastatic disease is striking, and has implications for the design of future clinical trials. Results indicate that CEA could be used to identify high risk patients, to estimate efficacy of chemotherapeutic regime, and to determine optimal duration of therapy.

Cisplatin versus Cisplatin plus D-Trp-6-LHRH in the Treatment of Ovarian Cancer: A Pilot Trial to Investigate the Effect of the Addition of a GnRH Analogue to Cisplatin

Thirty-four patients with histologically confirmed ovarian cancer were entered into a pilot study. Patients were randomized to receive cisplatin alone or cisplatin plus D-Trp-6-LHRH(decapeptyl). Objective response (complete and partial response) was documented in 9 of 14 patients on cisplatin and in 12 of 18 patients on cisplatin plus decapeptyl. Median time to treatment failure and median survival times were the same in the two treatment regimens. Toxicities were similar in the two treatment arms, except for hot flashes which only occurred in patients on cisplatin plus decapeptyl.

Postmenopausal Breast Cancer

SummaryIn summarising current drug treatment strategies for postmenopausal women with breast cancer, it is essential to emphasise that we are dealing with a group of diseases that are treatable, and that appropriate treatment decisions will give longer disease-free intervals for patients with early breast cancer, and better control with better survival for patients with advanced (i.e. locally advanced and/or metastatic) disease.Women greater than 65 years of age have a predictably better response to hormone treatment versus women less than 65 years of age. Hormone treatment may, therefore, be considered as primary treatment or as adjuvant treatment after limited surgery. Hormone treatment is also the treatment of first choice for elderly patients with advanced disease.For middle-aged women (45 to 65 years of age), various patient factors are important in predicting the value of treatment. Estrogen receptor (ER) status is prognostic of survival irrespective of treatment. Patients with ER-positive disease have a better prognosis than those with ER-negative disease, both in the adjuvant setting and in the face of metastatic disease. This is because ER-positive tumours tend to grow slower. The availability of the serotonin type 3 (5-hydroxytryptamine; 5-HT3) antagonists, which effectively control nausea and vomiting in most patients, make chemotherapy combinations more acceptable, and combination chemotherapy can more readily be considered as first treatment option both as adjuvant treatment and for treatment of advanced disease. For patients with organ metastases there is no doubt that combined chemotherapy treatment is indicated.

Antiemetic Efficacy of Tropisetron in Patients Failing Previous Antiemetic Therapy

Tropisetron was studied for efficacy and safety in 164 patients who were refractory to other antiemetic agents. 5 mg tropisetron was given intravenously, followed by 5 mg by mouth per day for 4 days. Complete prevention of nausea and vomiting was documented in 42% of patients on day 1 of cycle 1. Delayed nausea and vomiting were prevented in 41% in the first cycle. The antiemetic control did not decrease with subsequent cycles. Side effects ascribed to tropisetron were mild.

Mitomycin C + High-Dose Medroxyprogesterone versus Cyclophosphamide + Doxorubicin plus Fluorouracil as First- Line Treatment for Metastatic Breast Cancer

A pilot study was undertaken to compare mitomycin C plus oral high-dose medroxyprogesterone acetate (MMPA) to cyclophosphamide+doxorubicin+ fluorouracil (CAF). Thirty-four women were randomized at first relapse to receive MMPA or CAF. Patients were balanced with respect to age, performance status, hormone receptor status, prior adjuvant treatment, site of metastases, and number of metastatic sites. On MMPA 9/18 objective responses occurred and on CAF 12/18. Median time to treatment failure was 5.7 months on MMPA and 7.6 months on CAF; median survival on MMPA was 22.5 months and on CAF 16.7 months. Although there were more objective responses on CAF, this was not statistically significantly different, and CAF was associated with significantly more hemopoietic toxicity. It is concluded that mitomycin C should be further studied in front-line regimens for patients with metastatic breast cancer.