Phase II study of pegylated liposomal doxorubicin and carboplatin in patients with platinum-sensitive and partially platinum-sensitive metastatic ovarian cancer.

OBJECTIVE: This phase II study assessed the activity and safety of pegylated liposomal doxorubicin (PLD) plus carboplatin in relapsed ovarian cancer (ROC). METHOD: Forty women with platinum-sensitive and partially platinum-sensitive ROC were treated with PLD 50 mg/m2 plus carboplatin area under the curve 5 every 28 days in this South African multicenter study. All patients who completed 3 cycles of chemotherapy were evaluated for response. Primary outcome was response in the intent-to-treat population. RESULTS: Complete response was 35%, and partial response was 32.5% (overall response, 67.5%). Median time-to-progression was 11.9 months, and median survival was 30.0 months. Overall response was higher in platinum-sensitive (81%) versus partially platinum-sensitive patients (53%), as were median duration of response, median time-to-progression, and median survival. Treatment was well tolerated, with no grade 4 nonhematologic toxicities. Grade 3/4 hematologic toxicities included leukopenia (58%), neutropenia (55%), and thrombocytopenia (43%). CONCLUSION: Pegylated liposomal doxorubicin plus carboplatin is well tolerated and active in the treatment of platinum-sensitive and partially platinum-sensitive ROC.

Vinflunine: a new active drug for second-line treatment of advanced breast cancer. Results of a phase II and pharmacokinetic study in patients progressing after first-line anthracycline/taxane-based chemotherapy.

To evaluate the single agent activity, pharmacokinetics and tolerability of the novel tubulin targeted agent vinflunine (VFL) (320 mg m(-2) q 21 days) as second-line chemotherapy in patients with metastatic breast carcinoma (MBC). All patients had disease progression after anthracycline/taxane (A/T) therapy. They could have received a nonanthracycline adjuvant treatment and subsequently received a first-line A/T combination for advanced/metastatic disease; or relapsed >6 months after completion of adjuvant A/T therapy and were subsequently treated with the alternative agent; or relapsed within 6 months from an adjuvant A/T combination. Objective response was documented in 18 of 60 patients enrolled (RR: 30% (95% confidence interval (CI): 18.9-43.2%)). Among the responders, seven patients had relapsed during a period of <3 months from taxane-based regimen yielding a RR of 33.3%. The median duration of response was 4.8 months (95% CI: 4.2-7.2), median progression-free survival was 3.7 months (95% CI: 2.8-4.2) and median overall survival was 14.3 months (95% CI: 9.2-19.6). The most frequent adverse event was neutropenia (grade 3 in 28.3% and grade 4 in 36.7% of patients). No febrile neutropenia was observed. Fatigue (grade 3 in 16.7% of patients) and constipation (grade 3 in 11.7% of patients) were also common; these were non-cumulative and manageable permitting achievement of a good relative dose intensity of 93.5%. Vinflunine is an active agent with acceptable tolerance in the management of MBC patients previously treated with (A/T)-based regimens. These encouraging phase II results warrant further investigation of this novel agent in combination with other active agents in this setting or in earlier stages of disease.

Dalteparin for prevention of catheter-related complications in cancer patients with central venous catheters: final results of a double-blind, placebo-controlled phase III trial.

BACKGROUND: Cancer patients receiving chemotherapy experience thromboembolic complications associated with the use of long-term indwelling central venous catheters (CVCs). This prospective, double-blind, placebo-controlled, multicenter study evaluated whether prophylactic treatment with a low molecular weight heparin could prevent clinically relevant catheter-related thrombosis. PATIENTS AND METHODS: Patients with cancer undergoing chemotherapy for at least 12 weeks (n=439) were randomly assigned, in a 2:1 ratio, to receive either dalteparin (5000 IU) or placebo, by subcutaneous injection, once daily for 16 weeks. Patients underwent upper extremity evaluation with either venography or ultrasound at the time of a suspected catheter-related complication (CRC) or upon completion of study medication. The primary end point, as determined by a blinded adjudication committee, was the occurrence of a CRC, defined as the first occurrence of any one of the following: clinically relevant catheter-related thrombosis that was symptomatic or that required anticoagulant or fibrinolytic therapy; catheter-related clinically relevant pulmonary embolism; or catheter obstruction requiring catheter removal. RESULTS: There was no significant difference in the frequency of CRCs between the dalteparin arm (3.7%) and the placebo arm (3.4%; P=0.88), corresponding to a relative risk of 1.0883 (95% confidence interval 0.37-3.19). No difference in the time to CRC was observed between the two arms (P=0.83). There was no significant difference between the dalteparin and placebo groups in terms of major bleeding (1 versus 0) or overall safety. CONCLUSIONS: Dalteparin prophylaxis did not reduce the frequency of thromboembolic complications after CVC implantation in cancer patients. Dalteparin was demonstrated to be safe over 16 weeks of treatment in these patients.

First line therapy with paclitaxel (Taxol) and pegylated liposomal doxorubicin (Caelyx) in patients with metastatic breast cancer: a multicentre phase II study.

The aim of this multicentric phase II study was to investigate the efficacy and toxicity of a combination of chemotherapy containing paclitaxel (Taxol) and a novel compound, a liposomal encapsulated doxorubicin (Caelyx), as first line therapy for patients with metastatic breast cancer. Thirty-four patients with advanced breast cancer were treated with a combination of paclitaxel 175 mg/m2 and liposomal doxorubicin 30 mg/m2, every 3 weeks. The combination chemotherapy was effective in 73% of the patients (ITT) (95% CI 55-86%) (7 complete and 18 partial responses). Grade 3/4 toxicities were documented in a small number of patients. Two toxic deaths (6%) were documented, one a hepatorenal failure and another a febrile neutropenia. One patient experienced pulmonary embolism but continued on treatment after appropriate therapy. The combination of paclitaxel and liposomal encapsulated doxorubicin induces a high and durable response rate with a moderate toxicity profile.

A randomized study of radiotherapy alone versus radiotherapy plus 5-fluorouracil and platinum in patients with inoperable, locally advanced squamous cancer of the esophagus.

Squamous cell cancer of the esophagus is the most common cancer among black South African males, and 60% of patients present with localized inoperable disease. Combined chemoradiotherapy has been reported to be superior to radiotherapy alone for localized inoperable esophageal cancer in North American patients. A study was carried out to determine if this was also applicable to South African patients, who present with more advanced disease. From September 1991 through June 1995, 70 patients with locally advanced (T3N0-1M0) squamous cancer of the esophagus were prospectively randomized to receive radiotherapy alone or radiotherapy combined with cisplatin and 5-fluorouracil. There was no statistically significant survival difference between the two groups. The median survival was 144 days in the group receiving radiotherapy alone, and 170 days in the group receiving radiotherapy combined with chemotherapy (p = 0.42). The degree of weight loss before initiation of therapy had a significant effect on survival regardless of the treatment arm. Radiotherapy in combination with chemotherapy, as administered in this study for South African patients with locally advanced, inoperable squamous cancer of the esophagus, is no better than radiotherapy alone.

13-Cis-retinoic acid and interferon alpha-2a in patients with advanced esophageal cancer: a phase II trial.

The aim of this study was to investigate the possible therapeutic effect of 13-cis-retinoic acid plus interferon alpha-2a in patients with inoperable squamous cancer of the esophagus. Patients with advanced, measurable, histologically confirmed squamous carcinoma of the esophagus with an Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1 or 2 who had adequate bone marrow, liver, and renal function were eligible for study. Patients were given cis-retinoic acid 1 mg/kg/day per mouth continuously and interferon alpha-2a 3 Mu/day for 3 days followed by 6 Mu subcutaneously daily thereafter. Seventeen patients were entered on study. Fifteen patients were evaluable for toxicity. The most common toxicities were grade 1 and 2 cheilitis, dry skin and flu-like symptoms which occurred in all patients. Two patients had grade 3 toxicity (1 anorexia and 1 fatigue). No grade 4 toxicity occurred. Fifteen patients were evaluable for response. No objective response was documented. The median survival time was 15 weeks. With no response seen it is unlikely that the combination of treatment as used in this study will be of benefit in patients with advanced squamous cancer of the esophagus.

Whither primary health care research?

PIP: In a report of the House of Lords Select Committee on Science and Technology entitled Civil Research and Development the reasons for a government to become involved in research include: a) to stimulate the progress of science; b) to support policy formulation and implementation; c) to improve technology; d) to support decisions for the procurement of services and goods; e) to support certain statutory functions of the state; and f) to support other activities. The distribution of the research effort is highly skewed: 93% of years of useful life lost because of disease are in developing countries that receive only 5% of the world's health research funding. Sound policy and management decisions need essential national health research. Country-specific research that can inform decision makers is often neglected. Research is especially necessary in epidemiology and social sciences applied to health. Prerequisites for the success of health services research and development are: a) acceptance by the scientific community; b) acceptance by policy makers and politicians. High quality research that is useful to policy makers requires access to good information and reliable data. The rapid pace of change of the contemporary health care system means that the most relevant information is available in settings such as medical aid societies and government departments rather than in published works. Researchers in South Africa must use these data bases. The World Health Organization is developing advisory committees on health research on a global and regional level; these committees must collaborate with universities, training institutions, research institutes, and development agencies. Since funds are available for research on primary health care (PHC), prioritization of projects for funding is needed along with discussions and proposals to stimulate PHC research in South Africa in view of PHC as a priority.^ieng

The effect of seminal plasma on gonadotrophin secretion by sheep pituitary cells in culture.

We tested the effect of seminal plasma fractions of pooled normozoospermic and azoospermic seminal plasma on secretion of LH by sheep pituitary cells in culture. From these experiments we conclude that there is activity in seminal plasma (molecular mass 10.000-80.000) which inhibits LH secretion. This activity is not steroid-mediated and is absent in azoospermic seminal plasma. These data support our thesis that LH secretion is not only controlled by testosterone but also by spermatogenesis per se.

Second pregnancies among immunologically infertile women: a preliminary report.

Two females with sperm antibody activity in their blood serum and cervical mucus were treated with high dosages of methylprednisolone. Both patients became pregnant during therapy. Following the birth of their first offspring, one was treated with steroids and the other conceived without steroids in order to establish their second pregnancies. The sperm antibody activity showed a sharp decline in the blood serum and cervical mucus during therapy. The response of the females showed drastic modification in the antibody activity in that the females revealed a complete disappearance or a significant decrease in their initial sperm antibody reactions after treatment with high dosages of steroids.