Search

Thrombocytopenia, an abnormal reduction of platelets (clotting agents) in the blood, is a complication of HIV (human immunodeficiency virus) infection reported to affect between 3 and 9 percent of patients. It has been noted that occasionally patients who receive zidovudine show an improvement in their thrombocytopenia. A study was undertaken in Canada in which 74 volunteers, male homosexuals infected with HIV, were treated with increasing doses of zidovudine. They were first observed for three weeks and then were given 600 mg of zidovudine daily for 18 weeks, followed by 900 mg for nine weeks, and then 1,200 mg for another nine weeks. The drug was discontinued for a period of six weeks and then was restarted at 1,200 mg/day for 18 weeks. The patients were evaluated for blood platelet counts every three weeks. Patients were classified as thrombocytopenic (12 patients) or normal (57 patients), depending upon the level of their initial platelet count. The results indicated that zidovudine increased the platelet count in all patients regardless of their initial platelet count. In the normal group, this increase was small and transient; however, in the thrombocytopenic group the increase in platelet count was greater and longer lasting. The effect was not related to dose, within the dose range studied. Based upon the results of this study, patients with thrombocytopenia associated with HIV infection may benefit from treatment with zidovudine, and HIV-associated thrombocytopenia can be viewed as a relative indication for starting zidovudine treatment. (Consumer Summary produced by Reliance Medical Information, Inc.)

Weight gain is a commonly reported side effect of adjuvant chemotherapy. A change in resting energy expenditure during treatment has been a suggested mechanism for weight gain. We prospectively measured resting energy expenditure, weight change, and body composition (dual-energy x-ray absorptiometry) in 10 women undergoing adjuvant chemotherapy for breast cancer. There was no change in resting energy expenditure across cycles of chemotherapy (P=.78) or from baseline to the end of treatment (1,189.68 ± 80.27 vs 1,205.76 ± 56.71 kcal/d; P=.74). Overall, participants did not gain weight across treatment. However, there was an overall trend toward weight gain (66.3 ± 5.1 vs 68.2 ± 5.0 kg; P=.09), and participants did show an increase in total fat mass (24.2 ± 3.8 vs 26.5 ± 3.2 kg; P=.04), whereas muscle mass remained the same. Although no change in resting energy expenditure was seen, the observed increase in total fat mass is consistent with a decrease in physical activity level commonly reported with adjuvant chemotherapy treatment of breast cancer, and these body composition changes may have important health implications for survivors.

Combination chemotherapy has been at the forefront of cancer treatment for over 40 years. However, the rationale for selecting drug combinations and the process used to demonstrate clinical effectiveness has primarily followed trial and error methodology. Typically, the selection and assessment of combined drug therapies has been based on the effectiveness of each agent as monotherapy in treating the neoplasm and avoiding overlapping toxicities, followed by clinical trials to establish dose scheduling, toxicity, and efficacy. Unfortunately, this scheme is inefficient in terms of the time required to complete and revise these clinical trials based on the outcome to optimize the drug combination. A more rational approach for the development of combination oncology products should consider (i) in vitro assays for assessing therapeutic effects of drug combinations (antagonistic, additive or synergistic interactions) when added simultaneously; (ii) methods for measuring these interactions in vivo; (iii) the importance of understanding pharmacokinetic and biodistribution parameters when using drug combinations; (iv) the need to assess pathways known to contribute to cancer cell survival as well as metastasis; and (iv) the need to assess the fate of different cell populations (cancer and stroma) contributing to the development of cancer. Therefore, the goal of this article is to provide a road map for the preclinical development of drug combination products that will have improved therapeutic activity and a high likelihood of providing beneficial therapeutic outcomes in patients with aggressive cancers with a specific focus on patients with breast cancer.

Purpose:To define the maximum tolerated dose (MTD), recommended phase II dose (RD) and dose limiting toxicity (DLT) of liposomal lurtotecan, OSI-211 (formerly known as NX211), given as a short intravenous infusion on days 1, 2, and 3 every three weeks. Experimental design:Thirty-seven patients were enrolled and treated in a dose escalation study from a starting dose of 0.15 mg/m2daily × 3 to 2.1 mg/m2daily × 3. Detailed pharmacokinetic analyses of blood were done on both days 1 and 3 of the first cycle and toxicity was monitored. Results:Two MTDs were defined; one for patients defined as minimally pretreated and one for those heavily pretreated. Dose limiting toxicity was myelosuppression: primarily thrombocytopenia although neutropenia was also noted. The MTD was 2.1 mg/m2/d (total dose of 6.3 mg/m2) in minimally pretreated patients and 1.8 mg/m2/d (5.4 mg/m2total dose) in heavily pretreated patients. Pharmacokinetics revealed that AUC and Cmaxincreased with dose and were significantly higher than that of free lurtotecan (AUC approx. 100 fold higher). The half life and duration of the active lactone form were also significantly longer than historical data on free drug. Two partial responses were seen, one each in a patient with breast and ovarian cancer. Conclusions:Two Phase II recommended doses were established for OSI-211 given as a daily × 3 schedule every three weeks. The recommended phase II dose is 1.8 mg/m2daily × 3 for minimally pretreated patients and 1.5 mg/m2for those heavily pretreated. Phase II studies should be initiated in sensitive tumours.

Five hundred and twenty-one patients with ABC were randomized to receive PTX over 3-hr or 24-hr q 3 wks at an initial dose of 175mg/m2(with escalation when possible). The pre-randomization strata were defined according to prior chemotherapy (CT): none, adjuvant CT only, CT for ABC. Two-thirds of the patients had prior anthracycline exposure; 24% of these were anthracycline resistant, i.e. progressing on or relapsing within 6 months of an anthracycline regimen.The response rate was 29% in the 3-hr vs 32% in the 24-hr (P=0.629). It was 28% in both arms among anthracycline pretreated patients. Among all patients, treatment over 24-hr resulted in a longer time to progression (TTP) (median 3.8 mos vs 4.6 mos: P=0.021) and survival time (median 9.8 mosvs 13.4 mos; P=0.021). This difference was not apparent after adjustment for prognostic factors, TTP: P=0.081, survival: P=0.099. Treatment was well tolerated as documented by the # of crs administered (median 6 (1–22+) vs 7 (1–21); P<0.01). More patients in the 3-hr arm had their PTX dose escalated (65% in the 3-hr vs 33% in the 24-hr. P<0.001), resulting in an increased dose intensity (62 vs 57mg/m2/wk; P<0.001). The 2 treatment schedules were not equitoxic even after individual dose adjustments. The 24-hr infusion resulted in more severe hematologic (30% vs 79% grade IV neutropenia, P<0.001; 1% vs 17% febrile neutropenia, P<0.001), and GI toxicity (22% vs 45% mucositis, P<0.001; 25% vs 41% diarrhea, P<0.001). The 3-hr infusion with its higher dose intensity resulted in a higher incidence of peripheral neuropathy (78% vs 65%, P=0.001). To evaluate the risk-benefit ratio associated with therapy, we retrospectively analyze the time to either progression or to clinically important adverse events (febrile neutropenia, severe hypersensitivity reaction, and severe neuropathy), and found no statistically significant difference between the two arms (median 3.3 mos vs 3.4 mos; P=0.243). In the palliative setting, the 24-hr infusion of PTX had some efficacy advantage, but did not result in a significant increase in patient benefit as compared to the 3-hr infusion. This trial confirms the activity of PTX in the treatment of ABC pts, including anthracycline pretreated patients.

This study proposes to evaluate Docetaxel's activity in pts with advanced and/or metastatic NSCLC. Pts eligibility included no prior therapy measurable disease, Karnofsky performance status≥60, adequate bone marrow, hepatic, and renal function and a signed informed consent. Treatment (Rx) consisted of Docetaxel 100mg/m2given by IV infusion over one hour every three weeks with Dexamethasone 8 mg PO BID×5 days starting the day prior to Rx and Diphenhydramine 50mg IV 30 min. prior to Rx to prevent hypersensitivity reactions. Of the 45 pts entered, 38 have been completed Rx. All are eligible and 32 were evaluable. Of the 6 non evaluable pts, 3 had serious adverse effects, 2 an increase in symptoms and one never got treated. A total of 146 Rx were given. Toxic events included mild to severe hypersensitivity reaction and febrile and non febrile neutropenia. Two deaths were related to febrile neutropenia. One complete and 8 Partial responses were observed in 32 pts (28%). In conclusion, these preliminary results indicate that Docetaxel will probably be an active agent in the treatment of NSCLC.Supported by a grant from Rhone-Poulenc Rorer.