Phase I dose escalation study of gemcitabine and paclitaxel plus colony-stimulating factors in previously treated patients with advanced breast and ovarian cancer.

Gemcitabine and paclitaxel (PTX) are among the most active new drugs in advanced breast and ovarian cancer. In this Phase I study, we used fixed doses of gemcitabine administered on days 1 and 8 and escalating doses of paclitaxel on day 1 of a 21-day cycle in patients with pretreated metastatic breast or ovarian cancer. The dose of gemcitabine was fixed at 1,000 mg/m2; PTX was commenced in the first small patient group at a dose of 90 mg/m2, which was then escalated in subsequent groups by 30 mg/m2 per step. From the third dose level onwards, all patients received granulocyte colony-stimulating factor 300 microg by subcutaneous injection on days 5 and 6, and granulocyte macrophage colony-stimulating factor on days 15-18. Cohorts of at least 3 patients were treated at each dose level. Dose escalation was stopped if at least a third of the patients in a given cohort had dose-limiting toxicity (DLT), which was defined as grade 4 neutropenia or thrombocytopenia, or grade 3-4 non-haematological toxicity. The maximum tolerated dose (MTD) was defined as the dose level immediately below that causing DLT in one-third of the patients or more. Evaluation of the tumour response was performed every three cycles. Forty-five patients (31 with breast cancer, 14 with ovarian cancer) were treated at seven different dose levels. Only at the seventh PTX dose level was DLT observed after the first course of therapy: three grade 4 neutropenia, one grade 4 thrombocytopenia, and one grade 4 anaemia. DLT occurred in 5/6 patients at at PTX dose of 270 mg/m2; therefore dose escalation was stopped at that level and the dose immediately before it (PTX 240 mg/m2) was considered as the MTD and recommended for further studies. No toxic deaths occurred. Grade 3-4 uncomplicated neutropenia was observed in four patients. Three had uncomplicated grade 3-4 thrombocytopenia. One patient had grade 3 and one grade 4 anaemia. Nonhaematological side effects were generally mild. Among 30 evaluable patients with metastatic breast cancer, four complete responses (CR) (13%) and 12 partial responses (PR) (40%) were observed, for an overall response rate of 53% (95% confidence interval (CI) 34-72). The median duration of response was 31 weeks. Among 13 evaluable patients with advanced ovarian cancer, one CR (8%) and five PRs (38%) were observed, for an overall response rate of 46% (95% CI 19-78). The median duration of response was 32 weeks. Our study shows that gemcitabine and PTX can be administered in combination in patients with breast and ovarian cancer without unexpected toxicities and with encouraging therapeutic results.

Accelerated split-course (type B) thoracic radiation therapy plus vinorelbine/carboplatin combination chemotherapy in stage III inoperable non-small cell lung cancer.

43 patients with stage III NSCLC (non-small cell lung cancer) entered a phase II study aimed at evaluating the toxicity and the activity of a combined modality programme including an accelerated split-course schedule (type B) of thoracic radiation therapy and a combination chemotherapy with vinorelbine and carboplatin. An objective response was achieved in 18/42 evaluable patients (5 complete and 13 partial responses), for an overall response rate of 43% (95% confidence interval, 28-58%). Four complete responses had a duration which exceeded 16 months. Treatment was well tolerated; grade III myelotoxicity occurred in only 14% of patients and treatment was delayed in only 2 cases because of grade 3 oesophagitis. Both tolerability and efficacy data suggest that this regimen holds promise for the treatment of patients with stage III NSCLC.

[Treatment of secondary adolescent amenorrhea with purified FSH]. / Terapia dell'amenorrea secondaria adolescenziale con FSH purificato.

The dysfunctional features of adolescent secondary amenorrhea are here considered: anovulation, immaturity of estrogenic feed back, multi-follicular ovary. We described the opportunity of using gonadotrophin in the treatment of hypogonadotrophic amenorrhea. Among 64 patients with menstrual delay, we examined a group of 23 selected girls, 21 of them affected by secondary amenorrhea and 2 affected by primary amenorrhea; their average age is 17 years. The selection excludes organic and psychiatric pathologies, while includes anovulation, low rates of FSH and inadequate response to LHRH test, multi-follicular ovary. Some patients were also affected by acne, hypertrichosis, weight disorders, emotional stress. The therapeutic approach with purified FSH (urofollitrophin) is described on an amount of 48 treatments. We used 75/225 UI/day at 3 degrees to 5 degrees/7 degrees of each menstrual cycle, and for 3/5 cycles. Doses are in some subjects modified during the treatment in relation to menstrual response. Hormonal, echographic and clinical evaluation were given before and after each treatment. The results of giving FSH demonstrate an 81.2% of immediate success, while an 43.7% up to 12 months. We observed a significant reduction of LH rates as well as estrogenic increase and subsequent menstrual response. Ovarian follicles increased in number and volume, while no hyperstimulation effects appeared. In general we suppose these data are satisfactory; nevertheless we point out the opportunity of only treat selected patients, even in considering the complaint due to this therapeutic engagement and the eventual consequent renouncing.