Phase I trial of ixabepilone plus pegylated liposomal doxorubicin in patients with adenocarcinoma of breast or ovary.

BACKGROUND: Ixabepilone is a semisynthetic epothilone B analogue that is active in taxane-resistant cell lines and has shown activity in patients with refractory breast and ovarian cancer. We carried out a phase I trial of ixabepilone plus pegylated liposomal doxorubicin (PLD) in patients with advanced taxane-pretreated ovarian and breast cancer. METHODS: Patients with recurrent ovarian or breast carcinoma received PLD every 3 or 4 weeks plus five different dose schemas of ixabepilone in cohorts of three to six patients. RESULTS: Thirty patients received a total of 142 treatment cycles of the PLD-ixabepilone combination. The recommended phase II dose and schedule of ixabepilone was 16 mg/m(2) on days 1, 8, and 15 plus PLD 30 mg/m(2) given on day 1, repeated every 4 weeks. Hand-foot syndrome and mucositis were dose limiting when both ixabepilone and PLD were given every 3 or 4 weeks. Objective responses were observed in 3 of 13 patients (23%) with breast cancer and 5 of 17 patients (29%) with ovarian cancer. CONCLUSION: Ixabepilone may be safely combined with PLD, but tolerability is highly dependent upon the scheduling of both agents. This combination demonstrated efficacy in patients with breast and ovarian cancer and merits further evaluation in these settings.

A phase II trial of interferon alpha-2b with folinic acid and 5-fluorouracil administered by 4-hour infusion in metastatic colorectal carcinoma.

Preclinical data suggest that folinic acid as well as interferon alpha-2b may enhance the antitumor activity of 5-fluorouracil (5-FU). In a phase I trial, we recently showed that interferon alpha-2b (IFN), folinic acid and 5-FU can be safely administered with a 4-hour infusion of 5-FU. We therefore initiated a phase II trial evaluating the efficacy and safety of these three drugs. Forty-five evaluable patients with advanced metastatic colorectal cancer, documented progressive disease, and previously unexposed to chemotherapy were treated with sequential IFN 5 MU/d subcutaneously and folinic acid 200 mg/m2/d as bolus on days 1 to 7 followed by 5-FU in a 4-hour infusion at a dose of 500 mg/m2/d, resulting in a total dose of 3,500 mg/m2/course. This schedule was repeated on day 21. A total of 204 courses of therapy were completed. One of 45 patients (2%) achieved a complete response, and 13 of 45 patients (29%) achieved a partial response. An additional 16 patients (36%) had stable disease. The median time to disease progression was seven months (2 to 24 months). Despite the relatively high-dose intensity of 5-FU, toxicity was very mild. Grade 3 or 4 myelosuppression, stomatitis, and nausea/vomiting occurred in only three of 45 patients (7%). Four of 45 patients (9%) suffered from severe (grade 3/4) diarrhea. Neurotoxicity and infections of grade 2 to 4 did not occur. From these data we conclude that modulation of 5-FU with both folinic acid and IFN induces an overall response rate of 31% in disseminated colorectal cancer. Using a 4-hour application schedule of 5-FU, the therapeutic index can be improved even for high-dose intensity and requires further evaluation in combination with other modulators.

[A comparison of systemic radiotherapy, chemotherapy or local radiotherapy in the treatment of extensive small-cell bronchial carcinoma. Results of a randomized series]. / Vergleich zwischen systemischer Strahlentherapie, Chemotherapie oder lokaler Strahlentherapie bei der Behandlung des ausgedehnten kleinzelligen Bronchialkarzinoms. Ergebnisse einer randomisierten Serie.

Between 1982 and 1987 we carried out a prospective randomized study to compare the effectiveness of high-dose half-body irradiation (HBI) (A), intensive combined chemotherapy (B), and local or locoregional radiotherapy (C) in the therapy of extended small cell lung carcinoma (SCLC). 99 patients with a histologically proved SCLC were assigned to the three therapeutic groups of series: A = 31 patients, B = 37 patients, C = 31 patients. The median survival period showed a statistically significant advantage (p less than 0.01) for the chemotherapy group (B = 46 weeks) versus the two radiotherapy groups (A = 19 weeks, C = 23 weeks). The survival after half a year, one year, and two years also gave a clear advantage for the chemotherapy group. No difference was found between the radiotherapy groups A and C. The high-dose HBI gave no improvement of the sad therapeutic situation for the extended SCLC.

Phase II study of pirarubicin (THP-adriamycin) in metastatic breast cancer patients.

Fourteen patients with metastatic breast cancer previously treated with one chemotherapy regimen received Pirarubicin at a dose of 70 mg/m2 at 3-week intervals. In 7 patients the dose had to be reduced, in 1 patient to 40 mg/m2 and in 6 patients to 50-60 mg/m2. There were 1 complete and 2 partial remissions. These objective responses were observed in soft tissue, lung and pleural areas and lasted 1+; 4+ and 5+ months. Grade 3 and 4 leukopenia was found in 42%, grade 3 thrombocytopenia in 2%, grade 3 nausea/vomiting in 29% of the cycles. Grade 1 and 2 alopecia occurred in 64% of the patients, the remaining 36% of the patients did not suffer from any alopecia. No cardiotoxic side effects were observed in 13 patients. In 1 patient with severe coronary heart disease extrasystoles and reduction in left ventricular ejection fraction occurred. Pirarubicin has antitumor activity in previously treated metastatic breast cancer patients.

A randomized clinical trial comparing systemic radiotherapy versus chemotherapy versus local radiotherapy in small cell lung cancer.

Between 1982 and 1987 a prospectively randomized trial of sequential hemibody irradiation (SHBI) (A), a non-cross-resistant chemotherapy drug combination (B) and local and/or locoregional radiotherapy (C) in small cell lung cancer (SCLC) was conducted. Previously untreated patients with extensive SCLC were randomized into three arms: A = 31 patients, B = 37, C = 31. In the chemotherapy combination, the following were used: etoposide, doxorubicin, methotrexate (VAM) and procarbacine, vincristine, cyclophosphamide, lomustine (POCC) and prophylactic cranial irradiation (30 Gy). The results show that the median survival was significantly (P less than 0.01) better in chemotherapy (44 weeks) compared with 17 and 20 weeks in arms A and C, respectively. One year and 2 year survival rates were better for the chemotherapy arm. No differences were found between groups A and C. In comparing the total hospitalization time expressed as a percentage of overall survival, an advantage for group B was shown. In conclusion, high dose SHBI cannot be recommended as a standard therapy for extensive SCLC.

Neural and Pavlovian influences on immunity.

The traditional view that the nervous and immune systems are functionally independent (aside from general stress effects and autoimmune disorders of the nervous system) is being challenged by a new view that the nervous system regulates the activity of the immune system. If this is true, it should be possible to change the activity of the immune system by means of Pavlovian conditioning, just as it is possible to condition other physiological events influenced by the autonomic nervous system or neuroendocrine substances. Evidence for autonomic and neuroendocrine modulation of immune activity is briefly reviewed; and, the various studies reporting conditioned immune effects, the physiological mechanisms most likely involved, and their possible significance are discussed.

Effects of catecholamine agonist and antagonist drugs on acute stomach ulceration induced by medial hypothalamic lesions in rats.

In order to investigate the involvement of catecholamines (CAs) in acute stomach ulceration induced by hypothalamic lesions, rats were given bilateral electrolytic anodal lesions in the medial hypothalamus followed by a single subcutaneous injection of CA agonist or antagonist drugs. As in previous studies, lesioned rats that received no post operative drug treatment showed extensive gastric damage when examined 24 hr after the brain lesion. Chlorpromazine, amphetamine, desipramine and isoproterenol caused significant reductions in the extent (total length) and/or number of erosions induced by the brain lesion. Haloperidol and propranolol did not seem to affect ulcer formation. Clozapine increased the number but not the total length of ulcers. Phentolamine, alone or in combination with propranolol, significantly increased both the number and total length of lesion-induced ulcers. Similarities between these results and those reported for most of these drugs in the context of ulcers induced by various experimental stress procedures suggest a degree of commonality between acute stress ulcers and ulcers induced by hypothalamic lesions. The overall pattern of results obtained is also consistent with evidence indicating a protective role for catecholamines in acute ulcer formation.

Measurement of fecal C-14 excretion.

Simultaneous measurements of fecal C-14 and expired 14CO2 in the breath are necessary to evaluate patients with various ileal abnormalities and bile salt malabsorption. Following the oral ingestion of the labeled bile acid, glycine-[I-14C]cholic acid, detection of increased fecal C-14 without abnormal expiration of 14CO2 identifies patients with ileal resection. This contrasts with the normal fecal C-14 content and abnormal expired 14CO2 found in patients with bacterial overgrowth. Fecal C-14 content was determined by utilizing Van Slyke combustion of the specimen and trapping the liberated 14CO2 with Scintisorb C. The method is simple, rapid, and accurate, and expands the diagnostic usefulness of the bile salt absorption test.