Carboplatin, doxorubicin and etoposide in the treatment of tumours of unknown primary site.

The aim of this study was to assess the activity and toxicity of a platinum-based treatment on a group of patients with unknown primary tumours (UPTs). Patients with a diagnosis of UPT underwent a standard diagnostic procedure. Treatment was started within 2 weeks from diagnosis and consisted of carboplatin 400 mg m(-2) day 1, doxorubicin 50 mg m(-2) day 1, etoposide 100 mg m(-2) days 1-3, every 21 days. Response was evaluated after three courses and treatment continued in case of objective response (OR) or symptom control. A total of 102 patients were eligible. The median age was 59 years, sex male/female 54/48, histology was mainly adenocarcinoma or poorly differentiated carcinoma. Nodes, bone, liver and lung were the most frequently involved sites. In all, 79 patients received at least three courses of treatment; 26 patients received six courses or more. Six complete responses and 21 partial responses were observed, for a total of 27 of 102 ORs or 26.5% (95% confidence interval 18.2-36.1%). The median survival was 9 months and median progression-free survival was 4 months. Toxicity was moderate to severe, with 57.8% of patients experiencing grade III-IV haematological toxicity, mainly leucopenia. The regimen employed has shown activity in tumours of unknown primary site, but was associated with significant toxicity. Such toxicity may be considered unjustified, given the large proportion of patients with tumours not likely to respond. Efforts should therefore be addressed to identify predictors of response to chemotherapy, thus limiting aggressive treatment to those patients who could benefit from it.

A pilot clinical trial of postoperative intensive weekly chemotherapy using cisplatin, epi-doxorubicin, 5-fluorouracil, 6S-leucovorin, glutathione and filgrastim in patients with resected gastric cancer.

AIMS AND BACKGROUND: The study was performed to assess the feasibility and activity of an intensive chemotherapeutic regimen as adjuvant treatment for patients with resected gastric cancer at high risk of recurrence (pT(2)N(1-2); pT(3-4)N(any) M0). PATIENTS AND METHODS: Starting 21 to 28 days after potentially curative surgery for primary gastric cancer, 25 patients received 8 weekly cycles of cisplatin 40 mg/m2, 5-fluorouracil 500 mg/m2, epidoxorubicin 35 mg/m2, 6S-stereoisomer of leucovorin at a dose of 250 mg/m2, and glutathione at a dose of 1.5 g/m2. From the day after to the day before each cycle of chemotherapy, filgrastim was administered by subcutaneous injection at a dose of 5 microg/kg. RESULTS: After a median follow-up of 33 months, 80% of the patients were alive and disease-free. Five patients had relapsed: three in the liver, one in the peritoneum and one in the lymph nodes. Toxicity was mild: five patients experienced WHO grade III toxicity (three leukopenia, two thrombocytopenia); no toxic deaths occurred. CONCLUSION: Intensive weekly chemotherapy is a feasible postoperative treatment option for patients with resected gastric cancer at high risk of relapse. These data, together with recent results in advanced disease, make this approach of interest for the development of new programs of adjuvant therapy in this setting.

Phase II study of paclitaxel in pretreated advanced gastric cancer.

Patients with advanced gastric cancer unresponsive or progressing after PELF chemotherapy (5-fluorouracil, leucovorin, cisplatin and epidoxorubicin) received paclitaxel at the dose of 225 mg/m2 every 3 weeks, over 3 h infusion. Thirty-six patients entered the study, and all of them were evaluable for response and toxicity. Toxicity was mild: apart from alopecia, grade 3 toxicities were leukopenia and thrombocytopenia in six patients, and grade 2 neurotoxicity in seven patients. Eight patients (22.2%, 95% CI: 9-35%) achieved an objective response, with a median duration of 5 months. Median survival time for all patients was 8 months. In 16 of 36 patients (44%), treatment determined a significant relief of symptoms. Out-patient paclitaxel given over 3 h may be effective as salvage treatment in patients with advanced gastric cancer refractory to first line chemotherapy.

The role of a thymus-pineal axis in an immune mechanism of aging.

The Immune Theory of Aging cannot explain the cause of immune decline. It is hypothesized that the pineal gland acting in utero and during neonatal life in altricial mammals serves as a component of the immune system. Evidence in support of the presence of a thymus-pineal axis is presented. It is postulated that the pineal gland carries a considerable burden of immunological defense during maturation of the thymus, and also acts in the programming of the immune system. By relating thymus and immune function to the pineal and its known role as a neuroendocrine transducer for the entrainment and control of biorhythms, a consilence is developed between the role of the immune system in senescence and the pineal function in biorhythmicity. The relationships developed thus permit an extension of the immune theory as regards causative mechanisms.

Tin and the thymus gland: a review.

Experimental studies over the last decade have suggested an association between thymus immune and homeostatic function and exogenous tin. It has been hypothesized that the thymus gland synthesizes and secretes one or more tin bearing factors that enhance immune defenses against malignancy and retard the gradual loss of immune capacity with senescence. This review conciliates data from several divergent areas of research in order to explore the rationale for the above concepts.

Tin in the thymus gland of dogs.

The thymus glands from four mixed breed dogs were analyzed to determine the water content, chloroform extractable fraction and residue. The thymi samples were assayed for tin and compared to the tin in the spleen and muscle tissue. The tin content in the thymus gland (29.4 ppm) was higher than the muscle (14.9 ppm) or spleen (12.8 ppm). The tin content in the lipid portion of the thymus was approximately four times greater than the non-chloroform extractable fraction (primarily protein).

Organotin implications in anticarcinogenesis. Background and thymus involvement.

A comprehensive study of the scientific literature regarding tin content in normal and pathogenic human tissue has disclosed that various organotin materials retard both the onset and growth of cancer in laboratory animals, and decreased tissue tin in humans may be associated with tumour development. Initial studies by the authors have shown that the thymus gland of the mouse possesses a relatively high concentration of tin and is also the major site of accumulation for 14C-labelled tri-n-butyltin fluoride (TBTF). When mammary cancer-prone mice with transplanted tumours were orally dosed continuously with this agent in their drinking water, the tumour growth rate was significantly reduced. Both mouse mammary tumours and human lung tumours show low tin content compared to normal body tissue.

Organotin implications in anticarcinogenesis. Effects of several organotins on tumour growth rate in mice.

Several cohorts of cancerous mice were continuously dosed with 2,2'-bipyridyl dibutyltin dichloride, 1,10-phenanthroline dibutyltin and histidine dibutyltin; presented at 1 ppm and 10 ppm in drinking water. Tumour growth rates were significantly reduced. Tributyltin fluoride (TBTF) applied dermally, using dimethyl sulfoxide (DMSO) as the carrier, over the tumour site was ineffective. Variation in thymus and spleen weight between controls and tin-exposed mice indicates a lymphatic involvement. Analysis of mouse tissue for total tin content showed high tin concentrations in the thymus and spleen.

Accumulation and excretion of [1-14C]bis(tri-n-butyltin) oxide in mice.

Laboratory COBS strain albino mice were administered [1-14C]bis(tri-n-butyltin) oxide in dilute aqueous solutions. Test solutions were prepared by using an elastomeric controlled-release formulations that emitted the agent at a constant rate. Tissue and excreta were periodically analyzed for 14C by standard liquid scintillation counting methods. Assuming that the label was not cleaved from the tin, 90--96% of the ingested agent was excreted, predominantly in the feces. Of the remainder, kidney levels were high, possibly indicating metabolism; tissue accumulation was diffuse, with liver, spleen, and fat predominating. Blood levels were low. Termination of organotin ingestion led to rapid clearance of storage sites.