Concomitant versus sequential administration of epirubicin and paclitaxel as first-line therapy in metastatic breast carcinoma: results for the Gruppo Oncologico Nord Ovest randomized trial.

BACKGROUND: The authors performed a randomized trial comprising patients with metastatic breast carcinoma (MBC). They used a noninferiority design to evaluate whether the results of sequential administration of epirubicin and paclitaxel were not markedly worse than the concomitant administration in terms of objective response rates (ORRs). Toxicity profile, quality of life (QOL), and pharmacoeconomic evaluations were evaluated as well. METHODS: In the current study, 202 patients with MBC were randomized to receive either the combination of epirubicin at a dose of 90 mg/m2 plus paclitaxel at a dose of 200 mg/m2 for 8 cycles (concomitant arm, n = 108) or epirubicin at a dose of 120 mg/m2 for 4 cycles followed by paclitaxel at a dose of 250 mg/m2 over 3 hours for 4 cycles every 21 days (sequential arm, n = 94). RESULTS: The authors rejected the null hypothesis that the sequential treatment is less active than the standard concomitant regimen (ORRs: concomitant = 58.5%, sequential = 57.6%). The median progression-free and overall survival periods were 11.0 months (95% confidence interval [95% CI], 9.7-12.3) and 20.0 months (95% CI, 17.2-22.6), respectively, in the concomitant arm and 10.8 months (95% CI, 7.9-13.6) and 26 months (95% CI, 18.1-33.8), respectively, in the sequential arm (P = not significant). Patients who received the sequential regimen experienced a higher incidence of Grade 3/4 (according to the World Health Organization grading system) neutropenia (62.2% of courses vs. 50.62%; P = 0.003) and Grade > or = 2 neuropathy (45.5% vs. 30.4% of patients; P = 0.03), whereas 6 patients who received the concomitant regimen developed Grade II cardiotoxicity according to New York Heart Association criteria. QOL analyses failed to provide clear differences. CONCLUSIONS: The sequential administration of epirubicin and paclitaxel at full doses was found to be as active as their association. Therefore, both the sequential and the combined administration were acceptable options.

Nestin, a neuroectodermal stem cell marker molecule, is expressed in Leydig cells of the human testis and in some specific cell types from human testicular tumours.

The intermediate filament protein nestin is predominantly expressed in some stem/progenitor cells and appears to be a useful molecular tool to characterise tumours originating from precursor cells of neuroectodermal and mesenchymal lineages. Leydig cells originate in the adult testis by differentiation from stem cells and express a variety of neural and neuroendocrine markers. The possible expression of the neural stem cell marker nestin in Leydig cells and testicular tumour cells was determined by analysing the patterns of nestin expression in normal and pathological human testes by Western blot and immunohistochemical methods. In normal testis, nestin was found in some vascular endothelial cells, a subset of peritubular spindle-shaped cells and some Leydig cells; spermatogenic and Sertoli cells were unstained. In normal Leydig cells, nestin was distributed in the perinuclear cytoplasm and accumulated in the crystalloids of Reinke with ageing. In non-tumour pathologies (cryptorchidism, impaired spermatogenesis), the seminiferous tubules were immunonegative, whereas hyperplastic Leydig cells showed cytoplasmic immunolabelling. In testicular malignancies, nestin was localised in the Sertoli cells of the seminiferous tubules affected with intratubular germ cell neoplasia, in the hyperplastic Leydig cells associated with these tumours and in some components (mesenchymal and neuroepithelial cells) of teratomas; spermatocytic and non-spermatocytic seminomas were unstained. Some vascular endothelial cells were immunolabelled in all tumour samples. Thus, nestin is expressed in a population of normal and hyperplastic Leydig cells and in Sertoli cells in the presence of intratubular germ-cell neoplasia. Nestin may be a good marker for identifying components of testicular teratomas.

Ifosfamide and vinorelbine in advanced platinum-resistant ovarian cancer: excessive toxicity with a potentially active regimen.

OBJECTIVES: The aim of this study was to determine the activity and toxicity of a vinorelbine and ifosfamide combination in platinum-resistant advanced ovarian cancer. PATIENTS AND METHODS: Patients were treated with ifosfamide (2 g/m(2)/day) infused over 1 h x 3 days (with mesna uroprotection) and vinorelbine (30 mg/m(2)) on days 1 and 8. Treatment was repeated on a 21-day schedule. In order to avoid unacceptable toxicity in this subset of patients where the chemotherapy is mainly palliative, the Bryant and Day two-stage phase II trial design incorporating toxicity considerations was chosen. A cutoff point for the response rate (10%) and for severe toxicity (25%) was established for the first 14 patients. RESULTS: Between February 1997 and December 1998, 11 paclitaxel and platinum-resistant patients and 1 potentially platinum-sensitive patient were treated. Five patients (41%) experienced grade 3-4 central nervous toxicity requiring hospital admission. In accordance with the Bryant and Day design, the study was stopped early because greater than 25% of the first 14 patients developed grade 3-4 neurotoxicity. A retrospective review of clinical characteristics of these patients showed at least one well-known risk factor associated with ifosfamide central toxicity. Hematological toxicity was common, mainly grade 4 neutropenia, which was observed in all but 1 patient, usually of short duration, and there were 4 episodes of neutropenic fever. Ten patients were evaluated for response. Two complete responses and 1 partial response according to CA-125 criteria were observed. CONCLUSION: This combination may be active in platinum-resistant ovarian cancer but the high toxicity encountered, principally neurotoxicity in those with large central pelvic masses, means that further studies with this schedule may not be warranted.

Cost-minimisation analysis of three regimens of chemotherapy (docetaxel-cisplatin, paclitaxel-cisplatin, paclitaxel-carboplatin) for advanced non-small-cell lung cancer.

PURPOSE: To compare the efficiency (the evaluation of efficacy in relation to costs) of three first-line treatment options for advanced non-small cell lung cancer (stage IIIB and IV) used in the Eastern Cooperative Oncology Group (ECOG) study: docetaxel/cisplatin (75/75 mg/m(2)/day, 1 h intravenous (i.v.) infusion of docetaxel), paclitaxel/cisplatin (175/75 mg/m(2)/day, 3 or 24 h i.v. infusion of paclitaxel) and paclitaxel/carboplatin (175/400 or 225/400 mg/m(2)/day, 3 h i.v. infusion of paclitaxel). METHODS: The results of the ECOG 1594 phase III clinical trial (Proc. Am. Soc. Clin. Oncol. 19 (2000) 2) demonstrated equivalent efficacy (survival, objective response) between the treatment options. To differentiate between the treatment options, we performed a cost-minimisation analysis, using a pharmacoeconomic model. RESULTS: The average estimated treatment cost per patient (median, 4 cycles) with docetaxel/cisplatin would be 1067836 Spanish pesetas (Ptas) (6418 Euros; 5741 US dollars (USD)), 1365304 or 1439369 Ptas (8205 or 8651 Euros; 7340 or 7738 USD) with paclitaxel/cisplatin (3 or 24 h infusions, respectively), and 1417995 or 1616784 Ptas (8522 or 9717 Euros; 7623 or 8692 USD) (paclitaxel dose of 175 or 225 mg/m(2)/day, respectively) with paclitaxel/carboplatin. CONCLUSION: According to our study, the treatment option docetaxel/cisplatin, with equal efficacy, would result in a cost saving of between 297468 and 548948 Ptas (1788 and 3299 Euros; 1599 and 2951 USD) per patient treated. This difference is mainly due to the lower treatment cost of docetaxel.