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Background: Cisplatin-based chemotherapy is a standard treatment of metastatic urothelial carcinoma (UC), though carboplatin-based chemotherapy is frequently substituted due to improved tolerability. Because comparative effectiveness in clinical outcomes of cisplatin- versus carboplatin-based chemotherapy is lacking, a meta-analysis was carried out., Methods: PubMed was searched for articles published from 1966 to 2010. Eligible studies included prospective randomized trials evaluating cisplatin- versus carboplatin-based regimens in patients with metastatic UC. Individual patient data were not available and survival data were inconsistently reported. Therefore, the analysis focused on overall response (OR) and complete response (CR) rates. The Mantel-Haenszel method was used for combining trials and calculating pooled risk ratios (RRs)., Results: A total of 286 patients with metastatic UC from four randomized trials were included. Cisplatin-based chemotherapy was associated with a significantly higher likelihood of achieving a CR [RR = 3.54; 95% confidence interval (CI) 1.48-8.49; P = 0.005] and OR (RR = 1.34; 95% CI 1.04-1.71; P = 0.02). Survival end points could not be adequately assessed due to inconsistent reporting among trials., Conclusions: Cisplatin-based, as compared with carboplatin-based, chemotherapy significantly increases the likelihood of both OR and CR in patients with metastatic UC. The impact of improved response proportions on survival end points could not be assessed.

Purpose: To compare long-term survival in patients with locally advanced and metastatic transitional cell carcinoma (TCC) of the urothelium treated with gemcitabine plus cisplatin (GC) or methotrexate/vinblastine/doxorubicin/cisplatin (MVAC)., Patients and Methods: Efficacy data from a large randomized phase III study of GC versus MVAC were updated. Time-to-event analyses were performed on the observed distributions of overall survival time and progression-free survival., Results: Four hundred and five patients were randomized, 203 to the GC arm and 202 to the MVAC arm. At the time of this analysis, 347 patients have died (GC 176, MVAC 171). Overall survival was similar in both arms (HR 1.09; 95% confidence interval [CI] 0.88-1.34, P = 0.66) with a median survival of 14.0 months (95% CI 12.3-15.5 months) in the GC, and 15.2 months (95% CI 13.2-17.3 months) in the MVAC arm. The median progression-free survival was 7.7 months with GC (95% CI 6.8-8.8) and 8.3 months with MVAC (95% CI 7.3-9.7) with a HR of 1.09 (95% CI 0.89-1.34). Significant prognostic factors favoring overall survival included performance status (>70), TNM staging (M0 vs. M1), low/normal alkaline phosphatase expression, number of sites of disease <3, and the absence of visceral metastasis. By adjusting for these prognostic factors, the HR was 0.99 for overall survival and 1.01 for progression-free survival., Conclusions: Long-term overall and progression-free survival following treatment with GC or MVAC are similar. These results strengthen the role of GC as a standard of care in patients with locally advanced and metastatic transitional-cell carcinoma (TCC).

Background: Low-dose spiral computed tomography (sCT) showed a four-fold increase in the detection rate in high-risk subjects and a higher percentage of stage I lung cancer in comparison with chest X-ray. However, there is a considerable discrepancy among studies in the percentage of lung nodules, overall lung cancer and stage I detection rate., Subjects and Methods: From April to December 2001, 520 asymptomatic volunteers aged >or=55 years with a history of cigarette smoking >or=20 pack-years and no previous cancer were enrolled to receive an annual sCT of the chest for five consecutive years., Results: Seventy three per cent were male, median age was 59 years and 91% were current smokers. At baseline, nodules >or=5 mm were detected in 114 (22%) undergoing sCT; the size of lung nodules ranged from 5 to 9.9 mm in 81.5% of the cases. Five (1%) cases of lung cancer were detected. In two additional cases a pathological diagnosis of atypical adenomatous hyperplasia was made. Three new cases of lung cancer were detected in the second and third year of the study. One interval case was detected during the third year., Conclusions: Despite some promising data, convincing evidence from ongoing randomized trials is needed to support the routine use of sCT as a recommended tool for screening of lung cancer.

Background: To determine whether the addition of leucovorin to the combination 5-fluorouracil plus levamisole prolongs disease-free survival and overall survival in patients with radically resected colon cancer (Dukes' B(2-3) and C)., Patients and Methods: Patients (1703) were accrued between March 1992 and February 1995 in a large-scale clinical trial within five Italian cooperative groups. After stratification for center, patients were randomized as follows: arm A, 5-fluorouracil [450 mg/m(2) intravenous (i.v.) bolus on days 1-5] and levamisole (150 mg orally for 3 days, every 14 days for 6 months) versus arm B, 6-S-leucovorin (100 mg/m(2) i.v. bolus on days 1-5) followed by 5-fluorouracil (370 mg/m(2) i.v. bolus on days 1-5), plus levamisole (as arm A), every 4 weeks for six cycles., Results: After a median follow-up of 6.4 years no significant difference was seen for either disease-free survival (58% versus 60%, not significant) or 5-year overall survival (68% versus 71%, not significant), respectively. Gastrointestinal toxicity (World Health Organization grade 3/4) was more frequent in arm B (8% versus 18%, not significant)., Conclusions: In this trial the schedules used showed no statistically significant differences in terms of disease-free survival or overall survival in the treatment of colorectal cancer.

Background: Chromogranin A (CgA) is a secretory protein present in dense-core vesicles of neuroendocrine (NE) cells. Its ubiquitous presence in NE tissues makes it a suitable circulating marker of neoplasms of NE origin., Patients and Methods: Plasma CgA was determined in 178 patients with NE tumors and in 36 patients with non-endocrine malignancies. Circulating CgA was also serially evaluated in 39 NE cancer patients with advanced disease submitted to systemic therapy and in 14 patients with no evidence of disease (NED)., Results: Supranormal CgA values were found in 81% of patients with advanced NE tumors and in only 91% of NED cases. Plasma CgA in patients with well differentiated NE tumors, such as carcinoids, carcinoma of gastrointestinal tract, pheocromocytoma, pancreatic NE carcinoma (either functioning or not functioning), medullary thyroid carcinoma and NE tumors from various primary sites, was higher and more frequently elevated than in patients with small-cell lung cancer (P < 0.001). Plasma CgA did not discriminate patients with NE from those with non NE neoplasms since it was found elevated in 44% of the latter cases. Plasma CgA pattern correlated with the disease response in patients submitted to cytotoxic treatment and with changes in clinical symptomathology in patients receiving somatostatin analogs., Conclusions: Our data confirm that CgA is the best circulating neuroendocrine marker available up to now available for the management of differentiated neuroendocrine malignancies irrespective of tumor location and functional status. CgA plasma levels could also identify the coexistence of neuroendocrine differentiation in the context of non-endocrine malignancies. Circulating CgA seems to be less useful in undifferentiated tumors such as small-cell lung cancer.

Purpose: The biological behaviour of prostate cancer is highly variable and prediction by the commonly employed prognostic parameters is not sufficient. The concept of neuroendocrine (NE) differentiation in prostate adenocarcinoma has recently received increasing attention due to possible implications for prognosis and therapy., Materials and Methods: Core needle biopsies from 142 newly diagnosed patients were immunohistochemically examined for the coexistence of NE differentiation using an antibody against chromogranin A (CgA). Circulating CgA was available in 106 of these patients., Results: NE differentiation was found in 64 (45.1%) tumors. Among them 29 (20.4%) had CgA positive cells scattered or focally distributed in less than 5% per mm3 of tumor tissues, 26 (18.3%) between 5% and 10% and 9 (6.4%) more than 10%, respectively. There was a significant correlation between the extent of NE features and either Gleason score (P < 0.01) or stage of disease. Circulating CgA but not PSA correlated with immunohistochemical CgA (P < 0.03) particularly in metastatic cases., Conclusions: These data support the concept that NE differentiation in human prostate cancer has a negative prognostic significance. Circulating CgA levels reflect immunohistochemical findings.

Background: Neuroendocrine (NE) differentiation of prostate adenocarcinoma has received increasing attention in recent years as a result of possible implications for prognosis and therapy. The presence of NE tumor subpopulation can be gauged non invasively by measuring circulating levels of secretory products, primarily chromogranin A (CgA)., Methods: This article provides a review on published papers evaluating circulating CgA in prostate cancer patients., Results: Circulating CgA levels were found to be higher in prostate cancer patients than in patients with benign or pre-malignant prostatic diseases. In patients with malignancy, they correlated either to the stage of disease or to the condition of hormone refractoriness. CgA levels did not correlate with serum prostate specific antigen (PSA) and were supranormal in the majority of advanced patients with PSA within normality. In hormone refractory cases, elevated CgA was a significant predictor of poor prognosis, independently from serum PSA. CgA values were not substantially affected by either endocrine therapy or chemotherapy. They were found to increase during androgen deprivation in some cases and this trend preceded that of PSA. The administration of a somatostatin analog in hormone refractory cases was able to reduce plasma CgA values consistently., Conclusions: Present data suggest a potential role of circulating CgA in the management of prostate cancer patients. CgA determination may be useful diagnostically and prognostically and could offer complementary information with respect to PSA. Serial evaluation of circulating CgA could provide information on changes in the NE phenotype expression as a consequence of tumor progression and/or treatment administration.

Neuroendocrine tumors are rare, occurring in less than 1% of the population. They are divided clinically into functionally active or non-active tumors. Functionally active tumors produce a variety of substances (mainly peptides or serotonin) that are responsible for symptoms and sometimes can lead to the death of the patient independently from tumor proliferation. The most important compounds that can control symptoms in these patients are somatostatin analogs. Native somatostatin is not suitable for long-term clinical application due to its short half-life. Therefore, synthetic drugs were developed with improved pharmacokinetic characteristics. The best-characterized analog, octreotide, has been successfully applied to patients with functioning tumors. Octreotide can ameliorate symptoms in 30%-70% of the patients, mainly through a direct inhibitory effect on hormone production from the tumors. There is little or no effect on tumor growth during octreotide therapy; clinical responses were recorded in only 10%-30% of the patients. Recently, significant improvement in the management of the disease has been demonstrated with long-acting repeatable (LAR) octreotide. This new formulation requires only one monthly intramuscolar injection, and shows better acceptability and patient compliance to therapy. Data available to date show superimposable results of both standard octreotide and LAR octreotide in controlling symptoms, lowering hormone and tumor marker levels, and in reducing tumor growth. The availability of long-acting molecules have permitted the exploration of high-dose therapy in increasing tumor shrinkage and prolonging survival. Although there is a clear dose-response trend, the published data are not conclusive and further investigations are needed. The possible lack of cross-resistance between LAR octreotide and a different analog, Lanreotide, is a very stimulating finding and this might lead to the development of new therapeutical strategies in the management of neuroendocrine tumors.

Purpose: To determine the efficacy of gemcitabine and cisplatin combination therapy in patients with advanced and/or metastatic transitional cell urothelial carcinoma., Patients and Methods: Forty-two chemonaïve patients with Karnofsky performance status (KPS) > or = 70 were treated with cisplatin 35 mg/m2 followed by gemcitabine 1000 mg/m2 (30 min i.v. infusion) on days 1, 8, and 15 every twenty-eight days., Results: Thirty-eight patients were evaluable for efficacy. Half had visceral disease. There were seven complete (18%) and nine partial responses (24%), for a response rate of 42% (95% confidence interval (95% CI): 26%-59%). Responses were independently reviewed. Median response duration was 13.5 months (95% CI: 8.5-18.1 months), median time to progressive disease 7.2 months (95% CI: 4.0-9.1 months) and median survival 12.5 months (95% CI: 8.1-18.7 months); one-year survival was 52%. Laboratory toxicities included leucopenia (44% grade 3; 17% grade 4), neutropenia (25% grade 3; 33% grade 4) and thrombocytopenia (29% grade 3; 49% grade 4). Four patients had grade 4 symptomatic toxicity (three nausea and vomiting, one diarrhoea). There were no grade 4 infections and no toxic deaths., Conclusions: The combination of gemcitabine and cisplatin is active in patients with locally advanced and/or metastatic urothelial carcinoma. The weekly schedule of cisplatin is considered inappropriate.

Background: Experience with chemotherapeutic agents in the management of advanced medullary thyroid carcinoma (MTC) is limited and controversial. However, since MTC is a neuroendocrine neoplasm, we considered the possibility that cytotoxic drugs previously used in the treatment of these tumours could also have activity in MTC., Patients and Methods: Five patients (4 females and 1 male, aged 22-71 years) with locally advanced or metastatic MTC received 5 day intravenous courses of dacarbazine (DTIC) (250 mg/sqm) and 12 hour infusion 5-fluorouracil (450 mg/sqm), given every 4 weeks. Six cycles were administered to 4 patients and four to 1 patient., Results: Three partial responses lasting 9, 10+ and 8+ months were observed; one patient had stable disease and one progressive disease. Toxicity was acceptable with grade I thrombocytopenia and grade II leukopenia occurring in one patient, and grade II nausea and vomiting in four patients., Conclusions: In our experience, treatment of advanced thyroid carcinoma with DTIC and 5-FU appeared to have significant activity and was well tolerated.

Background: Locally advanced malignant thymomas are usually radically resectable in about 60% of stage III but hardly ever in stage IVA. Neoadjuvant chemotherapy followed by surgery could improve both resection rate and curability. Cisplatin containing regimens have repeatedly been found to be highly active in advanced disease, with overall response rates ranging from 80%-90%., Patients and Methods: 3 patients with stage III and 3 with stage IVA invasive thymomas, according to Masaoka staging, entered the study. Histology was: lymphoepithelial 4 cases, epithelial 2 cases. 4 cycles of the ADOC scheme--Adriamycin (40 mg/sqm), cisplatin (50 mg/sqm) on day 1, vincristine (0.6 mg/sqm) on day 2, and cyclophosphamide (700 mg/sqm) on day 3, every 21 days--were administered to 5 patients, while 1 patient received 5 cycles., Results: 5/6 patients (83.3%) attained partial responses and underwent radical surgery followed by two further ADOC cycles. The disease-free intervals were 5+, 6+, 15+, 16+, 26+ months. One patient showing stable disease at the end of the fifth cycle was referred to radiotherapy. Toxicity was tolerable: grade III (WHO) nausea/vomiting and leukopenia grade III occurred in 2 patients each., Conclusions: These results suggest that the ADOC scheme is active as a neoadjuvant approach in invasive thymoma stages III and IVA, rendering possible radical resectability in 83% of patients.