piperidines and Carcinoma--Transitional-Cell

To assess the efficacy and tolerability of the dual epidermal growth factor receptor/vascular endothelial growth factor receptor inhibitor, vandetanib, in combination with carboplatin and gemcitabine in the first-line treatment of patients with advanced transitional cell carcinoma urothelial cancer (UC) who were unsuitable for cisplatin.. From 2011 to 2014, 82 patients were randomised from 16 hospitals across the UK into the TOUCAN double-blind, placebo-controlled randomised Phase II trial, receiving six 21-day cycles of intravenous carboplatin (target area under the concentration versus time curve 4.5, day 1) and gemcitabine (1000 mg/m. The 82 patients were randomised 1:1 to vandetanib (n = 40) or placebo (n = 42), and 25 patients (30%) completed six cycles of all allocated treatment. Toxicity Grade ≥3 was experienced in 80% (n = 32) and 76% (n = 32) of patients in the vandetanib and placebo arms, respectively. The median PFS was 6.8 and 8.8 months for the vandetanib and placebo arms, respectively (hazard ratio [HR] 1.07, 95% confidence interval [CI] 0.65-1.76; P = 0.71); the median OS was 10.8 vs 13.8 months (HR 1.41, 95% CI 0.79-2.52; P = 0.88); and radiological response rates were 50% and 55%.. There is no evidence that vandetanib improves clinical outcome in this setting. Our present data do not support its adoption as the regimen of choice for first-line treatment in patients with UC who were unfit for cisplatin.

Topics: Aged; Antineoplastic Combined Chemotherapy Protocols; Carboplatin; Carcinoma, Transitional Cell; Cisplatin; Deoxycytidine; Double-Blind Method; Drug Combinations; Female; Gemcitabine; Humans; Male; Neoplasm Staging; Piperidines; Quinazolines; Treatment Outcome

In this study, the feasibility and activity of combined chemotherapy of the farnesyl transferase inhibitor SCH66336 and gemcitabine was evaluated. This therapy was used as second-line treatment in patients with advanced urothelial tract cancer and the influence of SCH66336 exposure on the pharmacokinetics of gemcitabine was also determined. Patients who had received one previous chemotherapy regime for advanced urothelial cancer were treated with a combination of SCH66336 (150 mg in the morning and 100 mg in the evening) and Gemcitabine (1000 mg/m2 on day 1, 8 and 15 per 28-day cycle). Dosages of gemcitabine and its metabolite dFdU were performed on day one of cycle 1 before exposure to SCH66336 and day one of cycle 2. A total of 152 cycles were administered in 33 patients (median 3, range: 1-15). No patients had severe hematological toxicity, defined as Grade 4 thrombocytopenia or febrile neutropenia. Nine partial responses and one complete response were achieved in 31 assessable patients and corresponded to an overall response rate of 32.3% [95% CI:17%-51%]. There was no influence of exposure to SCH66336 on the level of gemcitabine or dFdU in 11 assessable patients. In conclusion, a combination of SCH66336 and gemcitabine is feasible in terms of toxicity and active as second-line treatment in patients with advanced urothelial tract cancer. SCH66336 had no effect on the pharmacokinetics of gemcitabine. Randomised trials should be undertaken to clarify the role of SCH66336 in combination with gemcitabine in cancer treatment.

Topics: Adult; Aged; Aged, 80 and over; Alkyl and Aryl Transferases; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Transitional Cell; Deoxycytidine; Disease Progression; Farnesyltranstransferase; Feasibility Studies; Female; Gemcitabine; Humans; Male; Middle Aged; Piperidines; Pyridines; Salvage Therapy; Survival Analysis; Urologic Neoplasms

Canine prostate cancer is classified into adenocarcinoma, transitional cell carcinoma with prostatic involvement, and mixed forms. Early metastatic spread leads to poor prognosis and limited treatment options. Masitinib is approved for the treatment of canine mast cell tumours and inhibits tyrosine kinase c-Kit, tyrosine-protein kinase Lyn (Lyn), and platelet-derived growth factor receptors alpha and beta (PDGFR-α, PDGFR-β), which are known to be expressed in canine prostate cancer. The aim of this study was to evaluate masitinib in an in vitro model consisting of cell lines from primary prostate adenocarcinoma, the associated lymph node metastasis of the same patient, and transitional cell carcinoma. To assess the suitability of the model system, the targets of masitinib were investigated by immunocytochemistry in the cell lines and by immunohistochemistry in the respective formalin-fixed, paraffin-embedded (FFPE) original neoplastic tissue. After exposure to masitinib, cell viability, cell count, apoptosis induction, and protein expression of c-Kit, Lyn, PDGFR-α, and PDGFR-β were assessed. To hedge the efficacy, two application protocols of masitinib (single application or 12-h double-dose regimen) were compared. Immunocytochemical and immunohistochemical analysis revealed increased Lyn, PDGFR-α, and PDGFR-β expression in cell lines and FFPE original neoplastic tissue compared to healthy prostate tissue. Masitinib exposure increased apoptosis, while the cell counts and cell viability decreased in a dose- and application interval-dependent manner, with increased impact in the 12-h double-dose regimen. These in vitro effects of masitinib in canine prostate cancer and associated metastasis support further in vivo research and modifications of the clinical treatment protocol in future studies.

Topics: Adenocarcinoma; Animals; Benzamides; Carcinoma, Transitional Cell; Cell Line; Dog Diseases; Dogs; Male; Piperidines; Prostatic Neoplasms; Proto-Oncogene Proteins c-kit; Pyridines; Receptor, Platelet-Derived Growth Factor alpha; Receptor, Platelet-Derived Growth Factor beta; Thiazoles

The development of enhanced recovery after surgery (ERAS) protocols for patients undergoing radical cystectomy (RC) represents a significant advance in perioperative care.. To evaluate gastrointestinal (GI) complications following RC and urinary diversion (UD) using our institutional ERAS protocol.. We identified 377 consecutive cases of open RC and UD for which our ERAS protocol was used from May 2012 to December 2015. Exclusion criteria were consent refusal; non-bladder primary disease; palliative, salvage, or additional surgery; and prolonged postoperative intubation. A matched cohort of 144 patients for whom a traditional postoperative protocol (pre-ERAS) was used between 2003 and 2012 was selected for comparison.. A total of 292 ERAS patients with median age of 70 yr were included in the study, 65% of whom received an orthotopic neobladder. The median time to first flatus and bowel movement was 2 d. The median length of stay was 4 d. GI complications occurred in 45 patients (15.4%) during the first 30 d following RC, 93% of which were of minor grade. The most common GI complication was postoperative ileus (POI) in 34 cases (11.6%). Some 22 patients (7.5%) required a nasogastric tube, and parenteral nutrition was required in three patients. The rate of 30-d GI complications was significantly lower in the ERAS cohort than in the control group (13% vs 27%; p=0.003), as was the rate of POI (7% vs 23%; p<0.001). This effect was independent of other variables (hazard ratio 0.38, 95% confidence interval 0.18-0.82; p=0.01).. Our institutional ERAS protocol for RC is associated with significantly improved perioperative GI recovery and lower rates of GI complications. This protocol can be tested in multi-institutional studies to reduce GI morbidity associated with RC.. In this study, we showed that an enhanced recovery protocol for patients undergoing radical cystectomy for bladder cancer was associated with a significantly shorter length of hospital stay and lower rates of gastrointestinal complications, especially postoperative ileus.

Topics: Adult; Aged; Aged, 80 and over; Anemia; Carcinoma, Transitional Cell; Case-Control Studies; Clinical Protocols; Cystectomy; Dehydration; Female; Gastrointestinal Agents; Gastrointestinal Diseases; Humans; Ileus; Intubation, Gastrointestinal; Length of Stay; Male; Middle Aged; Parenteral Nutrition; Perioperative Care; Piperidines; Postoperative Complications; Proportional Hazards Models; Urinary Bladder Neoplasms; Urinary Diversion; Urinary Tract Infections

Alvimopan has decreased ileus and need for nasogastric tube (NGT) after radical cystectomy (RC). However, the natural history of ileus versus intestinal obstruction in patients receiving alvimopan is not well defined. We sought to examine the implications of NGT placement before and after the introduction of alvimopan for RC patients.. Retrospective review identified 278 and 293 consecutive patients who underwent RC before and after instituting alvimopan between June 2009 and May 2014. Baseline characteristics and postoperative outcomes were compared by alvimopan status. Multivariate logistic regression was performed to assess the impact of alvimopan on rates of NGT placement and reoperation for bowel complications.. The cohorts had similar age, stage, approach, and BMI. Patients receiving alvimopan had decreased ileus (16 vs 32 %, p < 0.01) but similar rates of reoperation for bowel complications (2.8 vs 2.7 %). On multivariate analysis, alvimopan was associated with lower risk of NGT placement (OR 0.30, p < 0.01). For patients requiring NGT placement, there was an increased rate of reoperation among patients receiving alvimopan compared with those who did not (28 vs 11 %, p = 0.03). Patients receiving alvimopan who needed NGT had significantly increased median length of stay (22 vs 7 days), need for TPN (66 vs 5.3 %), and readmission for ileus (10.3 vs 2.3 %) compared with those who did not require NGT.. Alvimopan significantly reduced the incidence of ileus and NGT placement following RC. NGT placement was associated with an increased need for reoperation for bowel complications in the setting of alvimopan.

Topics: Aged; Carcinoma, Transitional Cell; Cystectomy; Female; Gastrointestinal Agents; Humans; Ileus; Intubation, Gastrointestinal; Logistic Models; Male; Middle Aged; Multivariate Analysis; Piperidines; Postoperative Care; Postoperative Complications; Reoperation; Retrospective Studies; Urinary Bladder Neoplasms; Urinary Diversion