Lack of Cumulative Toxicity Associated With Cabazitaxel Use in Prostate Cancer

Cabazitaxel provided a survival advantage compared with mitoxantrone in patients with castration-resistant prostate cancer refractory to docetaxel. Grade 3 to 4 (G3–4) neutropenia and febrile neutropenia were relatively frequent in the registrative XRP6258 Plus Prednisone Compared to Mitoxantrone Plus Prednisone in Hormone Refractory Metastatic Prostate Cancer (TROPIC) trial, but their incidence was lower in the Expanded Access Program (EAP). Although cumulative doses of docetaxel are associated with neuropathy, the effect of cumulative doses of cabazitaxel is unknown. In this retrospective review of prospectively collected data, the authors assessed “per cycle” incidence and predictors of toxicity in the Italian cohort of the EAP, with a focus on the effect of cumulative doses of cabazitaxel.The study population consisted of 218 Italian patients enrolled in the cabazitaxel EAP. The influence of selected variables on the most relevant adverse events identified was assessed using a Generalized Estimating Equations model at univariate and multivariate analysis.“Per cycle” incidence of G 3 to 4 neutropenia was 8.7%, whereas febrile neutropenia was reported in 0.9% of cycles. All events of febrile neutropenia occurred during the first 3 cycles. Multivariate logistic regression analysis showed that higher prior dose of cabazitaxel was associated with decreased odds of having G3 to 4 neutropenia (OR = 0.90; 95% CI: 0.86–0.93; P < 0.01), febrile neutropenia (OR = 0.52; 95% CI: 0.34–0.81; P < 0.01) and G3 to 4 anemia (OR = 0.93; 95% CI: 0.86–1; P = 0.07). Patients with a body surface area >2 m² presented increased odds of having G 3 to 4 neutropenia (OR = 0.93; 95% CI: 0.86–1; P = 0.07), but decreased odds of having G3 to 4 anemia.Among the toxicities assessed, the authors did not identify any that appeared to be associated with a higher number of cabazitaxel cycles delivered. Prior cumulative dose was associated with reduced G3 to 4 neutropenia and anemia. The apparent protective effect associated with higher doses of cabazitaxel is likely to be affected by early dose reduction and early toxicity-related treatment discontinuation. Because this analysis is limited by its retrospective design, prospective trials are required to assess the optimal duration of cabazitaxel treatment.     

Pooled Analysis of Phase II Trials Evaluating Weekly or Conventional Cisplatin as First-Line Therapy for Advanced Urothelial Carcinoma

BackgroundWeekly gemcitabine with GC every 3-4 weeks is considered conventional first-line chemotherapy for advanced urothelial carcinoma (UC). Weekly split-dose cisplatin with wGC might be less toxic and have similar activity, but has not been compared with GC. We pooled published phase II trials of GC and wGC to compare efficacy and safety.Patients and MethodsTwo trials of wGC and 3 trials of GC were identified. Because the data were not derived from randomized trials, GC and wGC were not formally compared, and exact 95% quasi-binomial confidence intervals (CI), for response rates and grade ≥ 3 toxicities were calculated.ResultsThe 95% CI overlapped, suggesting agreement between wGC and GC. No clear difference in response rates and grade ≥ 3 toxicities between GC and wGC were observed.ConclusionGemcitabine combined with day 1 cisplatin and wGC yielded similar responses and grade ≥ 3 toxicities in advanced UC in a hypothesis-generating pooled analysis of phase II trials. Considering the probable lower nephrotoxicity of fractionated cisplatin, prospective evaluation of wGC might be warranted across cisplatin-eligible and -ineligible patients to develop a single chemotherapy template for the development of combinations with biological agents in a broad population of patients.     

The Impact of Gender on Outcomes in Patients With Metastatic Urothelial Carcinoma

BackgroundAlthough urothelial cancer is more common in men, women with urothelial cancer have inferior survival outcomes. The potential existence of gender-related disparities in patients with metastatic urothelial cancer has not been extensively explored.Patients and MethodsIndividual patient data were pooled from 8 phase II and phase III trials evaluating first-line cisplatin-based combination chemotherapy in patients with metastatic urothelial carcinoma. Adverse events, treatment delivery, response proportions, and survival outcomes were compared between male and female patients.ResultsOf the 543 patients included in the analysis, 100 patients (18%) were women. There was no significant difference in the number of cycles of chemotherapy administered or in the proportions of patients experiencing severe toxicities when comparing male and female patients. There was no difference in the survival distributions between male and female patients (P = .08); the median survival of male patients was 11.7 months (95% confidence interval [CI], 10.5-13.2) compared with 16.2 months for female patients (95% CI, 12.8-20.4). There was no significant difference in survival between men and women when controlling for baseline performance status and/or the presence of visceral metastases.ConclusionFemale patients with metastatic urothelial cancer tolerate cisplatin-based chemotherapy similarly to male patients and achieve comparable clinical outcomes. Although gender-associated survival disparities in patients with metastatic urothelial cancer cannot be completely ruled out, if such disparities exist, they are unlikely related to tolerability or efficacy of chemotherapy.     

Characteristics of hypertension in obstructive sleep apnea: An Asian experience

Obstructive sleep apnea (OSA) is a risk of hypertension and is associated with cardiovascular disease (CVD) incidence. In Asian countries, the prevalence of OSA is high, as in Western countries. When blood pressure (BP) is evaluated in OSA individuals using ambulatory BP monitoring (ABPM), the BP phenotype often indicates abnormal BP variability, such as increased nighttime BP or abnormal diurnal BP variation, that is, non‐dipper pattern, riser pattern, and morning BP surge, and all these conditions have been associated with increased CVD events. Asians have a higher prevalence of increased nighttime BP or morning BP surge than Westerners. Therefore, this review paper focused on OSA and hypertension from an Asian perspective to investigate the importance of the association between OSA and hypertension in the Asian population. Such abnormal BP variability has been shown to be associated with progression of arterial stiffness, and this association could provoke a vicious cycle between abnormal BP phenotypes and arterial stiffness, a phenomenon recognized as systemic hemodynamic atherothrombotic syndrome (SHATS). OSA may be one of the background factors that augment SHATS. An oxygen‐triggered nocturnal oscillometric BP measurement device combined with a pulse oximeter for continuous SpO₂ monitoring could detect BP variability caused by OSA. In addition to treating the OSA, accurate and reliable detection and treatment of any residual BP elevation and BP variability caused by OSA would be necessary to prevent CVD events. However, more detailed detection of BP variability, such as beat‐by‐beat BP monitoring, would further help to reduce CV events.     

The molecular structure of 4-(dimethylmaleimido)phenyl methacrylate

The molecular structure of 4-(dimethylmaleimido)phenyl methacrylate was determined by means of X-ray diffraction. Crystals are orthorhombic, space group F2dd, a = 3,993(1) Å, b = 36,650(6) Å, c = 39,460(8) Å and Z = 16; d_calc = 1,360 g · cm^?3, V = 5774,7 ų, M = 285,3, λ = 0,7107 Å, μ (MoK_α) = 1,06 cm^?1, F(000) = 2400. The structure was solved by direct methods and refined to R = 0,062 for 304 observed reflections. The molecule has a synperiplanar conformation as to the C?C and C?O double bonds about C(7)? C(8) and also as to the C?O and C? O bonds about C(7)? O(1).