Citations

Abstract Purpose A few previous studies report a direct relationship between older age and chemotherapy-induced neuropathy. This study further evaluated this adverse event's age-based risk. Methods CALGB 40101 investigated adjuvant paclitaxel (80 mg/m2 once per week or 175 mg/m2 every 2 weeks) in patients with breast cancer and served as a platform for the current study that investigated age-based differences in neuropathy. Grade 2 or worse neuropathy, as per Common Terminology Criteria for Adverse Events version 4, was the primary endpoint; patients were assessed at baseline, every 6 months for 2 years, and then annually for 15 years. Results Among these 1,881 patients, 230 were 65 years of age or older, 556 were 55–64 years, and 1,095 were younger than 55; 1,226 neuropathy events (commonly grade 1 or 2) were reported in 65% of the cohort. The number of grade 2 or worse events was 63 (27%), 155 (28%), and 266 (24%) within respective age groups (p = .14). In univariate analysis, only motor neuropathy had a higher age-based incidence: 19 (8%), 43 (8%), and 60 (5%), respectively (p = .04); in multivariate analyses, this association was no longer statistically significant. Other endpoints, such as time to onset of neuropathy (time from trial enrollment to neuropathy development) and time to improvement (time from maximal grade sensory neuropathy to a one-category improvement), showed no statistically significant age-based differences. In contrast, obesity was associated with neuropathy, and every 2-week paclitaxel was associated with trends toward neuropathy. Conclusion Although paclitaxel-induced neuropathy is common, older age is not an independent risk factor. Clinical trial identification number. NCT00041119 (CALGB 40101).

Abstract Background Axitinib is an oral small molecule that inhibits receptor tyrosine kinases vascular endothelial growth factor receptors 1 to 3. A phase 1 and pharmacokinetic (PK) trial evaluating axitinib was conducted in children with refractory solid tumors. Methods Axitinib was administered orally twice daily in continuous 28‐day cycles. Dose levels (2.4 mg/m 2 /dose and 3.2 mg/m 2 /dose) were evaluated using a rolling 6 design. Serial PKs (cycle 1, days 1 and 8) and exploratory biomarkers were analyzed. Results A total of 19 patients were enrolled; 1 patient was ineligible due to inadequate time having elapsed from prior therapy. The median age of the patients was 13.5 years (range, 5‐17 years). Two of 5 patients who were treated at dose level 2 experienced dose‐limiting toxicities (palmar‐plantar erythryodysesthesia syndrome in 1 patient and intratumoral hemorrhage in 1 patient). Frequent (>20%) grade 1 to 2 toxicities during cycle 1 included anemia, anorexia, fatigue, diarrhea, nausea, and hypertension. Nonhematological toxicities of grade ≥3 in subsequent cycles included hypertension and elevated serum lipase. PK analysis demonstrated variability in axitinib exposure, the median time to peak plasma concentration was 2 hours, and the half‐life ranged from 0.7 to 5.2 hours. Exposure and dose were not found to be significantly associated with hypertension. Five patients achieved stable disease for ≥6 cycles as their best response, including patients with malignant peripheral nerve sheath tumor (1 patient), Ewing sarcoma (1 patient), hepatocellular carcinoma (1 patient), and osteosarcoma (2 patients). One patient with alveolar soft part sarcoma achieved a partial response. Kidney injury biomarkers were found to be elevated at baseline; no trends were identified. Conclusions In children with refractory solid tumors, the maximum tolerated and recommended dose of axitinib appears to be 2.4 mg/m 2 /dose, which provides PK exposures similar to those of adults.

Abstract Rationale Improved therapeutic options are needed for patients with treatment-refractory nontuberculous mycobacterial lung disease caused by Mycobacterium avium complex (MAC). Objectives To evaluate the efficacy and safety of daily amikacin liposome inhalation suspension (ALIS) added to standard guideline-based therapy (GBT) in patients with refractory MAC lung disease. Methods Adults with amikacin-susceptible MAC lung disease and MAC-positive sputum cultures despite at least 6 months of stable GBT were randomly assigned (2:1) to receive ALIS with GBT (ALIS + GBT) or GBT alone. Once-daily ALIS was supplied in single-use vials delivering 590 mg amikacin to the nebulizer. The primary endpoint was culture conversion, defined as three consecutive monthly MAC-negative sputum cultures by Month 6. Measurements and Main Results Enrolled patients (ALIS + GBT, n = 224; GBT-alone, n = 112) were a mean 64.7 years old and 69.3% female. Most had underlying bronchiectasis (62.5%), chronic obstructive pulmonary disease (14.3%), or both (11.9%). Culture conversion was achieved by 65 of 224 patients (29.0%) with ALIS + GBT and 10 of 112 (8.9%) with GBT alone (odds ratio, 4.22; 95% confidence interval, 2.08–8.57; P < 0.001). Patients in the ALIS + GBT arm versus GBT alone were more likely to achieve conversion (hazard ratio, 3.90; 95% confidence interval, 2.00–7.60). Respiratory adverse events (primarily dysphonia, cough, and dyspnea) were reported in 87.4% of patients receiving ALIS + GBT and 50.0% receiving GBT alone; serious treatment-emergent adverse events occurred in 20.2% and 17.9% of patients, respectively. Conclusions Addition of ALIS to GBT for treatment-refractory MAC lung disease achieved significantly greater culture conversion by Month 6 than GBT alone, with comparable rates of serious adverse events. Clinical trial registered with www.clinicaltrials.gov (NCT02344004).

International normalized ratio (INR) measurements manage risks of bleeding and clotting sequelae in the population with left ventricular assist device (LVAD). Studies suggest that point-of-care (POC) INR does not significantly differ from plasma INR (P-INR) values in other patient populations, although this has not been validated in a multicenter LVAD study. We sought to determine whether POC-INR and P-INR values differ significantly in the LVAD population and reviewed patients with permanent LVAD implantation at seven institutions internationally. Our cohort comprised of 279 paired POC-INR and P-INR checks in patients supported on average 630 ± 598 days postimplant with predominately HeartWare, HeartMate II, and HeartMate III devices. The population averaged 57.9 years of age, and there were 86.7% male. We found no statistically significant difference between POC-INR and P-INR values. International normalized ratio accuracy correlated weakly with the time between INR measurements (p < 0.001). When the time difference was less than 4 hours, the difference between INR pairs was significantly lower than measurements greater than 8 hours (p = 0.006). There was no statistically significant difference when comparing paired INR values and time after implant to INR check (p = 0.43), age (p = 0.12), known coagulopathy (p = 0.12), bleeding history (p = 0.22), or thrombosis history (p = 0.34). This is the first large multicenter international study comparing POC-INR and P-INR measurements in patients with LVAD and found no statistically significant difference between either methods, particularly when measured within less than 4 hours of each other.