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Expression of epidermal growth factor receptor (EGFR) may be of prognostic value in renal cell cancer (RCC). Gene amplification of EGFR was investigated in a cohort of 315 patients with advanced RCC from a previously reported randomised study. Using fluorescent in situ hybridisation, only 2 patients (0.6%) had gene amplification; therefore gene amplification is of no prognostic value in RCC. [Copyright &y& Elsevier]

Summary: Asparaginase is essential in treating acute lymphoblastic leukaemia (ALL). Asparaginase‐related hypersensitivity causes treatment discontinuation, which is associated with decreased event‐free survival. To continue asparaginase treatment after hypersensitivity, a formulation of asparaginase encapsulated in erythrocytes (eryaspase) was developed. In NOR‐GRASPALL 2016 (NCT03267030) the safety and efficacy of eryaspase was evaluated in 55 patients (aged 1–45 years; median: 6.1 years) with non‐high‐risk ALL and hypersensitivity to asparaginase conjugated with polyethylene glycol (PEG‐asparaginase). Eryaspase (150 u/kg) was scheduled to complete the intended course of asparaginase (1–7 doses) in two Nordic/Baltic treatment protocols. Forty‐nine (96.1%) patients had asparaginase enzyme activity (AEA) ≥100 iu/l 14 ± 2 days after the first eryaspase infusion [median AEA 511 iu/l; interquartile range (IQR), 291–780], whereas six of nine (66.7%) patients had AEA ≥100 iu/l 14 ± 2 days after the fourth infusion (median AEA 932 iu/l; IQR, 496–163). The mean terminal half‐life of eryaspase following the first infusion was 15.3 ± 15.5 days. Few asparaginase‐related adverse events were reported; five patients (9.1%) developed clinical allergy associated with enzyme inactivation. Replacement therapy was successfully completed in 50 patients (90.9%). Eryaspase was well tolerated, and most patients had AEA levels above the therapeutic target after the first infusion. The half‐life of eryaspase confirmed that a 2‐week schedule is appropriate. [ABSTRACT FROM AUTHOR]

HSP90 inhibitors have been shown to kill Epstein–Barr virus (EBV)-infected cells by reducing the level of EBV EBNA-1 and/or LMP1. We treated virus-infected cells with ganetespib, an HSP90 inhibitor currently being evaluated in multiple clinical trials for cancer and found that the drug killed EBV-positive B and T cells and reduced the level of both EBV EBNA-1 and LMP1. Treatment of cells with ganetespib also reduced the level of pAkt. Ganetespib delayed the onset of EBV-positive lymphomas and prolonged survival in SCID mice inoculated with one EBV-transformed B-cell line, but not another B-cell line. The former cell line showed lower levels of EBNA-1 after treatment with ganetespibin vitro. Treatment of a patient with T-cell chronic active EBV with ganetespib reduced the percentage of EBV-positive cells in the peripheral blood. These data indicate that HSP90 inhibitors may have a role in the therapy of certain EBV-associated diseases. [ABSTRACT FROM AUTHOR]

Abstract: Background: This randomised Phase II study assessed the activity and safety of concurrent chemoradiotherapy (CRT) and lapatinib followed by maintenance treatment in locally advanced, unresected stage III/IVA/IVB head and neck cancer. Patients and methods: Patients were randomised 1:1 to concurrent CRT and placebo followed by placebo or concurrent CRT and lapatinib followed by lapatinib. Treatment continued until disease progression or study withdrawal. Primary end-point was complete response rate (CRR) by independent review 6 months post-CRT. Results: Sixty-seven patients (median age 56 years; 97% Eastern Cooperative Oncology Group performance status ⩽1; 82% stage IV) were recruited. CRT dose intensities were unaffected by lapatinib: median radiation dose 70Gy (lapatinib, placebo), duration 49 (lapatinib) and 50 days (placebo); median cisplatin dose 260mg/m2 (lapatinib) and 280mg/m2 (placebo). Lapatinib combined with CRT was well-tolerated. Grade 3/4 toxicities during CRT were balanced between arms, with the exception of an excess of grade 3 diarrhoea (6% versus 0%) and rash (9% versus 3%) and two grade 4 cardiac events in the lapatinib arm. CRR at 6 months post-CRT was 53% with lapatinib versus 36% with placebo in the intent-to-treat population. The progression-free survival (PFS) and overall survival rates at 18 months were 55% versus 41% and 68% versus 57% for the lapatinib and placebo arms, respectively. The difference between study arms was greatest in p16-negative disease (median PFS >20.4 months [lapatinib] versus 10.9 [placebo]). Conclusion: Lapatinib combined with CRT is well-tolerated with numeric increases in CRR at 6 months post-CRT and median PFS in p16-negative disease. [Copyright &y& Elsevier]

Background: This phase I study investigated the maximum tolerated dose (MTD), safety, pharmacokinetics and antitumor activity of ganetespib in patients with solid malignancies. Methods: Patients were enrolled in cohorts of escalating ganetespib doses, given as 1 hour IV infusion, once weekly for 3 weeks, followed by a 1-week rest until disease progression or unacceptable toxicity. Endpoints included safety, pharmacokinetic and pharmacodynamic parameters and preliminary clinical activity. Results: Fifty-three patients were treated at doses escalating from 7 to 259 mg/m2. The most common adverse events were Grade 1 and 2 diarrhea, fatigue, nausea or vomiting. Dose-limiting toxicities (DLT) observed were: one Grade 3 amylase elevation (150 mg/m2), one Grade 3 diarrhea and one Grade 3 and one Grade 4 asthenia (259 mg/m2). The MTD was 216 mg/m2 and the recommended phase 2 dose was established at 200 mg/m2 given IV at Days 1, 8, and 15 every 4 weeks. There was a linear relationship between dose and exposure. Plasma HSP70 protein levels remained elevated for over a week post treatment. Disease control rate (objective response and stable disease at ⩾ 16 weeks) was 24.4%. Conclusions: Ganetespib is well tolerated as a weekly infusion for 3 of every 4 weeks cycle. The recommended phase II dose is 200 mg/m2, and is associated with an acceptable tolerability profile [ABSTRACT FROM AUTHOR]

Abstract: Purpose: Aim of this study was to correlate dose to pharyngeal constrictors (PC) with subjective and observer-based assessments of swallowing in patients with head and neck cancer undergoing concomitant chemo-IMRT. Materials and methods: Dose–volume histograms (DVHs) for superior constrictor (SC), middle constrictor (MC) and inferior constrictor (IC) were generated for 37 patients. Mean doses to SC, MC and IC were correlated to objective dysphagia grade (1year, RTOG scoring) and global, total physical (TP) and most relevant components of the physical section (P6, P8) of the MD Anderson dysphagia inventory (MDADI) which was evaluated post-treatment. Odds ratios of dysphagia (>grade 0), poor global (<3), TP (<32), P6 (<3) and P8 (<3) for patients with mean dose>60Gy to SC and IC were calculated. Results: There was no significant correlation between mean dose to PC and any of the analysed MDADI parameters and observer-assessed dysphagia grade. Odds ratio of dysphagia (>grade 0), poor global (<3), TP (<32), P6 (<3) and P8 (<3) for patients with mean dose>60Gy to IC and SC were not significantly higher than those for patients receiving <60Gy. Conclusion: This study did not find a statistically significant correlation between radiation dose to the PC and observer-assessed dysphagia grade or patient-reported MDADI questionnaire at 1year. [Copyright &y& Elsevier]

Summary: Population-based data on head and neck cancer (HNC) stage and histological type are poorly described for England; these data are essential for clinical management and research. The aim of this study was to describe the distribution and incidence of all HNC and selected anatomical sites by sex, age, stage and histological type using a population-based cancer registry in South East England, and determine if the incidence changed between 1995–1999 and 2000–2004. We identified all HNC cancer cases registered by the Thames Cancer Registry for 1995–1999 and 2000–2004. Frequency distributions and age-standardised incidence rates were calculated by sex, age, stage and histological type and trends in incidence between the two time periods were described using incidence rate ratios and 95% confidence intervals. A total of 8700 HNC cases were reported in 2000–2004, representing an age-standardised incidence rate of 8.59 per 100000, which did not change significantly from 1995–1999. The three commonest HNC sites were intra-oral cavity, larynx and tonsil. Males were two to six times as likely as females to be diagnosed with HNC and there was a trend toward younger age at diagnosis over time. Significant increases in the incidence rate of intra-oral cavity cancer for both sexes and tonsillar cancer among males were observed. Conversely, laryngeal cancer incidence decreased over time. Staging data was only available for about 40% of HNC cases. Seventy six percent of HNC cases were squamous cell carcinomas. Trends in incidence varied between HNC sites, highlighting the importance of presenting data for individual HNC sites. The high proportion of unstaged cancers may result from incomplete recording in medical records; thus, the reporting of staging data should be made a priority. [Copyright &y& Elsevier]

The article presents a study on the use of lapatinib as the second-line treatment for patients having metastatic transitional cell carcinoma. The study reveals that the main endpoint of an objective response rate (ORR) >10% was discovered in 1.7% patients however, 18 patients attained stable disease (SD). It shows that the median time to overall survival and disease progression were 17.9 weeks and 8.6 weeks, respectively.

Abstract: Background: In this phase I/II study, the addition of lapatinib (LAP) was investigated in combination with the sequential use of both approaches TPF induction chemotherapy (ICT) followed by chemoradiation (CRT) in locally advanced larynx or hypopharynx squamous cell carcinoma. Patients and methods: Objectives were to assess maximum tolerated dose, dose-limiting toxicity (DLT) and to recommend a safe dose of LAP when administered with 4 cycles of TPF followed by CRT. Results: Seven male patients were included. Three patients were included in the first cohort, at dose level 1 (LAP 500mg daily plus TPF). Renal toxicity was observed among these three patients (grade 3 [n =1], grade 2 [n =1] and grade 1 [n =1]), with 1 DLT, leading to treatment interruption in this group. Nephrotoxicity was reversible after stopping LAP and hydration of the patients. In a second cohort of four patients administering docetaxel from the second cycle, 3 more DLTs were observed (grade 2 renal toxicity and grade 3 diarrhea, grade 3 anorexia and grade 3 stomatitis, and grade 4 neutropenia). Based on the occurrence of 4 DLTs at the first dose level of LAP, patient recruitment was closed. Conclusion: These data indicate that LAP cannot be combined safely with full dose TPF. [Copyright &y& Elsevier]

Background: This phase I study investigated the maximum tolerated dose (MTD), safety, pharmacokinetics and antitumor activity of ganetespib in patients with solid malignancies.Methods: Patients were enrolled in cohorts of escalating ganetespib doses, given as 1 hour IV infusion, once weekly for 3 weeks, followed by a 1-week rest until disease progression or unacceptable toxicity. Endpoints included safety, pharmacokinetic and pharmacodynamic parameters and preliminary clinical activity.Results: Fifty-three patients were treated at doses escalating from 7 to 259 mg/m(2). The most common adverse events were Grade 1 and 2 diarrhea, fatigue, nausea or vomiting. Dose-limiting toxicities (DLT) observed were: one Grade 3 amylase elevation (150 mg/m(2)), one Grade 3 diarrhea and one Grade 3 and one Grade 4 asthenia (259 mg/m(2)). The MTD was 216 mg/m(2) and the recommended phase 2 dose was established at 200 mg/m(2) given IV at Days 1, 8, and 15 every 4 weeks. There was a linear relationship between dose and exposure. Plasma HSP70 protein levels remained elevated for over a week post treatment. Disease control rate (objective response and stable disease at ≥ 16 weeks) was 24.4%.Conclusions: Ganetespib is well tolerated as a weekly infusion for 3 of every 4 weeks cycle. The recommended phase II dose is 200 mg/m(2), and is associated with an acceptable tolerability profile.Trial Registration: NCT00687934. [ABSTRACT FROM AUTHOR]