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Purpose:To determine the feasibility of induction chemotherapy and chemo-IMRT in head and neck squamous cell cancers at risk of bilateral nodal spread (midline tumours) and to evaluate whether bilateral superficial lobe parotid-sparing IMRT can reduce the incidence of ⩾G2 subjective xerostomia.Methods:Patients with midline tumours were enrolled to a phase II trial to receive induction platinum/5-fluorouracil and concomitant platinum with combined superficial lobe parotid-sparing IMRT. The primary site and involved nodal levels received 65 Gy in 30 fractions (f) and at risk nodal levels, 54 Gy/30f. Incidence of ⩾G2 subjective xerostomia was defined as the primary endpoint. Secondary endpoints included incidences of acute and late toxicities and survival outcomes dependent on human papilloma virus (HPV) status.Results:One hundred and twenty patients with midline cancers completed treatment between December 2005 and May 2010 with median follow-up of 50 months. Incidences of ⩾G2 acute toxicities were: dysphagia 75%; xerostomia 65%; mucositis 86%; pain 83%; and fatigue 64%. At 12 months, ⩾G2 subjective xerostomia was observed in 21% (17% in HPV +ve). Two-year loco-regional progression-free survival (PFS) was 90.7% (95% CI: 85.2-96.2). According to HPV status, there was a significant difference for 2-year loco-regional PFS, 76.8% (HPV-negative) vs 98.6% (HPV-positive), P=0.001. 2-year overall survival was 93% for HPV-positive compared with 52% for HPV-negative cases, P<0.001.Conclusions:Sequential chemotherapy/chemo-IMRT for midline tumours is feasible, with excellent survival outcomes. At 1 year, 21% experience ⩾G2 subjective xerostomia. Two-year survival outcomes differ significantly between HPV-positive and HPV-negative disease, suggesting development of different treatment schedules for the different disease entities. [ABSTRACT FROM AUTHOR]

Crizanlizumab is an anti-P-selectin monoclonal antibody indicated to reduce the frequency/prevent recurrence of vaso-occlusive crises (VOCs) in patients with sickle cell disease (SCD) aged ≥16 years. This analysis of an ongoing phase 2, nonrandomized, open-label study reports the pharmacokinetics (PK), pharmacodynamics (PD), safety, and efficacy of crizanlizumab 5.0 mg/kg (N = 45) and 7.5 mg/kg (N = 12) in patients with SCD with a history of VOCs. The median treatment duration was 104.7 and 85.7 weeks in the 5.0 and 7.5 mg/kg groups, respectively. For both doses, serum crizanlizumab concentrations rose to near maximum levels shortly after infusion, and near complete and sustained ex vivo P-selectin inhibition was observed. Grade ≥3 adverse events (AEs) occurred in 48.9% and 33.3% of patients in the 5.0 and 7.5 mg/kg groups, respectively; only 1 event was deemed treatment-related (7.5 mg/kg group). No treatment-related serious AEs occurred. One infusion-related reaction was recorded (5.0 mg/kg, grade 2 "pain during infusion"), which resolved without treatment withdrawal. Infections occurred in 57.8% and 41.7% of patients in the 5.0 and 7.5 mg/kg groups, respectively; none were drug-related. No treatment-related bleeding events were reported. No patients developed immunogenicity. The median (range) absolute reduction from baseline in the annualized rate of VOCs leading to a health care visit was -0.88 (-14.7 to 13.3) and -0.93 (-2.0 to 0.4) in the 5.0 and 7.5 mg/kg groups, respectively. Results here demonstrate the PK/PD properties of crizanlizumab in patients with SCD and the potential sustained efficacy and long-term safety of the drug after >12 months' treatment. This trial was registered at www.clinicaltrials.gov as #NCT03264989., (© 2023 by The American Society of Hematology. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.)

Objectives: Despite advances in novel drug development for patients with advanced non-small cell lung cancer (NSCLC), there are still only a limited number of approved treatments. We therefore evaluated the clinical outcomes of patients with advanced NSCLC referred to a dedicated phase I clinical trials unit assessed baseline clinical factors associated with successful enrollment onto phase I trials., Material and Methods: We conducted a retrospective study involving patients with advanced NSCLC referred to the Drug Development Unit at the RMH between January 2005 and December 2013., Results: 257 patients with advanced NSCLC were referred for consideration of phase I trials, of which only 89 (35%) patients successfully commenced phase I trials. The commonest reasons for not entering study included poor ECOG performance status and rapid disease progression. A multivariate analysis identified that ECOG performance status (0-1) and RMH prognostic score (0-1) were associated with successful enrollment onto phase I trials (p<0.001). Single agent therapies included novel agents against the phosphatidylinositol-3 kinase pathway, insulin growth factor-1 receptor and pan-HER family tyrosine kinases. These trial therapies were well tolerated and mainly associated with grade 1-2 adverse events, with a minority experiencing grade 3 toxicities. Nine (10%) patients, 4 with known EGFR or KRAS mutations, achieved RECIST partial responses. Median time to progression was 2.6 months and median overall survival was 8.1 months for patients enrolled., Conclusions: Phase I trial therapies were generally well tolerated with potential antitumor benefit for patients with advanced NSCLC. Early referral to drug development units at time of disease progression should be considered to enhance the odds of patient participation in these studies., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Background: Dysregulation of the phosphatidylinositol 3-kinase/protein kinase B/mammalian target of rapamycin (PI3K/AKT/mTOR) pathway is implicated in human cancer growth and progression. Agents targeting this pathway are associated with hyperglycemia due to interaction with the insulin-glucose regulatory axis. Identifying the predictive factors for hyperglycemia in patients treated with these agents may help direct future management., Materials and Methods: Clinical characteristics and outcomes of patients treated consecutively with PI3K, AKT, or mTOR inhibitors in the Drug Development Unit, The Royal Marsden (RM) National Health Service (NHS) Foundation Trust, between 2007 and 2012 were recorded. Baseline variables and their association with grade 3 hyperglycemia (Common Terminology Criteria for Adverse Events, version 3.0) were analyzed by using the chi-square test and Fisher exact test for categorical variables and binary logistic regression for continuous variables., Results: A total of 341 patients were treated in 12 phase I trials of PI3K/AKT/mTOR inhibitors, and 298 patients (87.4%) developed hyperglycemia. Hyperglycemia was grade 1 in 217 (72.8%) and grade 2 in 61 (20.5%) patients, respectively. Grade ≥3 hyperglycemia was seen in 6.7% of patients (n = 20). According to the chi-square test, age <65 years (p = .03), history of diabetes (p = .003), and treatment with AKT and dual PI3K/mTOR inhibitors (p < .0005) predicted the occurrence of grade 3 hyperglycemia. Of 24 patients requiring intervention, 20 received metformin, 2 dietary advice, 1 insulin, and 1 both metformin and insulin. One patient required dose reduction. There were no permanent drug discontinuations, and no hyperglycemia-related dose-limiting toxicities were observed; thus, the recommended phase II dose was not affected by the hyperglycemia observed in our cohort., Conclusion: Hyperglycemia is common in patients treated with PI3K/AKT/mTOR inhibitors; however, it is manageable with conventional treatment. Predictive factors of age, history of diabetes, and administration of AKT and dual PI3K/mTOR inhibitors warrant prospective validation., Implications for Practice: This study reviewed the clinical data of 341 patients treated in 12 phase I trials of agents targeting phosphatidylinositol3-kinase (PI3), protein kinase B (AKT), and mammalian target of rapamycin (mTOR), as well as dual inhibitors. Hyperglycemia was evident in 87.4% of patients but was ≥grade 3 in just 6.7%. Age <65 years, history of diabetes, and treatment with AKT and dual PI3K/mTOR inhibitors were each associated with grade 3 hyperglycemia. Management of patients was uncomplicated, and no permanent drug discontinuations were necessary. Despite the small study size, these findings support continued caution about enrolling patients with a history of diabetes into such trials. However, clinicians may be reassured, pending prospective validation of these results, that significant hyperglycemia is not frequent and, when it occurs, is manageable., (©AlphaMed Press.)

This study evaluates the efficacy of low-fat dietary interventions in the management of gastrointestinal (GI) symptoms due to bile acid malabsorption. In total, 40 patients with GI symptoms and a 7-day (75)selenium homocholic acid taurine (SeHCAT) scan result of <20%, were prospectively recruited and then advised regarding a low-fat dietary intervention. Before and after dietary intervention, patients rated their GI symptoms using a 10-point numerical scale, and recorded their intake in 7-day dietary diaries. After dietary intervention, the median scores for all GI symptoms decreased, with a significant reduction for urgency, bloating, lack of control, bowel frequency (p ≥: 0.01). Mean dietary fat intake reduced to 42 g fat after intervention (p ≥: 0.01). Low-fat dietary interventions in patients with a SeHCAT scan result of <20% leads to clinically important improvement in GI symptoms and should be widely used., (© Royal College of Physicians 2015. All rights reserved.)

Background: Some guidelines suggest that poor performance status (PS) is a contraindication to 1st line chemotherapy. Poor PS is a known adverse prognostic factor in advanced epithelial ovarian cancer (EOC). We show in this retrospective analysis that 1st line chemotherapy in this patient group is not only safe but is associated with good outcomes., Patients and Methods: A retrospective review of 114 patients with stage III/IV EOC, who presented with a PS ≥3 at diagnosis and treated as inpatients with upfront platinum-based chemotherapy between 2000 and 2013, at the Royal Marsden Hospital, was conducted. The association between clinical parameters and the likelihood of completion of chemotherapy and overall survival (OS) was assessed., Results: 66% of patients completed ≥6cycles of platinum-based chemotherapy. Prognostic factors for completion of chemotherapy were improvement of PS during hospital stay (p<0.001) and doublet-chemotherapy with carboplatin/paclitaxel compared to single-agent carboplatin (p=0.004). A negative trend for completion of treatment was seen for patients with low albumin (<25g/l) and low CA125 levels at baseline. The median OS for all patients was 13.1months (95% CI: 10.4-15.8) and 21.2months (95% CI: 16.5-25.8) for those who completed 6cycles of chemotherapy., Conclusion: Upfront platinum-based chemotherapy is feasible, beneficial and tolerable for the majority of patients with advanced EOC and poor PS. Guidelines suggesting that best supportive care is the preferred option for poor PS patients with solid tumours should be revised to exclude those with advanced EOC. An aggressive approach utilising neoadjuvant carboplatin plus paclitaxel should be regarded as standard of care., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Objectives: We previously described dose-escalated intensity-modulated radiotherapy (IMRT) in squamous cell cancer of the larynx/hypopharynx (SCCL/H) to offer improved locoregional control with a low incidence of toxicity at 2 years. We now present outcome and safety data at 5 years., Materials and Methods: A sequential cohort Phase I/II trial design was used. Patients with SCCL/H received IMRT at two dose levels (DL): DL1, 63 Gy/28 fractions to planning target volume 1 (PTV1) and 51.8 Gy/28 Fx to PTV2; DL2, 67.2 Gy/28 Fx and 56 Gy/28 Fx to PTV1 and PTV2, respectively. Patients received induction cisplatin/5-fluorouracil and concomitant cisplatin., Results: Between 09/2002 and 01/2008, 60 patients (29 DL1, 31 DL2) with stage III (41% DL1, 52% DL2) and stage IV (52% DL1, 48% DL2) disease were recruited. Median (range) follow-up for DL1 was 5.7 (1.0-10.2) years and for DL2 was 6.0 (0.3-8.4) years. Five-year local control rates (95% confidence interval) for DL1 and DL2, respectively, were 68% (50.6-85.4%) and 75% (58.9-91.1%), locoregional progression-free survival rates were 54% (35.6-72.4%) and 62.6% (44.8-80.4%), and overall survival was 61.9% (44.1-79.7) and 67.6 (51.1-84.1%). Five-year laryngeal preservation rates were 66.7% (37.4-87.9%) and 71.4% (44.4-85.8%), respectively. Cumulative toxicities reported were: one patient in DL1 and 2 in DL2 developed benign pharyngeal strictures. No other G3/4 toxicities were reported., Conclusions: Dose-escalated IMRT at DL2 achieves higher 5-year local control, larynx preservation and survival rates with acceptable late toxicity. Recruitment into a Cancer Research UK Phase III study (ART-DECO), with DL2 as the experimental arm, is ongoing., (Copyright © 2014. Published by Elsevier Ltd.)

Background and Purpose: Thrombolysis in patients >80 years remains controversial; we hypothesized that >80-year-old patients with wake-up ischemic stroke (WUIS) will benefit from thrombolysis despite risks because of poor outcomes with no treatment., Methods: The study included 68 thrombolysed patients with WUIS (33 [48%] >80 years), 54 nonthrombolysed patients with WUIS (21 [39%] >80 years), and 117 patients (>80 years old) thrombolysed within 4.5 hours of symptom onset (reference group). Mortality and modified Rankin Scale (mRS) were assessed at 90 days., Results: Baseline characteristics of thrombolysed and nonthrombolysed >80 and ≤80-year-old patients with WUIS were comparable. Thrombolysis outcomes in >80-year-old patients with WUIS were better than in nonthrombolysed >80-year-old patients with WUIS (90-day mortality: 24% versus 47%, P=0.034; mRS 0-2: 30% versus 5%, P=0.023; mRS 0-1: 15% versus 5%, P=0.24) and comparable with thrombolysed ≤80-year-old patients with WUIS. Thrombolysis was associated with odds ratio 0.27 (95% confidence interval, 0.05-0.97) for mortality and odds ratio 28.6 (95% confidence interval, 1.8-448) for mRS 0 to 2 at 90 days in >80-year-old patients with WUIS after adjusting for stroke severity and risk factors., Conclusions: Thrombolysis may be associated with greater benefit in >80-year-old patients with WUIS but a selection bias favoring thrombolysis in those most likely to benefit may significantly reduce interpretability of these findings.

Background and Purpose: Wake-up ischemic stroke (WUIS) patients are not thrombolysed even if they meet other criteria for treatment. We hypothesized that patients with WUIS showing no or early ischemic changes on brain imaging will have thrombolysis outcomes comparable with those with known time of symptom onset., Methods: Consecutive sampling of a prospective registry of patients with stroke between January 2009 and December 2010 identified 394 thrombolysed patients meeting predefined inclusion criteria, 326 presenting within 0 to 4.5 hours of symptom onset (Reference Group) and 68 WUIS patients. Inclusion criteria were last seen normal<12 hours or >4.5 hours (WUIS) or presented <4.5 hours (Reference Group), had National Institutes of Health Stroke Scale score ≥5, and no or early ischemic changes on imaging at presentation. The primary outcome measure was the modified Rankin Scale of 0 to 2 at 90 days measured by trained assessors blinded to patient grouping. Other outcome measures were symptomatic intracerebral hemorrhage, modified Rankin Scale 0 to 1, and mortality at 90 days., Results: The groups were comparable for mean age (72.8 versus 73.9 years; P=0.58) and baseline median National Institutes of Health Stroke Scale score (median 13 versus 12; P=0.34). The proportions of patients with modified Rankin Scale 0 to 2 (38% versus 37%; P=0.89) and modified Rankin Scale 0 to 1 (24% versus 16%; P=0.18) at 90 days, any ICH (20% versus 22%; P=0.42) and symptomatic intracerebral hemorrhage (3.4% versus 2.9%; P=1.0) were comparable after adjusting for age, stroke severity, and imaging changes. Only 9/394 (2%) patients were lost to follow-up., Conclusions: Thrombolysis in selected patients with WUIS is feasible, and its outcomes are comparable with those thrombolysed with 0 to 4.5 hours.

Background and Purpose: Wake-up ischemic stroke (WUIS) patients are not eligible for thrombolysis; the a priori hypothesis was that thrombolysis of selected WUIS patients who meet clinical and imaging criteria for treatment is associated with better outcomes., Methods: The sample consisted of consecutive WUIS patients who fulfilled predefined criteria: (1) were last seen normal >4.5 hours and <12 hours before presentation; (2) National Institute of Health Stroke Scale score ≥ 5; (3) No or early ischemic changes <1/3 middle cerebral artery territory on computed tomography imaging; (4) No absolute contraindications to thrombolysis. The primary outcome measure was the modified Rankin Scale of 0 to 2 at 90 days. Other outcome measures were mortality and symptomatic intracerebral hemorrhage., Results: WUIS patients constituted 10.5% (193/1836) of all stroke admissions. Inclusion criteria were fulfilled by 122 (63%) patients, of whom 68 (56%) were thrombolysed. Thrombolysed and nonthrombolysed patients were comparable for baseline characteristics, but the median baseline National Institute of Health Stroke Scale score was higher in thrombolysed patients (9 versus 11.5; P=0.034). There was no difference in modified Rankin Scale 0 to 2 (25 [37%] versus 14 [26%]; P=0.346), death (10 [15%] versus 14 [26%]; P=0.122), and symptomatic intracerebral hemorrhage (2 versus 0; P=0.204) between thrombolysed and nonthrombolysed patients. After adjusting for age, sex, and baseline National Institute of Health Stroke Scale score thrombolysis was associated with odds ratio of 5.2 (95% confidence interval 1.3-20.3), P=0.017 for modified Rankin Scale 0 to 2 at 90 days and odds ratio of 0.09 (95% confidence interval 0.02-0.44), P=0.003 for death., Conclusions: Thrombolysis in selected WUIS patients is feasible and may have potential of benefit.