Explore the vast range of titles available.

This title provides a comprehensive survey and study of the theatre produced in the 1960s. It features a critical analysis and reevaluation of the work of four key playwrights authored by a team of experts, together with an extensive commentary on the period.

Bevacizumab, a monoclonal antibody that targets VEGF, has shown restricted activity in patients with advanced melanoma. We aimed to assess the role of bevacizumab as adjuvant treatment for patients with resected melanoma at high risk of recurrence. We report results from the preplanned interim analysis. We did a multicentre, open-label, randomised controlled phase 3 trial at 48 centres in the UK between July 18, 2007, and March 29, 2012. Patients aged 16 years or older with American Joint Committee on Cancer stage (AJCC) stage IIB, IIC, and III cutaneous melanoma were randomly allocated (1:1), via a central, computer-based minimisation procedure, to receive intravenous bevacizumab 7·5 mg/kg, every 3 weeks for 1 year, or to observation. Randomisation was stratified by Breslow thickness of the primary tumour, N stage according to AJCC staging criteria, ulceration of the primary tumour, and patient sex. The primary endpoint was overall survival; secondary endpoints included disease-free interval, distant-metastases interval and quality of life. Analysis was by intention-to-treat. This trial is registered as an International Standardised Randomised Controlled Trial, number ISRCTN81261306. 1343 patients were randomised to either the bevacizumab group (n=671) or the observation group (n=672). Median follow-up was 25 months (IQR 16–37) in the bevacizumab group and 25 months (17–37) in the observation group. At the time of interim analysis, 286 (21%) of 1343 enrolled patients had died: 140 (21%) of 671 patients in the bevacizumab group, and 146 (22%) of 672 patients in the observation group. 134 (96%) of patients in the bevacizumab group died because of melanoma versus 139 (95%) in the observation group. We noted no significant difference in overall survival between treatment groups (hazard ratio [HR] 0·97, 95% CI 0·78–1·22; p=0·76); this finding persisted after adjustment for stratification variables (HR 1·03; 95% CI 0·81–1·29; p=0·83). Median duration of treatment with bevacizumab was 51 weeks (IQR 21–52) and dose intensity was 86% (41–96), showing good tolerability. 180 grade 3 or 4 adverse events were recorded in 101 (15%) of 671 patients in the bevacizumab group, and 36 (5%) of 672 patients in the observation group. Bevacizumab resulted in a higher incidence of grade 3 hypertension than did observation (41 [6%] vs one [<1%]). There was an improvement in disease-free interval for patients in the bevacizumab group compared with those in the observation group (HR 0·83, 95% CI 0·70–0·98, p=0·03), but no significant difference between groups for distant-metastasis-free interval (HR 0·88, 95% CI 0·73–1·06, p=0·18). No significant differences were noted between treatment groups in the standardised area under the curve for any of the quality-of-life scales over 36 months. Three adverse drug reactions were regarded as both serious and unexpected: one patient had optic neuritis after the first bevacizumab infusion, a second patient had persistent erectile dysfunction, and a third patient died of a haemopericardium after receiving two bevacizumab infusions and was later identified to have had significant predisposing cardiovascular risk factors. Bevacizumab has promising tolerability. Longer follow-up is needed to identify an effect on the primary endpoint of overall survival at 5 years. Cancer Research UK.

Regorafenib inhibits VEGF receptors 1, 2, and 3 and PDGF receptors like other anti-angiogenic tyrosine-kinase inhibitors approved for treatment of advanced renal-cell cancer. Regorafenib also inhibits other potentially important angiogenic kinases like TIE2, activation of which is thought to be important in tumour escape mechanisms. This phase 2, open-label, non-randomised study assessed the safety and efficacy of the multikinase inhibitor regorafenib for treatment of renal-cell carcinoma. Patients were recruited from 18 academic oncology centres across Europe and USA. Patients with previously untreated metastatic or unresectable clear-cell renal-cell carcinoma received oral regorafenib (160 mg per day) in repeating cycles of 3 weeks on, 1 week off until disease progression or until patients met the criteria for removal from study. The primary efficacy endpoint was the proportion of patients who achieved an objective overall response, assessed in all patients who were evaluable for response. The trial has finished. This trial is registered with ClinicalTrials.gov, number NCT00664326. The study was done between April 30, 2008, and June 1, 2011. We screened 64 patients, of whom 49 received regorafenib. Median duration of treatment was 7·1 months (range 0·7–34·4, IQR 2·5–18·0) and at the time of data cutoff, six patients (12%) were still receiving treatment. 48 patients were assessable for tumour response. 19 patients (39·6%, 90% CI 27·7–52·5) had an objective response, all of which were partial responses. Drug-related adverse events occurred in 48 patients (98%) and drug-related serious adverse events in 17 (35%). Grade 3 drug-related adverse events were common, most frequently hand and foot skin reaction (16 patients, 33%), diarrhoea (five patients, 10%), renal failure (five patients, 10%), fatigue (four patients, 8%), and hypertension (three patients, 6%). Two patients had grade 4 treatment-related adverse events: two cardiac ischaemia or infarction, one hypomagnesaemia, and one pain in the chest or thorax. Four patients died during study treatment or within 30 days of last dose, of which two were deemed likely to be related to the study drug. Regorafenib has antitumour activity as first-line treatment for metastatic or unresectable renal-cell carcinoma. The drug's safety profile requires close monitoring. Bayer HealthCare Pharmaceuticals.

Cisplatin-based chemotherapy is standard of care for patients with transitional cell bladder cancer; however, many of these patients suffer from renal impairment and are considered unfit for such treatment. Nicholson discusses whether this degree of caution is warranted, and what alternatives should be considered in patients for whom cisplatin is genuinely contraindicated. Carcinoma of the bladder is a common, chemosensitive malignancy. The value of chemotherapy for transitional cell carcinoma (the commonest malignant bladder histology in the developed world) has been demonstrated in both the palliative and the neoadjuvant settings, with survival benefits in both scenarios being achieved with cisplatin-based regimens. Conventional drug treatment is, therefore, dependent on adequate renal function, but renal impairment is a common confounding factor in patients with bladder cancer, due in part to obstruction of the urinary tract and in part to comorbidity in an elderly population. A recent consensus statement deems patients with impaired renal function unsuitable for cisplatin treatment, but the limited available evidence does not support the exclusion of cisplatin in patients with moderate renal impairment. The literature on which to base alternative, non-cisplatin-based chemotherapy is inadequate, but the perception that carboplatin-based combinations are inferior to cisplatin-based combinations is probably incorrect. Trials are needed to specifically examine chemotherapy in patients with bladder cancer and renal impairment.

Essential for students of theatre studies, Methuen Drama’s Decades of Modern British Playwriting series provides a comprehensive survey and study of the theatre produced in each decade from the 1950s to 2009 in six volumes. Each volume features a critical analysis and reevaluation of the work of four key playwrights from that decade authored by a team of experts, together with an extensive commentary on the period. The 1960s was a decade of seismic changes in British theatre as in society at large. This important new study in Methuen Drama’s Decades of Modern British Playwriting series explores how theatre-makers responded to the changes in society. Together with a thorough survey of the theatrical activity of the decade it offers detailed reassessments of the work of four of the leading playwrights. The 1960s volume provides in-depth studies of the work of four of the major playwrights who came to prominence: Edward Bond (by Steve Nicholson), John Arden (Bill McDonnell), Harold Pinter (Jamie Andrews) and Alan Ayckbourn (Frances Babbage). It examines their work then, its legacy today, and how critical consensus has changed over time.

BackgroundWe investigated the first-line activity of vinflunine in patients with penis cancer. Cisplatin-based combinations are commonly used, but survival is not prolonged; many patients are unfit for such treatment or experience toxicity that outweighs clinical benefit.MethodsTwenty-five patients with inoperable squamous carcinoma of the penis were recruited to a single-arm, Fleming–A’Hern exact phase II trial. Treatment comprised 4 cycles of vinflunine 320 mg/m2, given every 21 days. Primary endpoint was clinical benefit rate (CBR: objective responses plus stable disease) assessed after 4 cycles. Seven or more objective responses or disease stabilisations observed in 22 evaluable participants would exclude a CBR of <15%, with a true CBR of >40% being probable.ResultsTwenty-two participants were evaluable. Ten objective responses or disease stabilisations were confirmed. CBR was 45.5%, meeting the primary endpoint; partial response rate was 27.3%. Seven patients received >4 cycles of vinflunine. Dose reduction or treatment delay was required for 20% of cycles. In all, 68% of patients experienced at least one grade 3 adverse event. Two deaths on treatment were not caused by disease progression.ConclusionsPre-specified clinical activity threshold was exceeded. Toxicity was in keeping with experience in other tumours. Vinflunine merits further study in this disease.Trial registrationNCT02057913.

The management of uncommon urological malignancies is rarely based on evidence from prospective trials, and ad hoc treatment by individual clinicians who seldom encounter the cancer is not ideal for the patient. In this article, Nicholson identifies key issues in developing a trial strategy for treating rare urological malignancies.