SummaryBackgroundThe incidence of human papillomavirus (HPV)-positive oropharyngeal cancer, a disease affecting younger patients, is rapidly increasing. Cetuximab, an epidermal growth factor receptor inhibitor, has been proposed for treatment de-escalation in this setting to reduce the toxicity of standard cisplatin treatment, but no randomised evidence exists for the efficacy of this strategy.MethodsWe did an open-label randomised controlled phase 3 trial at 32 head and neck treatment centres in Ireland, the Netherlands, and the UK, in patients aged 18 years or older with HPV-positive low-risk oropharyngeal cancer (non-smokers or lifetime smokers with a smoking history of <10 pack-years). Eligible patients were randomly assigned (1:1) to receive, in addition to radiotherapy (70 Gy in 35 fractions), either intravenous cisplatin (100 mg/m2 on days 1, 22, and 43 of radiotherapy) or intravenous cetuximab (400 mg/m2 loading dose followed by seven weekly infusions of 250 mg/m2). The primary outcome was overall severe (grade 3–5) toxicity events at 24 months from the end of treatment. The primary outcome was assessed by intention-to-treat and per-protocol analyses. This trial is registered with the ISRCTN registry, number ISRCTN33522080.FindingsBetween Nov 12, 2012, and Oct 1, 2016, 334 patients were recruited (166 in the cisplatin group and 168 in the cetuximab group). Overall (acute and late) severe (grade 3–5) toxicity did not differ significantly between treatment groups at 24 months (mean number of events per patient 4·8 [95% CI 4·2–5·4] with cisplatin vs 4·8 [4·2–5·4] with cetuximab; p=0·98). At 24 months, overall all-grade toxicity did not differ significantly either (mean number of events per patient 29·2 [95% CI 27·3–31·0] with cisplatin vs 30·1 [28·3–31·9] with cetuximab; p=0·49). However, there was a significant difference between cisplatin and cetuximab in 2-year overall survival (97·5% vs 89·4%, hazard ratio 5·0 [95% CI 1·7–14·7]; p=0·001) and 2-year recurrence (6·0% vs 16·1%, 3·4 [1·6–7·2]; p=0·0007).InterpretationCompared with the standard cisplatin regimen, cetuximab showed no benefit in terms of reduced toxicity, but instead showed significant detriment in terms of tumour control. Cisplatin and radiotherapy should be used as the standard of care for HPV-positive low-risk patients who are able to tolerate cisplatin.FundingCancer Research UK.

BackgroundMost patients with pulmonary embolism (PE) spend 5–7 days in hospital even though only 4.5% will develop serious complications during this time. In particular, the group of patients with incidentally diagnosed PE (i-PE) includes many patients with low risk features potentially ideal for outpatient management; however the evidence for their optimal management is lacking hence relative practices may vary considerably. We describe the development process, components, links and function of a nurse-led service for the management of patients with i-PE, developed in accordance to the UK Medical Research Council complex intervention guidance.MethodsPhase 0 (Theoretical underpinning): The Pulmonary Embolism Severity Index (PESI) was selected for patient risk assessment and the American Society of Clinical Oncology (ASCO) guideline for the management of PE in cancer patients (2007) was selected as quality measure. Historical registry and audit data from our centre regarding i-PE incidence and management for the period between 2006 and 2009 illustrating the then current practices were reviewed. Phase 1 (Modelling): Modelling of the pathway included the following: a) Identification of training needs, planning and implementation of training schemes and development of transferable competencies and training materials. b) Mapping patient pathways and flow and c) Production of key documentation and Standard Operating Procedures for the delivery of the service.ResultsPhase 2 (Implementation and testing of the intervention): During the initial 12 months of implementation, remedial action was taken to address identified deficiencies regarding patient referral to the pathway, compliance with treatment protocol, patient follow up, selection challenges from the use of PESI in cancer patients and challenges regarding the “first-pass” identification of i-PE.ConclusionWe have developed and piloted a complex intervention to manage cancer patients with incidental PE in an outpatient setting. Adherence to evidence- based care, improvement of communication between professionals and patients, and improved quality of data is demonstrated.

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TOL101 is a murine IgM mAb targeting the αβ TCR. Unlike other T cell targets, the αβ TCR has no known intracellular signaling domains and may provide a nonmitogenic target for T cell inactivation. We report the 6-month Phase 2 trial data testing TOL101 in kidney transplantation. The study was designed to identify a dose that resulted in significant CD3 T cell modulation (<25 T cell/mm3), to examine the safety and tolerability of TOL101 and to obtain preliminary efficacy information. Thirty-six patients were enrolled and given 5–10 daily doses of TOL101; 33 patients completed dosing, while three discontinued after two doses due to a self-limiting urticarial rash. Infusion adjustments, antihistamines, steroids and dose escalation of TOL101 reduced the incidence of the rash. Doses of TOL101 above 28mg resulted in prolonged CD3 modulation, with rapid recovery observed 7 days after therapy cessation. There were no cases of patient or graft loss. Few significant adverse events were reported, with one nosocomial pneumonia. There were five biopsy-confirmed acute cellular rejections (13.9%); however, no donor-specific antibodies were detected. Overall TOL101 was well-tolerated, supporting continued clinical development using the dose escalating 21– 28–42–42–42mg regimen.

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