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.

This is the official guideline endorsed by the specialty associations involved in the care of head and neck cancer patients in the UK. Significantly new data have been published on laryngeal cancer management since the last edition of the guidelines. This paper discusses the evidence base pertaining to the management of laryngeal cancer and provides updated recommendations on management for this group of patients receiving cancer care.Recommendations• Radiotherapy (RT) and transoral laser microsurgery (TLM) are accepted treatment options for T1a–T2a glottic carcinoma. (R)• Open partial surgery may have a role in the management of selected tumours. (R)• Radiotherapy, TLM and transoral robotic surgery are reasonable treatment options for T1–T2 supraglottic carcinoma. (R)• Supraglottic laryngectomy may have a role in the management of selected tumours. (R)• Most patients with T2b–T3 glottic cancers are suitable for non-surgical larynx preservation therapies. (R)• Concurrent chemoradiotherapy should be regarded as the standard of care for non-surgical management. (R)• Subject to the availability of appropriate surgical expertise and multi-disciplinary rehabilitation services, TLM or open partial surgical procedures ± post-operative RT, may be also be appropriate in selected cases. (R)• In the absence of clinical or radiological evidence of nodal disease, elective treatment (RT or surgery ± post-operative RT) is recommended to at least lymph node levels II, III and IV bilaterally. In node positive disease, it is recommended that lymph node levels II–V should be treated on the involved side. If level II nodes are involved, then elective irradiation of ipsilateral level Ib nodes may be considered. (R)• Most patients with T3 supraglottic cancers are suitable for non-surgical larynx preservation therapies. (R)• Concurrent chemoradiotherapy should be regarded as the standard of care for non-surgical management. (R)• Subject to the availability of appropriate surgical expertise and multi-disciplinary rehabilitation services, TLM or open partial surgical procedures ± post-operative RT, may also be appropriate in selected cases. (R)• In the absence of clinical or radiological evidence of nodal disease, elective treatment (RT or surgery ± post-operative RT) is recommended to at least lymph node levels II, III and IV bilaterally. In node positive disease, lymph node levels II–V should be treated on the involved side. (R)• As per the PET-Neck clinical trial, patients with N2 or N3 neck disease who undergo treatment with chemoradiotherapy to their laryngeal primary and experience a complete response with a subsequent negative post-treatment positron emission tomography combined with computed tomography (PET–CT) scan do not require an elective neck dissection. In contrast, patients who have a partial response to treatment or have increased uptake on a post-treatment PET–CT scan should have a neck dissection. (R)• Larynx preservation with concurrent chemoradiotherapy should be considered for T4 tumours, unless there is tumour invas...

IMPORTANCE Malignant spinal canal compression, a major complication of metastatic cancer, is managed with radiotherapy to maintain mobility and relieve pain, although there is no standard radiotherapy regimen. OBJECTIVE To evaluate whether single-fraction radiotherapy is noninferior to 5 fractions of radiotherapy. DESIGN, SETTING, AND PARTICIPANTS Multicenter noninferiority randomized clinical trial conducted in 42 UK and 5 Australian radiotherapy centers. Eligible patients (n = 686) had metastatic cancer with spinal cord or cauda equina compression, life expectancy greater than 8 weeks, and no previous radiotherapy to the same area. Patients were recruited between February 2008 and April 2016, with final follow-up in September 2017. INTERVENTIONS Patients were randomized to receive external beam single-fraction 8-Gy radiotherapy (n = 345) or 20 Gy of radiotherapy in 5 fractions over 5 consecutive days (n = 341). MAIN OUTCOMES AND MEASURES The primary end point was ambulatory status at week 8, based on a 4-point scale and classified as grade 1 (ambulatory without the use of aids and grade 5 of 5 muscle power) or grade 2 (ambulatory using aids or grade 4 of 5 muscle power). The noninferiority margin for the difference in ambulatory status was −11%. Secondary end points included ambulatory status at weeks 1, 4, and 12 and overall survival. RESULTS Among 686 randomized patients (median [interquartile range] age, 70 [64-77] years; 503 (73%) men; 44% had prostate cancer, 19% had lung cancer, and 12% had breast cancer), 342 (49.8%) were analyzed for the primary end point (255 patients died before the 8-week assessment). Ambulatory status grade 1 or 2 at week 8 was achieved by 115 of 166 (69.3%) patients in the single-fraction group vs 128 of 176 (72.7%) in the multifraction group (difference, −3.5% [1-sided 95% CI, −11.5% to ϱ]; P value for noninferiority = .06). The difference in ambulatory status grade 1 or 2 in the single-fraction vs multifraction group was −0.4% (63.9% vs 64.3%; [1-sided 95% CI, −6.9 to ϱ]; P value for noninferiority = .004) at week 1, −0.7% (66.8% vs 67.6%; [1-sided 95% CI, −8.1 to ϱ]; P value for noninferiority = .01) at week 4, and 4.1% (71.8% vs 67.7%; [1-sided 95% CI, −4.6 to ϱ]; P value for noninferiority = .002) at week 12. Overall survival rates at 12 weeks were 50% in the single-fraction group vs 55% in the multifraction group (stratified hazard ratio, 1.02 [95% CI, 0.74-1.41]). Of the 11 other secondary end points that were analyzed, the between-group differences were not statistically significant or did not meet noninferiority criterion. CONCLUSIONS AND RELEVANCE Among patients with malignant metastatic solid tumors and spinal canal compression, a single radiotherapy dose, compared with a multifraction dose delivered over 5 days, did not meet the criterion for noninferiority for the primary outcome (ambulatory at 8 weeks). However, the extent to which the lower bound of the CI overlapped with the noninferiority margin should be considered when interpreting the clinical importance of this...

The purpose of this ethics committee approved prospective study was to evaluate an image acquisition and registration protocol for hyperpolarized helium-3 magnetic resonance imaging ((3)He-MRI) and x-ray computed tomography. Nine patients with non-small cell lung cancer (NSCLC) gave written informed consent to undergo a free-breathing CT, an inspiration breath-hold CT and a 3D ventilation (3)He-MRI in CT position using an elliptical birdcage radiofrequency (RF) body coil. (3)He-MRI to CT image fusion was performed using a rigid registration algorithm which was assessed by two observers using anatomical landmarks and a percentage volume overlap coefficient. Registration of (3)He-MRI to breath-hold CT was more accurate than to free-breathing CT; overlap 82.9 +/- 4.2% versus 59.8 +/- 9.0% (p < 0.001) and mean landmark error 0.75 +/- 0.24 cm versus 1.25 +/- 0.60 cm (p = 0.002). Image registration is significantly improved by using an imaging protocol that enables both (3)He-MRI and CT to be acquired with similar breath holds and body position through the use of a birdcage (3)He-MRI body RF coil and an inspiration breath-hold CT. Fusion of (3)He-MRI to CT may be useful for the assessment of patients with lung diseases.

Human papillomavirus (HPV) infection is causally related to a subset of oropharyngeal carcinomas (OPC) and is linked to a more favourable prognosis compared to HPV-negative OPC. The mechanisms underlying this effect on prognosis are not fully understood, but interactions with the tumour microenvironment may be pivotal. Here, we investigated the role of the tumour microenvironment in HPV-positive compared to HPV-negative cancer using 2D and 3D modelling of OPC interactions with stromal fibroblasts. HPV-negative, but not HPV-positive, OPC-derived cell lines induced a rapid fibroblast secretory response that supported 2D cancer cell migration and invasion in vitro. Array profiling of this HPV-negative induced fibroblast secretome identified hepatocyte growth factor (HGF) as the principal secreted factor that promoted cancer cell migration. The interaction between HPV-negative cell lines and fibroblasts in 2D was prevented using c-Met (HGF receptor) inhibitors, which further restricted both HPV-negative and positive cell invasion in 3D co-culture models. Furthermore, we discovered a synergistic relationship between HGF and IL-6 in the support of migration that relates JAK activation to HGF responsiveness in HPV-negative lines. In summary, our data show significant differences in the interactions between HPV-positive and HPV-negative OPC cells and stromal fibroblasts. In addition, we, provide in vitro evidence to support the clinical application of c-MET inhibitors in the control of early HPV-negative OPC.