Piers Gaunt

Surgical excision margins in primary cutaneous melanoma: A meta-analysis and Bayesian probability evaluation.

BACKGROUND Surgery is the only curative treatment for primary cutaneous melanoma, therefore it is important to determine excision margins that minimise risk of local recurrence, distant recurrence and death. METHODS MEDLINE, EMBASE and Cochrane CENTRAL were searched from 2009 to 2015. Inclusion criteria were: population/setting - patients with primary melanoma; comparison - narrow versus wide margins; outcomes - overall survival, melanoma-specific survival, recurrence-free survival, and loco-regional recurrence; design - randomized controlled trials (RCTs). Results were pooled using meta-analysis and data explored using likelihood Bayesian probability plots. RESULTS Six RCTs with 4233 patients were included. Narrow margins were defined as 1 or 2 cm of clinically normal skin around the melanoma; wide margins as 3, 4 or 5 cm. Hazard ratios (HR) were as follows (HR>1 indicates wide margin better): overall survival 1.09 (95% CI 0.98-1.22; p=0.1); melanoma-specific survival 1.17 (CI 1.03-1.34; p=0.02); recurrence-free survival 1.08 (CI 0.97-1.20; p=0.2); loco-regional recurrence 1.10 (CI 0.96-1.26; p=0.2), with no evidence of heterogeneity between trials for any end point or within subgroup analyses. There was an 94% probability that overall survival was worse with a narrow margin and a 43% probability that it was more than 10% worse in proportional terms (i.e. HR>1.1). Probabilities that narrow margins were worse were 99%, 92% and 92% for melanoma-specific survival, recurrence-free survival and loco-regional recurrence respectively. CONCLUSIONS Contrary to recommendations in several national guidelines that narrow margins are safe, this systematic review and meta-analysis provides evidence that a narrow margin may lead to a worse outcome than a wide margin.

Identifying patients with nonalcoholic steatohepatitis that are nonresponders to therapy

Alessandra Mangia, M.D. Gregory J. Dore, M.D., Ph.D. Andrew R. Lloyd, M.D., Ph.D. Jacob George, M.D., Ph.D. Mohammed Eslam, M.D., Ph.D. Storr Liver Centre Westmead Millennium Institute and Westmead Hospital University of Sydney Sydney, Australia Division of Hepatology Ospedale Casa Sollievo della Sofferenza, IRCCS San Giovanni Rotondo, Italy Kirby Institute The University of New South Wales Sydney, NSW, Australia School of Medical Sciences, University of New South Wales, Sydney, Australia

Feasibility of Dose-escalated Hypofractionated Chemoradiation in Human Papilloma Virus-negative or Smoking-associated Oropharyngeal Cancer

AIMS Oropharyngeal squamous cell carcinoma (OPSCC) can be divided into favourable and poor prognostic groups by association with human papilloma virus (HPV) and smoking. This study prospectively investigated a dose-intensified schedule in poor/intermediate prognosis OPSCC. MATERIALS AND METHODS Patients with p16/HPV-negative or p16-positive N2b OPSCC with a greater than 10 pack-year smoking history were eligible. Patients were planned to receive 64 Gy in 25 fractions with cisplatin. The primary end point was absence of grade 3 mucositis at 3 months. RESULTS Fifteen patients were recruited over 14 months. All patients completed a minimum of 2 years of follow-up. All patients completed full-dose radiotherapy within a median treatment time of 32 days (31-35). Grade 3 mucositis was absent in all patients at 3 months. There was one grade 4 toxicity event due to cisplatin (hypokalaemia). Complete response rates at 3 months were 100% and 93% for local disease and lymph nodes, respectively. One patient developed metastatic disease and subsequently died. Overall survival at 2 years was 93% (95% confidence interval 61-99%). CONCLUSIONS The schedule of 64 Gy in 25 fractions with concomitant chemotherapy is tolerable in patients with poor and intermediate prognosis OPSCC.

Identifying patients with NASH that are non‐responders to therapy

Alessandra Mangia, M.D. Gregory J. Dore, M.D., Ph.D. Andrew R. Lloyd, M.D., Ph.D. Jacob George, M.D., Ph.D. Mohammed Eslam, M.D., Ph.D. Storr Liver Centre Westmead Millennium Institute and Westmead Hospital University of Sydney Sydney, Australia Division of Hepatology Ospedale Casa Sollievo della Sofferenza, IRCCS San Giovanni Rotondo, Italy Kirby Institute The University of New South Wales Sydney, NSW, Australia School of Medical Sciences, University of New South Wales, Sydney, Australia

The design of a multi-arm multi-stage (MAMS) phase III randomised controlled trial comparing alternative regimens for escalating (COMPARE) treatment of intermediate and high-risk oropharyngeal cancer with reflections on the complications of introducing a new experimental ARM

CompARE is a pragmatic multicentre open-label phase III randomised controlled trial aiming to determine if intensification of treatment in intermediate and high risk oropharyngeal cancer (OPC) patients improves the definitive primary outcome measure of overall survival time. The trial evaluates three experimental arms separately against one control arm using a MAMS design, with three interim assessments of disease-free survival time. Experimental arms will be discontinued if they fail to meet the interim assessment criteria. The timing of these assessments is driven by the number of control events, with the study engineered so these occur approximately annually. The design characteristics will be presented. A potential additional experimental arm for treatment of OPC was proposed during CompARE initiation, and could be introduced into the trial after one year if approved. The straightforward implication is an increase in the number of patients required to recruit per year or an increase in trial duration. However in a complex MAMS design, a balance of multiple factors such as a feasible sample size, trial duration and appropriate number and timing of interim assessments with appropriate statistical error rates, have to be carefully considered. Using the nstage and artpep programs in Stata, a review of the operating characteristics of both the original design and expanded design with the new experimental arm was undertaken. The recruitment and statistical implications of the addition of the new experimental arm and an evaluation of the study duration to changes in recruitment predictions will be presented.

The hypoxia marker CAIX is prognostic in the UK phase III VorteX-Biobank cohort: an important resource for translational research in soft tissue sarcoma

Background:Despite high metastasis rates, adjuvant/neoadjuvant systemic therapy for localised soft tissue sarcoma (STS) is not used routinely. Progress requires tailoring therapy to features of tumour biology, which need exploration in well-documented cohorts. Hypoxia has been linked to metastasis in STS and is targetable. This study evaluated hypoxia prognostic markers in the phase III adjuvant radiotherapy VorteX trial.Methods:Formalin-fixed paraffin-embedded tumour biopsies, fresh tumour/normal tissue and blood were collected before radiotherapy. Immunohistochemistry for HIF-1α, CAIX and GLUT1 was performed on tissue microarrays and assessed by two scorers (one pathologist). Prognostic analysis of disease-free survival (DFS) used Kaplan–Meier and Cox regression.Results:Biobank and outcome data were available for 203 out of 216 randomised patients. High CAIX expression was associated with worse DFS (hazard ratio 2.28, 95% confidence interval: 1.44–3.59, P<0.001). Hypoxia-inducible factor-1α and GLUT1 were not prognostic. Carbonic anhydrase IX remained prognostic in multivariable analysis.Conclusions:The VorteX-Biobank contains tissue with linked outcome data and is an important resource for research. This study confirms hypoxia is linked to poor prognosis in STS and suggests that CAIX may be the best known marker. However, overlap between single marker positivity was poor and future work will develop an STS hypoxia gene signature to account for tumour heterogeneity.

Reply to response to Wheatley et al., “Surgical excision margins in primary cutaneous melanoma: A meta-analysis and Bayesian probability evaluation” Cancer Treatment Reviews April 2016;45:76

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