A. Hartley

Cancer of the anal canal.

Anal cancer is an uncommon tumour that represents 4% of all cancers of the lower gastrointestinal tract. Its pathogenesis and treatment have undergone substantial reassessment over the past two decades, and this is likely to continue. Anal cancer can be cured by synchronous chemoradiotherapy, a treatment that both enables anal continence to be retained and reserves abdominoperineal resection of the rectum and anal canal (with formation of a permanent colostomy) for recurrent or residual disease after primary chemoradiotherapy. Overall, survival from anal cancer is now around 70-80% at 5 years. Future challenges will be influenced by an increasing incidence due to human papillomavirus and HIV infection, more accurate characterisation and treatment of early (in situ) disease, and optimisation of chemoradiation regimens.

PET-CT Surveillance versus Neck Dissection in Advanced Head and Neck Cancer

BACKGROUND The role of image-guided surveillance as compared with planned neck dissection in the treatment of patients with squamous-cell carcinoma of the head and neck who have advanced nodal disease (stage N2 or N3) and who have received chemoradiotherapy for primary treatment is a matter of debate. METHODS In this prospective, randomized, controlled trial, we assessed the noninferiority of positron-emission tomography-computed tomography (PET-CT)-guided surveillance (performed 12 weeks after the end of chemoradiotherapy, with neck dissection performed only if PET-CT showed an incomplete or equivocal response) to planned neck dissection in patients with stage N2 or N3 disease. The primary end point was overall survival. RESULTS From 2007 through 2012, we recruited 564 patients (282 patients in the planned-surgery group and 282 patients in the surveillance group) from 37 centers in the United Kingdom. Among these patients, 17% had nodal stage N2a disease and 61% had stage N2b disease. A total of 84% of the patients had oropharyngeal cancer, and 75% had tumor specimens that stained positive for the p16 protein, an indicator that human papillomavirus had a role in the causation of the cancer. The median follow-up was 36 months. PET-CT-guided surveillance resulted in fewer neck dissections than did planned dissection surgery (54 vs. 221); rates of surgical complications were similar in the two groups (42% and 38%, respectively). The 2-year overall survival rate was 84.9% (95% confidence interval [CI], 80.7 to 89.1) in the surveillance group and 81.5% (95% CI, 76.9 to 86.3) in the planned-surgery group. The hazard ratio for death slightly favored PET-CT-guided surveillance and indicated noninferiority (upper boundary of the 95% CI for the hazard ratio, <1.50; P=0.004). There was no significant difference between the groups with respect to p16 expression. Quality of life was similar in the two groups. PET-CT-guided surveillance, as compared with neck dissection, resulted in savings of £1,492 (approximately

A Recombinant Modified Vaccinia Ankara Vaccine Encoding Epstein–Barr Virus (EBV) Target Antigens: A Phase I Trial in UK Patients with EBV-Positive Cancer

2,190 in U.S. dollars) per person over the duration of the trial. CONCLUSIONS Survival was similar among patients who underwent PET-CT-guided surveillance and those who underwent planned neck dissection, but surveillance resulted in considerably fewer operations and it was more cost-effective. (Funded by the National Institute for Health Research Health Technology Assessment Programme and Cancer Research UK; PET-NECK Current Controlled Trials number, ISRCTN13735240.).

HYPOFRACTIONATED ACCELERATED RADIOTHERAPY WITH CONCURRENT CHEMOTHERAPY FOR LOCALLY ADVANCED SQUAMOUS CELL CARCINOMA OF THE HEAD AND NECK

Purpose: Epstein–Barr virus (EBV) is associated with several cancers in which the tumor cells express EBV antigens EBNA1 and LMP2. A therapeutic vaccine comprising a recombinant vaccinia virus, MVA-EL, was designed to boost immunity to these tumor antigens. A phase I trial was conducted to demonstrate the safety and immunogenicity of MVA-EL across a range of doses. Experimental Design: Sixteen patients in the United Kingdom (UK) with EBV-positive nasopharyngeal carcinoma (NPC) received three intradermal vaccinations of MVA-EL at 3-weekly intervals at dose levels between 5 × 107 and 5 × 108 plaque-forming units (pfu). Blood samples were taken at screening, after each vaccine cycle, and during the post-vaccination period. T-cell responses were measured using IFNγ ELISpot assays with overlapping EBNA1/LMP2 peptide mixes or HLA-matched epitope peptides. Polychromatic flow cytometry was used to characterize functionally responsive T-cell populations. Results: Vaccination was generally well tolerated. Immunity increased after vaccination to at least one antigen in 8 of 14 patients (7/14, EBNA1; 6/14, LMP2), including recognition of epitopes that vary between EBV strains associated with different ethnic groups. Immunophenotypic analysis revealed that vaccination induced differentiation and functional diversification of responsive T-cell populations specific for EBNA1 and LMP2 within the CD4 and CD8 compartments, respectively. Conclusions: MVA-EL is safe and immunogenic across diverse ethnicities and thus suitable for use in trials against different EBV-positive cancers globally as well as in South-East Asia where NPC is most common. The highest dose (5 × 108 pfu) is recommended for investigation in current phase IB and II trials. Clin Cancer Res; 20(19); 5009–22. ©2014 AACR.

Correlation of currently used radiobiological parameters with local control and acute and late mucosal toxicity in randomised studies of altered fractionation for locally advanced head and neck cancer.

AIMS Hypofractionated accelerated radiotherapy with concurrent carboplatin utilises both advantages of altered fractionation and synchronous chemotherapy to maximise local control in locally advanced head and neck cancer. Such fractionation schedules are increasingly used in the intensity-modulated radiotherapy era and the aim of this study was to determine the outcome of hypofractionated accelerated radiotherapy with carboplatin. MATERIALS AND METHODS One hundred and fifty consecutive patients with squamous cell carcinoma of the larynx, oropharynx, oral cavity and hypopharynx (International Union Against Cancer [IUAC] stage II-IV) treated with 55Gy in 20 fractions over 25 days with concurrent carboplatin were analysed. Outcome measures were 2 year overall survival, local control and disease-free survival. RESULTS The median follow-up in surviving patients was 25 months. IUAC stages: II n=15; III n=42; IV n=93. Two year overall survival for all patients was 74.9% (95% confidence interval 66.0-81.7%). Two year local control was 78.3% (95% confidence interval 69.6-84.8%). Two year disease-free survival was 67.2% (95% confidence interval 58.3-74.7%). There were 135 patients with stage III and IV disease. For these patients, the 2 year overall survival, local control and disease-free survival were 74.3% (95% confidence interval 64.7-81.6%), 79.1% (95% confidence interval 69.8-85.9%) and 67.6% (95% confidence interval 58.0-75.4%), respectively. Prolonged grade 3 and 4 mucositis seen at ≥4 weeks were present in 9 and 0.7%, respectively. Late feeding dysfunction (determined by dependence on a feeding tube at 1 year) was seen in 13% of the surviving patients at 1 year. CONCLUSION Hypofractionated accelerated radiotherapy with concurrent carboplatin achieves a high local control. This regimen should be considered for a radiotherapy dose-escalation study using intensity-modulated radiotherapy.

Revising the Radiobiological Model of Synchronous Chemotherapy in Head-and-Neck Cancer: A New Analysis Examining Reduced Weighting of Accelerated Repopulation

AIMS There has been a resurgence in interest in radiobiological modelling in head and neck cancer. The aim of this study was to determine if currently used parameters accurately predict both tumour and toxicity outcomes. MATERIALS AND METHODS Trials were identified from a recent meta-analysis of altered fractionation. The tumour biologically effective dose (tBED; α/β=10Gy, t(k) [onset time of accelerated repopulation]=22 days, t(p) [average doubling time during accelerated repopulation]=3 days, α=0.3Gy(-1)), acute mucosal biologically effective dose (amBED; α/β=10Gy, t(k)=7 days, t(p)=2.5 days, α=0.3Gy(-1)) and late mucosal biologically effective dose (lmBED; α/β=3Gy) were calculated for each arm of each trial. The correlation between the absolute percentage difference in BED between treatment arms and the observed percentage difference in local control, acute grade 3 mucositis and late grade 3 mucosal reaction was then assessed. RESULTS A strong correlation was observed between the percentage difference in tBED and the percentage difference in local control (P=0.006). A trend towards a correlation was seen between the percentage difference in amBED and the percentage difference in acute grade 3 mucositis (P=0.06). A significant correlation was observed between the percentage difference in lmBED and the percentage difference in grade 3 late mucosal toxicity (P=0.02). However, a 15% decrease in lmBED between control and experimental arms of the study was necessary for any sparing of late mucosal toxicity to be observed. CONCLUSIONS Currently used parameters for tumour accurately predict outcomes in randomised trials of altered fractionation. Although the relationship may be more complex for late mucosal reaction, the presence of a correlation is noteworthy given the infrequent reporting or occurrence of this toxicity. In the future, radiobiological modelling with the addition of volumetric parameters will be highly relevant, given attempts to dose escalate with intensity-modulated radiotherapy in poor risk patients and de-escalate in patients with an excellent prognosis.

PET-NECK: a multicentre randomised Phase III non-inferiority trial comparing a positron emission tomography-computerised tomography-guided watch-and-wait policy with planned neck dissection in the management of locally advanced (N2/N3) nodal metastases in patients with squamous cell head and neck cancer

PURPOSE Previous studies of synchronous chemoradiation therapy have modeled the additional effect of chemotherapy as additional radiation therapy biologically effective dose (BED). Recent trials of accelerated versus conventional fractionation chemoradiation have cast doubt on such modeling. The purpose of this study was to identify alternative models. METHODS AND MATERIALS Nine trials of platinum-based chemoradiation were identified. In radiation therapy-alone arms, the radiation therapy BED for tumor was calculated using standard parameters. In chemoradiation arms, 3 methods were used to calculate tumor BED (tBED): additional BED, addition of 9.3 Gy BED for tumor to the radiation therapy BED; zero repopulation, BED with no correction for repopulation; variable t(p) (the average doubling time during accelerated repopulation), values of t(p) 3-10 were used to examine a partial suppression of repopulation. The correlations between the calculated percentage change in tBED for each method and observed percentage change in local control were assessed using the Pearson product moment correlation. RESULTS Significant correlations were obtained for all 3 methods but were stronger with zero repopulation (P=.0002) and variable tp (t(p) = 10) (P=.0005) than additional BED (P=.02). CONCLUSIONS Radiobiological models using modified parameters for accelerated repopulation seem to correlate strongly with outcome in chemoradiation studies. The variable tp method shows strong correlation for outcome in local control and is potentially a more suitable model in the chemoradiation setting. However, a lack of trials with an overall treatment time of more than 46 days inhibits further differentiation of the optimal model.

WITHDRAWN: Does Dose to an Oral Mucosa Organ at Risk Predict the Duration of Grade 3 Mucositis after Intensity-modulated Radiotherapy for Oropharyngeal Cancer?

BACKGROUND Planned neck dissection (ND) after radical chemoradiotherapy (CRT) for locally advanced nodal metastases in patients with head and neck squamous cell carcinoma (HNSCC) remains controversial. Thirty per cent of ND specimens show histological evidence of tumour. Consequently, a significant proportion of clinicians still practise planned ND. Fludeoxyglucose positron emission tomography (PET)-computerised tomography (CT) scanning demonstrated high negative predictive values for persistent nodal disease, providing a possible alternative paradigm to ND. Evidence is sparse and drawn mainly from retrospective single-institution studies, illustrating the need for a prospective randomised controlled trial. OBJECTIVES To determine the efficacy and cost-effectiveness of PET-CT-guided surveillance, compared with planned ND, in a multicentre, prospective, randomised setting. DESIGN A pragmatic randomised non-inferiority trial comparing PET-CT-guided watch-and-wait policy with the current planned ND policy in HNSCC patients with locally advanced nodal metastases and treated with radical CRT. Patients were randomised in a 1 : 1 ratio. Primary outcomes were overall survival (OS) and cost-effectiveness [incremental cost per incremental quality-adjusted life-year (QALY)]. Cost-effectiveness was assessed over the trial period using individual patient data, and over a lifetime horizon using a decision-analytic model. Secondary outcomes were recurrence in the neck, complication rates and quality of life. The recruitment of 560 patients was planned to detect non-inferior OS in the intervention arm with a 90% power and a type I error of 5%, with non-inferiority defined as having a hazard ratio (HR) of no higher than 1.50. An intention-to-treat analysis was performed by Coxs proportional hazards model. SETTINGS Thirty-seven head and neck cancer-treating centres (43 NHS hospitals) throughout the UK. PARTICIPANTS Patients with locally advanced nodal metastases of oropharynx, hypopharynx, larynx, oral or occult HNSCC receiving CRT and fit for ND were recruited. INTERVENTION Patients randomised to planned ND before or after CRT (control), or CRT followed by fludeoxyglucose PET-CT 10-12 weeks post CRT with ND only if PET-CT showed incomplete or equivocal response of nodal disease (intervention). Balanced by centre, planned ND timing, CRT schedule, disease site and the tumour, node, metastasis stage. RESULTS In total, 564 patients were recruited (ND arm, n = 282; and surveillance arm, n = 282; 17% N2a, 61% N2b, 18% N2c and 3% N3). Eighty-four per cent had oropharyngeal cancer. Seventy-five per cent of tested cases were p16 positive. The median time to follow-up was 36 months. The HR for OS was 0.92 [95% confidence interval (CI) 0.65 to 1.32], indicating non-inferiority. The upper limit of the non-inferiority HR margin of 1.50, which was informed by patient advisors to the project, lies at the 99.6 percentile of this estimate (p = 0.004). There were no differences in this result by p16 status. There were 54 NDs performed in the surveillance arm, with 22 surgical complications, and 221 NDs in the ND arm, with 85 complications. Quality-of-life scores were slightly better in the surveillance arm. Compared with planned ND, PET-CT surveillance produced an incremental net health benefit of 0.16 QALYs (95% CI 0.03 to 0.28 QALYs) over the trial period and 0.21 QALYs (95% CI -0.41 to 0.85 QALYs) over the modelled lifetime horizon. LIMITATIONS Pragmatic randomised controlled trial with a 36-month median follow-up. CONCLUSIONS PET-CT-guided active surveillance showed similar survival outcomes to ND but resulted in considerably fewer NDs, fewer complications and lower costs, supporting its use in routine practice. FUTURE WORK PET-CT surveillance is cost-effective in the short term, and long-term cost-effectiveness could be addressed in future work. TRIAL REGISTRATION Current Controlled Trials ISRCTN13735240. FUNDING This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 21, No. 17. See the NIHR Journals Library website for further project information.

Revised radiobiological modelling of the contribution of synchronous chemotherapy to the rate of grades 3-4 mucositis in head and neck cancer.

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

Biological effective dose (BED) calculations modelled on reduced accelerated repopulation when synchronous chemotherapy is delivered significantly correlate with observed differences in local control in randomised trials of platinum‐based chemoradiation. The purpose of this study was to examine whether a similar relationship existed in the context of grades 3–4 mucositis.