Mesorectal radiotherapy for early stage rectal cancer: A novel target volume

With the introduction of population-based bowel cancer screening, rectal cancer is diagnosed at earlier stages, yet standard treatment still requires the same extensive surgery that is used for more advanced stages. Organ preserving treatment is rapidly developing and is subject of investigation in numerous clinical trials. The STAR-TREC trial is an international, multi-centre randomised trial investigating organ preservation using (chemo)radiotherapy. Patients with small mrT1-3bN0V0M0 tumours are randomized between three arms: standard TME, organ preservation with SCRT or with CRT. In this trial, the clinical target volume has been tailored to the early staged disease of the included patients. This mesorectal irradiation volume includes the mesorectum and pre-sacral lymph nodes at the level of the tumour, two centimetres below and cranially up to the S2-3 interspace level. In contrast to conventional irradiation volumes, the lateral lymph nodes and the nodes along the superior rectal artery are excluded. As a result, the dose to the bowel, bladder, anal sphincter and the neurovascular plexus in the lower pelvis is substantially decreased, especially when combined with modern irradiation techniques, such as dynamic arc therapy. These lower doses are expected to lead to decreasing acute and late toxicity and beneficial functional outcomes. The implementation of this novel target volume will be accompanied by an extensive quality assurance program in the STAR-TREC trial. We describe the rationale behind the novel, mesorectal only radiotherapy treatment used in the STAR-TREC trial specifically tailored for early stage disease, with the goal of organ preservation

A phase 1 trial of the safety, tolerability and biological effects of intravenous Enadenotucirev, a novel oncolytic virus, in combination with chemoradiotherapy in locally advanced rectal cancer (CEDAR)

Background: Chemoradiotherapy remains the standard of care for locally advanced rectal cancer. Efforts to intensify treatment and increase response rates have yet to yield practice changing results due to increased toxicity and/or absence of increased radiosensitization. Enadenotucirev (EnAd) is a tumour selective, oncolytic adenovirus which can be given intravenously. Pre-clinical evidence of synergy with radiation warrants further clinical testing and assessment of safety with radiation. Methods: Eligibility include histology confirmed locally advanced rectal cancer that require chemoradiation. The trial will use a Time-to-Event Continual Reassessment Model-based (TiTE-CRM) approach using toxicity and efficacy as co-primary endpoints to recommend the optimal dose and treatment schedule 30 patients will be recruited. Secondary endpoints include pathological complete response the neoadjuvant rectal score. A translational program will be based on a mandatory biopsy during the second week of treatment for ‘proof-of-concept’ and exploration of mechanism. The trial opened to recruitment in July 2019, at an expected rate of 1 per month for up to 4 years. Discussion: Chemoradiation with Enadenotucirev as a radiosensitiser in locally Advanced Rectal cancer (CEDAR) is a prospective multicentre study testing a new paradigm in radiosensitization in rectal cancer. The unique ability of EnAd to selectively infect tumour cells following intravenous delivery is an exciting opportunity with a clear translational goal. The novel statistical design will make efficient use of both toxicity and efficacy data to inform subsequent studies. Trial registration: ClinicalTrial.gov, NCT03916510. Registered 16th April 2019

Long-term swallow function after chemoradiotherapy for oropharyngeal cancer: The influence of a prophylactic gastrostomy or reactive nasogastric tube

Aims: Two contrasting approaches of a prophylactic gastrostomy or a nasogastric tube as needed are widely used to support patients receiving chemoradiotherapy for head and neck cancer. The influence of the type and timing of enteral feeding tube support upon long-term swallowing is uncertain. This study analysed the patients' perspective on long-term swallowing, comparing two groups of patients who received chemoradiotherapy for oropharyngeal cancer managed with the two approaches. Materials and methods: The MD Anderson Dysphagia Inventory (MDADI) was posted to 63 consecutive patients with oropharyngeal squamous cell cancer treated with concurrent chemoradiotherapy between January 2007 and June 2009, who had not required therapeutic enteral feeding before treatment and who were disease free on follow-up at least 2 years after treatment. Results: In total, 56/63 patients completed questionnaires; 43 had been managed with a prophylactic gastrostomy and 13 with a policy of nasogastric tube as needed. There were no significant differences in all global, emotional, physical or functional domains of the MDADI according to enteral feeding strategy. Diet at 6 months after treatment was significantly correlated with better MDADI scores. Conclusions: In this study, the choice of a prophylactic gastrostomy or nasogastric tube as needed did not seem to influence long-term swallowing function

Next-generation sequencing identifies germline MRE11A variants as markers of radiotherapy outcomes in muscle-invasive bladder cancer

Background Muscle-invasive bladder cancer (MIBC) can be cured by radical radiotherapy (RT). We previously found tumour MRE11 expression to be predictive of survival following RT in MIBC, and this was independently validated in a separate institute. Here, we investigated germline MRE11A variants as possible predictors of RT outcomes in MIBC, using next-generation sequencing (NGS). Patients and methods The MRE11A gene was amplified in germline DNA from 186 prospectively recruited MIBC patients treated with RT and sequenced using bar-coded multiplexed NGS. Germline variants were analysed for associations with cancer-specific survival (CSS). For validation as a prognostic or predictive marker, rs1805363 was then genotyped in a cystectomy-treated MIBC cohort of 256 individuals. MRE11A mRNA isoform expression was measured in bladder cancer cell lines and primary tumour samples. Results Carriage of at least one of six (five novel) rare variants was associated with the worse RT outcome (hazard ratio [HR] 4.04, 95% confidence interval [95% CI] 1.42–11.51, P = 0.009). The single-nucleotide polymorphism (SNP), rs1805363 (minor allele frequency 11%), was also associated with worse CSS (per-allele HR 2.10, 95% CI 1.34–3.28, Ptrend = 0.001) following RT in MIBC, with a gene-dosage effect observed, but no effect seen on CSS in the cystectomy cohort (Ptrend = 0.89). Furthermore, rs1805363 influenced relative MRE11A isoform expression, with increased isoform 2 expression with carriage of the rs1805363 minor A allele. Conclusions Germline MRE11A SNP rs1805363 was predictive of RT, but not of cystectomy outcome in MIBC. If successfully validated in an independent RT-treated cohort, this SNP could be a useful clinical tool for selecting patients for bladder-conserving treatment

Next-generation sequencing identifies germline <em>MRE11A </em>variants as markers of radiotherapy outcomes in muscle-invasive bladder cancer

Mode of access: Internet

MRE11 as a predictive biomarker of outcome following radiotherapy in bladder cancer

Purpose: Organ-confined muscle-invasive bladder cancer is treated with cystectomy or bladder preservation techniques, including radiation therapy. There are currently no biomarkers to inform management decisions and aid patient choice. Previously we showed high levels of MRE11 protein, assessed by immunohistochemistry (IHC), predicted outcome after radiation therapy, but not cystectomy. Therefore, we sought to develop the MRE11 IHC assay for clinical use and define its relationship to clinical outcome in samples from 2 major clinical trials.Methods and Materials: Samples from the BCON and BC2001 randomized controlled trials and a cystectomy cohort were stained using automated IHC methods and scored for MRE11 in 3 centers in the United Kingdom.Results: Despite step-wise creation of scoring cards and standard operating procedures for staining and interpretation, there was poor intercenter scoring agreement (kappa, 0.32; 95% confidence interval, 0.17-0.47). No significant associations between MRE11 scores and cause-specific survival were identified in BCON (n = 132) and BC2001 (n = 221) samples. Reoptimized staining improved agreement between scores from BCON tissue microarrays (n = 116), but MRE11 expression was not prognostic for cause-specific survival.Conclusions: Manual IHC scoring of MRE11 was not validated as a reproducible biomarker of radiation-based bladder preservation success. There is a need for automated quantitative methods or a reassessment of how DNA-damage response relates to clinical outcomes.</br

MRE11 as a predictive biomarker of outcome following radiotherapy in bladder cancer

Purpose Organ-confined muscle-invasive bladder cancer is treated with cystectomy or bladder preservation techniques, including radiation therapy. There are currently no biomarkers to inform management decisions and aid patient choice. Previously we showed high levels of MRE11 protein, assessed by immunohistochemistry (IHC), predicted outcome after radiation therapy, but not cystectomy. Therefore, we sought to develop the MRE11 IHC assay for clinical use and define its relationship to clinical outcome in samples from 2 major clinical trials.Methods and materials Samples from the BCON and BC2001 randomized controlled trials and a cystectomy cohort were stained using automated IHC methods and scored for MRE11 in 3 centers in the United Kingdom.Results Despite step-wise creation of scoring cards and standard operating procedures for staining and interpretation, there was poor intercenter scoring agreement (kappa, 0.32; 95% confidence interval, 0.17-0.47). No significant associations between MRE11 scores and cause-specific survival were identified in BCON (n = 132) and BC2001 (n = 221) samples. Reoptimized staining improved agreement between scores from BCON tissue microarrays (n = 116), but MRE11 expression was not prognostic for cause-specific survival.Conclusions Manual IHC scoring of MRE11 was not validated as a reproducible biomarker of radiation-based bladder preservation success. There is a need for automated quantitative methods or a reassessment of how DNA-damage response relates to clinical outcomes