SCOPE 2 - Still Answering the Unanswered Questions in Oesophageal Radiotherapy? SCOPE 2: a Randomised Phase II/III Trial to Study Radiotherapy Dose Escalation in Patients with Oesophageal Cancer Treated with Definitive Chemoradiation with an Embedded Phase II Trial for Patients with a Poor Early Response using Positron Emission Tomography/Computed Tomography.

The SCOPE 2 trial of definitive chemoradiotherapy in oesophageal cancer investigates the benefits of radiotherapy dose escalation and systemic therapy optimisation. The trial opened in 2016. The landscape of oesophageal cancer treatment over the lifetime of this trial has changed significantly and the protocol has evolved to reflect this. However, with the recent results of the Dutch phase III ART DECO study showing no improvement in local control or overall survival with radiotherapy dose escalation in a similar patient group, we sought to determine if the SCOPE 2 trial is still answering the key unanswered questions for oesophageal radiotherapy. Here we discuss the rationale behind the SCOPE 2 trial, outline the trial schema and review current data on dose escalation and outline recommendations for future areas of research.

The impact of endoscopic ultrasound on the management and outcome of patients with oesophageal cancer: an update of a systematic review.

AIM: To provide an updated systematic review concerning the impact of endoscopic ultrasound (EUS) in the modern era of oesophageal cancer staging. MATERIALS AND METHODS: To update the previous systematic review, databases including MEDLINE and EMBASE were searched and studies published from 2005 onwards were selected. Studies reporting primary data in patients with oesophageal or gastro-oesophageal junction cancer who underwent radiological staging and treatment, regardless of intent, were included. The primary outcome was the reported change in management after EUS. Secondary outcomes were recurrence rate and overall survival. Two reviewers extracted data from included articles. This study was registered with PROSPERO (CRD42021231852). RESULTS: Eighteen studies with 11,836 patients were included comprising 2,805 patients (23.7%) who underwent EUS compared to 9,031 (76.3%) without EUS examination. Reported change of management varied widely from 0% to 56%. When used, EUS fine-needle aspiration precluded curative treatment in 37.5%-71.4%. Overall survival improvements ranged between 121 and 639 days following EUS intervention compared to patients without EUS. Smaller effect sizes were observed in a randomised controlled trial, compared to larger differences reported in observational studies. CONCLUSION: Current evidence for the effectiveness of EUS in oesophageal cancer pathways is conflicting and of limited quality. In particular, the extent to which EUS adds value to contemporary cross-sectional imaging techniques is unclear and requires formal re-evaluation.

Prediction of long-term survival after gastrectomy using random survival forests.

BACKGROUND: No well validated and contemporaneous tools for personalized prognostication of gastric adenocarcinoma exist. This study aimed to derive and validate a prognostic model for overall survival after surgery for gastric adenocarcinoma using a large national dataset. METHODS: National audit data from England and Wales were used to identify patients who underwent a potentially curative gastrectomy for adenocarcinoma of the stomach. A total of 2931 patients were included and 29 clinical and pathological variables were considered for their impact on survival. A non-linear random survival forest methodology was then trained and validated internally using bootstrapping with calibration and discrimination (time-dependent area under the receiver operator curve (tAUC)) assessed. RESULTS: The median survival of the cohort was 69 months, with a 5-year survival of 53.2 per cent. Ten variables were found to influence survival significantly and were included in the final model, with the most important being lymph node positivity, pT stage and achieving an R0 resection. Patient characteristics including ASA grade and age were also influential. On validation the model achieved excellent performance with a 5-year tAUC of 0.80 (95 per cent c.i. 0.78 to 0.82) and good agreement between observed and predicted survival probabilities. A wide spread of predictions for 3-year (14.8-98.3 (i.q.r. 43.2-84.4) per cent) and 5-year (9.4-96.1 (i.q.r. 31.7-73.8) per cent) survival were seen. CONCLUSIONS: A prognostic model for survival after a potentially curative resection for gastric adenocarcinoma was derived and exhibited excellent discrimination and calibration of predictions.

In this study the authors used a large nationwide dataset from England and Wales and tried to make a predictive model that estimated how long patients would survive after surgery for gastric cancer. They found that using a machine learning methodology provided excellent results and accuracy in predictions, significantly in excess of any other published model and traditional staging methods. The model will be useful to provide individualized prediction of survival to patients and in the future could be used to stratify treatments.

Comparative Dosimetric Analysis and Normal Tissue Complication Probability Modelling of Four-Dimensional Computed Tomography Planning Scans Within the UK NeoSCOPE Trial.

AIMS: NeoSCOPE is a trial of two different neoadjuvant chemoradiotherapy regimens for resectable oesophageal cancer and was the first multicentre trial in the UK to incorporate four-dimensional computed tomography (4D-CT) into radiotherapy planning. Despite 4D-CT being increasingly accepted as a standard of care for lower third and junctional oesophageal tumours, there is limited evidence of its benefit over standard three-dimensional computed tomography (3D-CT). MATERIALS: Using NeoSCOPE 4D-CT cases, we undertook a dosimetric comparison study of 3D-CT versus 4D-CT plans comparing target volume coverage and dose to organs at risk. We used established normal tissue complication probability models to evaluate the potential toxicity reduction of using 4D-CT plans in oesophageal cancer. RESULTS: 4D-CT resulted in a smaller median absolute PTV volume and lower dose levels for all reported constraints with comparable target volume coverage. NTCP modelling suggests a significant relative risk reduction of cardiac and pulmonary toxicity endpoints with 4D-CT. CONCLUSION: Our work shows that incorporating 4D-CT into treatment planning may significantly reduce the toxicity burden from this treatment.

Brachytherapy in the Palliation of Oesophageal Cancer: Effective but Impractical?

Dysphagia in people with advanced oesophageal cancer can be treated by oesophageal stents, external beam radiotherapy (EBRT) and intraluminal brachytherapy. Despite guidelines recommending brachytherapy for patients with a predicted life expectancy exceeding 3 months, its uptake in the UK has been limited. Here we examine the strength of the evidence supporting the use of brachytherapy compared with oesophageal stents and EBRT and possible reasons for its limited uptake. Trials and observational studies suggest brachytherapy alone confers a benefit to patients, but its impact is less immediate than oesophageal stents; the evidence on effectiveness and value-for-money is limited. Moreover, stronger evidence will probably be insufficient to increase uptake, due to the extra complexity of delivery compared with stents and EBRT and a lack of experience among specialists.

Hypofractionated Radiotherapy in Oesophageal Cancer for Patients Unfit for Systemic Therapy: A Retrospective Single-Centre Analysis.

AIMS: Chemoradiotherapy (CRT) is established as a superior treatment option to definitive radiotherapy in the non-surgical management of oesophageal cancer. For patients precluded from CRT through choice or comorbidity there is little evidence to guide delivery of single-modality radiotherapy. In this study we outline outcomes for patients unfit for CRT who received a hypofractionated radiotherapy (HRT) regimen. MATERIALS AND METHODS: A retrospective UK single-centre analysis of 61 consecutive patients with lower- or middle-third adenocarcinoma (OAC; 61%) or squamous cell carcinoma of the oesophagus managed using HRT with radical intent between April 2009 and 2014. Treatment consisted of 50 Gy in 16 fractions (n = 49, 80.3%) or 50-52.5 Gy in 20 fractions (n = 12, 19.7%). Outcomes were referenced against a contemporaneous comparator cohort of 80 (54% OAC) consecutive patients managed with conventionally fractionated CRT within the same centre. RESULTS: Three-year and median overall survival were, respectively, 56.9% and 29 months with HRT compared with 55.5% and 26 months for CRT; adjusted hazard ratio 0.79 (95% confidence interval 0.48-1.28). Grade 3 and 4 toxicity rates were low at 16.4% (n = 10) for those receiving HRT and 40.2% (n = 32) for the CRT group. In patients with OAC, CRT delivered superior overall survival (hazard ratio 0.46; 95% confidence interval 0.25-0.85) and progression-free survival (hazard ratio 0.45; 95% confidence interval 0.23-0.88) when compared with HRT. CONCLUSIONS: The HRT regimen described here was safe and tolerable in patients unable to receive CRT, and delivered promising survival outcomes. The use of HRT for the treatment of oesophageal cancer, both alone and as a sequential or concurrent treatment with chemotherapy, requires further study. New precision radiotherapy technologies may provide additional scope for improving outcomes in oesophageal cancer using HRT-based approaches and should be evaluated.

Driving developments in UK oesophageal radiotherapy through the SCOPE trials.

BACKGROUND: The SCOPE trials (SCOPE 1, NeoSCOPE and SCOPE 2) have been the backbone of oesophageal RT trials in the UK. Many changes in oesophageal RT techniques have taken place in this time. The SCOPE trials have, in addition to adopting these new techniques, been influential in aiding centres with their implementation. We discuss the progress made through the SCOPE trials and include details of a questionnaire sent to participating centres. to establish the role that trial participation played in RT changes in their centre. METHODS: Questionnaires were sent to 47 centres, 27 were returned. RESULTS: 100% of centres stated their departmental protocol for TVD was based on the relevant SCOPE trial protocol. 4DCT use has increased from 42 to 71%. Type B planning algorithms, mandated in the NeoSCOPE trial, were used in 79.9% pre NeoSCOPE and now in 83.3%. 12.5% of centres were using a stomach filling protocol pre NeoSCOPE, now risen to 50%. CBCT was mandated for IGRT in the NeoSCOPE trial. 66.7% used this routinely pre NeoSCOPE/SCOPE 2 which has risen to 87.5% in the survey. CONCLUSION: The results of the questionnaires show how participation in national oesophageal RT trials has led to the adoption of newer RT techniques in UK centres, leading to better patient care.

A Comparative Assessment of Implant Site Viability in Humans and Rats.

Our long-term objective is to devise methods to improve osteotomy site preparation and, in doing so, facilitate implant osseointegration. As a first step in this process, we developed a standardized oral osteotomy model in ovariectomized rats. There were 2 unique features to this model: first, the rats exhibited an osteopenic phenotype, reminiscent of the bone health that has been reported for the average dental implant patient population. Second, osteotomies were produced in healed tooth extraction sites and therefore represented the placement of most implants in patients. Commercially available drills were then used to produce osteotomies in a patient cohort and in the rat model. Molecular, cellular, and histologic analyses demonstrated a close alignment between the responses of human and rodent alveolar bone to osteotomy site preparation. Most notably in both patients and rats, all drilling tools created a zone of dead and dying osteocytes around the osteotomy. In rat tissues, which could be collected at multiple time points after osteotomy, the fate of the dead alveolar bone was followed. Over the course of a week, osteoclast activity was responsible for resorbing the necrotic bone, which in turn stimulated the deposition of a new bone matrix by osteoblasts. Collectively, these analyses support the use of an ovariectomy surgery rat model to gain insights into the response of human bone to osteotomy site preparation. The data also suggest that reducing the zone of osteocyte death will improve osteotomy site viability, leading to faster new bone formation around implants.

Impact of Positron Emission Tomography and Endoscopic Ultrasound Length of Disease Difference on Treatment Planning in Patients with Oesophageal Cancer.

AIMS: Treatment decision making and planning in patients with oesophageal cancer are guided by radiological measurement of length of disease (LoD). This study aimed to investigate differences in positron emission tomography (PET) and endoscopic ultrasound (EUS) LoD. Their prognostic significance was also assessed. MATERIALS AND METHODS: LoD was measured from PET and EUS staging investigations by one observer for each modality. Bland-Altman analysis and Wilcoxon signed rank tests assessed agreement and differences in measurements. In terms of radiotherapy planning, the proportion of cases with a clinically significant difference of more than 2 cm between PET and EUS was also calculated. Univariable and multivariable analysis assessed association with overall survival. A P-value < 0.05 was considered statistically significant. RESULTS: Consecutive patients (n = 160, median age 66.0 years [range 24-83], males = 124, adenocarcinomas = 115) staged with PET/CT and EUS between 2011 and 2014 were included. PET tended to under-measure LoD compared with EUS. The median PET and EUS LoD was 6.4 and 8.0 cm, respectively. PET and EUS LoD was significantly different (Z = -7.021, P < 0.001). EUS LoD was more than 2 cm longer than PET LoD in 61 cases (38.1%). In eight cases (5.0%), PET LoD was more than 2 cm longer than EUS LoD. Both variables had prognostic significance in univariable analysis, but were not independent predictors of overall survival. CONCLUSION: There are significant differences in PET and EUS measurement of LoD. This could affect clinical decision making and radiotherapy treatment planning. Clinically significant differences between EUS and PET LoD could lead to a risk of geographical miss in up to 38.1% of cases if the PET/CT measurement alone had been used for radiotherapy planning. These results highlight the continued benefit of EUS in the oesophageal cancer staging and treatment pathway.

ICORG 10-14: NEOadjuvant trial in Adenocarcinoma of the oEsophagus and oesophagoGastric junction International Study (Neo-AEGIS).

BACKGROUND: Neoadjuvant therapy is increasingly the standard of care in the management of locally advanced adenocarcinoma of the oesophagus and junction (AEG). In randomised controlled trials (RCTs), the MAGIC regimen of pre- and postoperative chemotherapy, and the CROSS regimen of preoperative chemotherapy combined with radiation, were superior to surgery only in RCTs that included AEG but were not powered on this cohort. No completed RCT has directly compared neoadjuvant or perioperative chemotherapy and neoadjuvant chemoradiation. The Neo-AEGIS trial, uniquely powered on AEG, and including comprehensive modern staging, compares both these regimens. METHODS: This open label, multicentre, phase III RCT randomises patients (cT2-3, N0-3, M0) in a 1:1 fashion to receive CROSS protocol (Carboplatin and Paclitaxel with concurrent radiotherapy, 41.4Gy/23Fr, over 5 weeks). The power calculation is a 10% difference in favour of CROSS, powered at 80%, two-sided alpha level of 0.05, requiring 540 patients to be evaluable, 594 to be recruited if a 10% dropout is included (297 in each group). The primary endpoint is overall survival, with a minimum 3-year follow up. Secondary endpoints include: disease free survival, recurrence rates, clinical and pathological response rates, toxicities of induction regimens, post-operative pathology and tumour regression grade, operative in-hospital complications, and health-related quality of life. The trial also affords opportunities for establishing a bio-resource of pre-treatment and resected tumour, and translational research. DISCUSSION: This RCT directly compares two established treatment regimens, and addresses whether radiation therapy positively impacts on overall survival compared with a standard perioperative chemotherapy regimen Sponsor: Irish Clinical Research Group (ICORG). TRIAL REGISTRATION: NCT01726452 . Protocol 10-14. Date of registration 06/11/2012.

Long-term results and recurrence patterns from SCALOP: a phase II randomised trial of gemcitabine- or capecitabine-based chemoradiation for locally advanced pancreatic cancer.

BACKGROUND: SCALOP, a randomised, phase II trial, tested the activity and safety of gemcitabine (GEM)-based and capecitabine (CAP)-based chemoradiation (CRT) for locally advanced pancreatic cancer (LAPC). Here we present the long-term outcomes. METHODS: Eligibility: histologically proven LAPC ⩽7 cm. Following 12 weeks of induction GEMCAP chemotherapy (three cycles: GEM 1000 mg m-2 days 1, 8, 15; CAP 830 mg m-2 days 1-21 q28 days) patients with stable/responding disease, tumour ⩽6 cm, and WHO Performance Status 0-1 were randomised to receive one cycle GEMCAP followed by CAP (830 mg m-2 b.d. on weekdays only) or GEM (300 mg m-2 weekly) with radiation (50.4 Gy per 28 fractions). RESULTS: One-hundred fourteen patients (28 UK centres) were registered between 24 December 2009 and 25 October 2011, and 74 were randomised (CAP-RT=36; GEM-RT=38). At the time of this analysis, 105 of the 114 patients had died and the surviving 9 patients had been followed up for a median of 10.9 months (IQR: 2.9-18.7). Updated median OS was 17.6 months (95% CI: 14.6-22.7) in the CAP-CRT arm and 14.6 months (95% CI: 11.1-16.0) in the GEM-CRT arm (intention-to-treat adjusted hazard ratio (HR): 0.68 (95% CI: 0.38-1.21, P=0.185)); median progression-free survival (PFS) was 12.0 months (95% CI: 10.0-15.2) in the CAP-CRT arm and 10.4 months (95% CI: 8.8-12.7) in the GEM-CRT arm (intention-to-treat adjusted HR: 0.60 (95% CI: 0.32-1.14, P=0.120)). In baseline multivariable model, age ⩾65 years, better performance status, CA19.9<613 IU l-1, and shorter tumour diameter predicted improved OS. CAP-CRT, age ⩾65 years, better performance status, CA19.9 <46 IU ml-1 predicted improved OS and PFS in the pre-radiotherapy model. Nine-month PFS was highly predictive of OS. CONCLUSIONS: CAP-CRT remains the superior regimen. SCALOP showed that patients with CA19.9 <46 IU ml-1 after induction chemotherapy are more likely to benefit from CRT.

Long-term results and recurrence patterns from SCOPE-1: a phase II/III randomised trial of definitive chemoradiotherapy +/- cetuximab in oesophageal cancer.

BACKGROUND: The SCOPE-1 study tested the role of adding cetuximab to conventional definitive chemoradiotherapy (dCRT), and demonstrated greater toxicity and worse survival outcomes. We present the long-term outcomes and patterns of recurrence. METHODS: SCOPE-1 was a phase II/III trial in which patients were randomised to cisplatin 60 mg m-2 (day 1) and capecitabine 625 mg m-2 bd (days 1-21) for four cycles +/- cetuximab 400 mg m-2 day 1 then by 250 mg m-2 weekly. Radiotherapy consisted of 50 Gy/25# given concurrently with cycles 3 and 4. Recruitment was between February 2008 and February 2012, when the IDMC recommended closure on the basis of futility. RESULTS: About 258 patients (dCRT=129; dCRT+cetuximab (dCRT+C)=129) were recruited from 36 centres. About 72.9% (n=188) had squamous cell histology. The median follow-up (IQR) was 46.2 (35.9-48.3) months for surviving patients. The median overall survival (OS; months; 95% CI) was 34.5 (24.7-42.3) in dCRT and 24.7 (18.6-31.3) in dCRT+C (hazard ratio (HR)=1.25, 95% CIs: 0.93-1.69, P=0.137). Median progression-free survival (PFS; months; 95% CI) was 24.1 (15.3-29.9) and 15.9 (10.7-20.8) months, respectively (HR=1.28, 95% CIs: 0.94-1.75; P=0.114). On multivariable analysis only earlier stage, full-dose RT, and higher cisplatin dose intensity were associated with improved OS. CONCLUSIONS: The mature analysis demonstrates that the dCRT regimen used in the study provided useful survival outcomes despite its use in patients who were largely unfit for surgery or who had inoperable disease. Given the competing risk of systemic and local failure, future studies should continue to focus on enhancing local control as well as optimising systemic therapy.

Provisional epidemiological cutoff values for standard broth microdilution susceptibility testing of Flavobacterium columnare.

The gliding aquatic bacterium Flavobacterium columnare causes columnaris disease, a common problem for wild and farmed freshwater fish worldwide. Recently, a broth microdilution method was standardized to test the susceptibility of F. columnare against antimicrobials commonly used in aquaculture. We used this new method to measure the minimal inhibitory concentrations (MICs) of ten antimicrobials against 120 F. columnare isolates. The resulting MIC frequency distributions for each antimicrobial (1 MIC/isolate) were used to estimate epidemiological cut-off values (ECVs) which separate isolates with typical wild-type (WT) susceptibility from isolates with decreased non-wild-type (NWT) susceptibility. We identified 22 NWT isolates with elevated MICs relative to the ECV that covered 99.9% of the MIC distribution against one or more of the antimicrobials: ampicillin, enrofloxacin, erythromycin, florfenicol, flumequine, oxolinic acid or oxytetracycline. Ten of the NWT isolates had decreased susceptibility to a single antimicrobial class, six isolates to two antimicrobial classes and six isolates to three or more antimicrobial classes. The MIC frequency distributions and provisional cut-off values provide data needed to set epidemiological cut-off values to monitor for the development of antimicrobial resistance among F. columnare.