Efficacy of dose-escalated chemoradiation on complete tumour response in patients with locally advanced rectal cancer (RECTAL-BOOST); a phase 2 randomised controlled trial

Purpose Pathological complete tumour response following chemoradiation in patients with locally advanced rectal cancer (LARC) is associated with favourable prognosis and allows organ-sparing treatment strategies. We aimed to investigate the effect of an external radiation boost to the tumour prior to chemoradiation on pathological or sustained clinical complete tumour response in LARC. Methods and materials This multicentre, non-blinded, phase 2, randomised controlled trial followed the trials within cohorts-design, which is a pragmatic trial design allowing cohort participants to be randomized for an experimental intervention. Patients in the intervention group are offered the intervention (and can accept or refuse this), whereas patients in the control group are not notified about the randomisation. Participants of a colorectal cancer cohort referred for chemoradiation of LARC to either of two radiotherapy centres were eligible. Patients were randomised to no boost or an external radiation boost (5 x 3 Gy) without concurrent chemotherapy directly followed by standard pelvic chemoradiation (25 x 2 Gy with concurrent capecitabine). The primary outcome was pathological complete response (pCR, i.e. ypT0N0) in patients with planned surgery at 12 weeks or, as surrogate for pCR, a 2-year sustained clinical complete response for patients treated with an organ preservation strategy. Analyses were intention to treat. The study was registered with ClinicalTrials.gov, number NCTXXXXXX. Results Between Sept 2014 and July 2018, 128 patients were randomised. Fifty-one of the 64 (79.7%) patients in the intervention group accepted and received a boost. Compared with the control group, fewer patients in the intervention group had a cT4-stage and a low rectal tumour (31.3% versus 17.2% and 56.3% versus 45.3% respectively), and more patients had a cN2-stage (59.4% versus 70.3% respectively). Rate of pathological or sustained clinical complete tumour response was similar between the groups: 23 of 64 (35.9%, 95%CI 24.3-48.9) in the intervention group versus 24 of 64 (37.5%, 95%CI 25.7-50.5) in the control group (OR=0.94 95%CI 0.46-1.92). Near-complete or complete tumour regression was more common in the intervention group: 34 of 49 (69.4%) versus 24 of 53 (45.3%) in the control group (OR=2.74, 95%CI 1.21-6.18). Grade >3 acute toxicity was comparable: 6 of 64 (9.4%) in the intervention group versus 5 of 64 (7.8%) in the control group (OR=1.22 95%CI 0.35-4.22). Conclusion Dose escalation with an external radiotherapy boost to the tumour prior to neoadjuvant chemoradiation did not increase the pathological or sustained clinical complete tumour response rate in LARC

Factors affecting 30-day postoperative complications after emergency surgery during the COVID-19 outbreak: A multicentre cohort study

Introduction: Coronavirus disease 2019 (COVID-19) has influenced (surgical) care worldwide. Measures were taken to prioritize surgical care in order to maintain capacity for COVID-19 healthcare. However, the influence of these measures on emergency surgery is limited. Therefore, the aim of this study is to describe the trends in emergency surgery and determine the factors influencing the risk of postoperative complications during the first wave of the COVID-19 pandemic. Methods: This multicentre retrospective cohort study investigated all emergency patients operated on from March 9th to June 30th, 2020. The primary endpoint was identifying the number of emergency surgical procedures performed. Secondary endpoints were determining the number of postoperative complications and factors determining the risk of postoperative complications, which were calculated by multivariate analysis with odds ratio (OR) and 95% confidence (CI) intervals. Results: In total, 1399 patients who underwent an emergency surgical procedure were included. An increase in the number of emergency vascular and trauma surgical procedures occurred during the study period. In contrast, the number of emergency general and oncological surgical procedures performed remained stable. An increased age (OR 1.01, 95% CI 1.00–1.02; p = 0.024), American Society of Anaesthesiologists (ASA) (OR 1.34, 95% CI 1.09–1.64; p = 0.005), and surgical discipline were independent predictors for an increased risk of postoperative complications. Conclusion: The performance of emergency vascular and trauma surgical procedures increased. The performance of emergency general and oncological surgical procedures remained stable. In addition, increased age, ASA, and surgical discipline were independent predictors for an increased risk of postoperative complications

Risk factors of postoperative intensive care unit admission during the COVID-19 pandemic: A multicentre retrospective cohort study

Background: During the Coronavirus disease 2019 (COVID-19) pandemic, intensive care unit (ICU) capacity was scarce. Since surgical patients also require ICU admission, determining which factors lead to an increased risk of postoperative ICU admission is essential. This study aims to determine which factors led to an increased risk of unplanned postoperative ICU admission during the COVID-19 pandemic. Methods: This multicentre retrospective cohort study investigated all patients who underwent surgery between 9 March 2020 and 30 June 2020. The primary endpoint was the number of surgical patients requiring postoperative ICU admission. The secondary endpoint was to determine factors leading to an increased risk of unplanned postoperative ICU admission, calculated by multivariate analysis with odds ratios (OR's) and 95% confidence (CI) intervals. Results: One hundred eighty-five (4.6%) of the 4051 included patients required unplanned postoperative ICU admission. COVID-19 positive patients were at an increased risk of being admitted to the ICU compared to COVID-19 negative (OR 3.14; 95% CI 1.06–9.33; p = 0.040) and untested patients (OR 0.48; 95% CI 0.32–0.70; p = 0.001). Other predictors were male gender (OR 1.36; 95% CI 1.02–1.82; p = 0.046), body mass index (BMI) (OR 1.05; 95% CI 1.02–1.08; p = 0.001), surgical urgency and surgical discipline. Conclusion: A confirmed COVID-19 infection, male gender, elevated BMI, surgical urgency, and surgical discipline were independent factors for an increased risk of unplanned postoperative ICU admission. In the event of similar pandemics, postponing surgery in patients with an increased risk of postoperative ICU admission may be considered

Functional Dyspepsia and Irritable Bowel Syndrome are Highly Prevalent in Patients with Gallstones and Are Negatively Associated with Outcomes after Cholecystectomy: A Prospective, Multicenter, Observational Study (PERFECT-Trial)

Objective:To determine the prevalence of FD and IBS in patients eligible for cholecystectomy and to investigate the association between presence of FD/ IBS and resolution of biliary colic and a pain-free state.Summary Background Data:More than 30% of patients with symptomatic cholecystolithiasis reports persisting pain postcholecystectomy. Coexistence of FD/IBS may contribute to this unsatisfactory outcome.Methods:We conducted a multicenter, prospective, observational study (PERFECT-Trial). Patients ≥18years with abdominal pain and gallstones were included at 5 surgical outpatient clinics between 01/2018 and 04/2019. Follow-up was 6months. Primary outcomes were prevalence of FD/IBS, and the difference between resolution of biliary colic and pain-free state in patients with and without FD/IBS. FD/IBS was defined by the Rome IV criteria, biliary colic by the Rome III criteria, and pain-free by an Izbicki Pain Score ≤10 and visual analogue scale ≤4.Results:We included 401 patients with abdominal pain and gallstones (assumed eligible for cholecystectomy), mean age 52years, 76% females. Of these, 34.9% fulfilled criteria for FD/IBS. 64.1% fulfilled criteria for biliary colic and 74.9% underwent cholecystectomy, with similar operation rates in patients with and without FD/IBS. Postcholecystectomy, 6.1% of patients fulfilled criteria for biliary colic, with no significant difference between those with and without FD/IBS at baseline (4.9% vs 8.6%, P = 0.22). Of all patients, 56.8% was pain-free after cholecystectomy, 40.7% of FD/IBS-group vs 64.4% of no FD/IBS-group, P 40%, particularly in those with FD/IBS precholecystectomy. Clinicians should take these symptom-dependent outcomes into account in their shared decision-making process.Trial Registration:The Netherlands Trial Register NTR-7307. Registered on 18 June 2018

Health-related quality of life in rectal cancer patients undergoing neoadjuvant chemoradiation with delayed surgery versus short-course radiotherapy with immediate surgery : a propensity score-matched cohort study

Background: Neoadjuvant chemoradiation with delayed surgery (CRT-DS) and short-course radiotherapy with immediate surgery (SCRT-IS) are two commonly used treatment strategies for rectal cancer. However, the optimal treatment strategy for patients with intermediate-risk rectal cancer remains a discussion. This study compares quality of life (QOL) between SCRT-IS and CRT-DS from diagnosis until 24 months after treatment. Methods: In a prospective colorectal cancer cohort, rectal cancer patients with clinical stage T2-3N0-2M0 undergoing SCRT-IS or CRT-DS between 2013 and 2017 were identified. QOL was assessed using EORTC-C30 and EORTC-CR29 questionnaires before the start of neoadjuvant treatment (baseline) and at 3, 6, 12, 18 and 24 months after. Patients were 1:1 matched using propensity sore matching. Between- and within-group differences in QOL domains were analyzed with linear mixed-effects models. Symptoms and sexual interest at 12 and 24 months were compared using logistic regression models. Results: 156 of 225 patients (69%) remained after matching. The CRT-DS group reported poorer emotional functioning at 3, 6, 12, 18 and 24 months (mean difference with SCRT-IS: −9.4, −12.1, −7.3, −8.0 and −7.9 respectively), and poorer global health, physical-, role-, social- and cognitive functioning at 6 months (mean difference with SCRT-IS: −9.1, −9.8, −14.0, −9.2 and −12.6, respectively). Besides emotional functioning, all QOL domains were comparable at 12, 18 and 24 months. Within-group changes showed a significant improvement of emotional functioning after baseline in the SCRT-IS group, whereas only a minor improvement was observed in the CRT-DS group. Symptoms and sexual interest in male patients at 12 and 24 months were comparable between the groups. Conclusions: In rectal cancer patients, CRT-DS may induce a stronger decline in short-term QOL than SCRT-IS. From 12 months onwards, QOL domains, symptoms and sexual interest in male patients were comparable between the groups. However, emotional functioning remained higher after SCRT-IS than after CRT-DS

Patient- and physician-reported radiation-induced toxicity of short-course radiotherapy with a prolonged interval to surgery for rectal cancer

Aim A prolonged interval (>4 weeks) between short-course radiotherapy (25 Gy in five fractions) (SCRT-delay) and total mesorectal excision for rectal cancer has been associated with a decreased postoperative complication rate and offers the possibility of organ preservation in the case of a complete tumour response. This prospective cohort study systematically evaluated patient-reported bowel dysfunction and physician-reported radiation-induced toxicity for 8 weeks following SCRT-delay. Method Patients who were referred for SCRT-delay for intermediate risk, oligometastatic or locally advanced rectal cancer were included. Repeated measurements were done for patient-reported bowel dysfunction (measured by the low anterior resection syndrome [LARS] questionnaire and categorized as no, minor or major LARS) and physician-reported radiation-induced toxicity (according to Common Terminology Criteria for Adverse Events version 4.0) before start of treatment (baseline), at completion of SCRT and 1, 2, 3, 4, 6 and 8 weeks thereafter. Results Fifty-one patients were included; 31 (61%) were men and the median age was 67 years (range 44-91). Patient-reported bowel dysfunction and physician-reported radiation-induced toxicity peaked at weeks 1-2 after completion of SCRT and gradually declined thereafter. Major LARS was reported by 44 patients (92%) at some time during SCRT-delay. Grade 3 radiation-induced toxicity was reported in 17 patients (33%) and concerned predominantly diarrhoea. No Grade 4-5 radiation-induced toxicity occurred. Conclusion During SCRT-delay, almost every patient experiences temporary mild-moderate radiation-induced toxicity and major LARS, but life-threatening toxicity is rare. SCRT-delay is a safe alternative to SCRT-direct surgery that should be proposed when counselling rectal cancer patients on neoadjuvant strategies

Towards Response ADAptive Radiotherapy for organ preservation for intermediate-risk rectal cancer (preRADAR):protocol of a phase I dose-escalation trial

Introduction Organ preservation is associated with superior functional outcome and quality of life (QoL) compared with total mesorectal excision (TME) for rectal cancer. Only 10% of patients are eligible for organ preservation following short-course radiotherapy (SCRT, 25 Gy in five fractions) and a prolonged interval (4-8 weeks) to response evaluation. The organ preservation rate could potentially be increased by dose-escalated radiotherapy. Online adaptive magnetic resonance-guided radiotherapy (MRgRT) is anticipated to reduce radiation-induced toxicity and enable radiotherapy dose escalation. This trial aims to establish the maximum tolerated dose (MTD) of dose-escalated SCRT using online adaptive MRgRT. Methods and analysis The preRADAR is a multicentre phase I trial with a 6+3 dose-escalation design. Patients with intermediate-risk rectal cancer (cT3c-d(MRF-)N1M0 or cT1-3(MRF-)N1M0) interested in organ preservation are eligible. Patients are treated with a radiotherapy boost of 2×5 Gy (level 0), 3×5 Gy (level 1), 4×5 Gy (level 2) or 5×5 Gy (level 3) on the gross tumour volume in the week following standard SCRT using online adaptive MRgRT. The trial starts on dose level 1. The primary endpoint is the MTD based on the incidence of dose-limiting toxicity (DLT) per dose level. DLT is a composite of maximum one in nine severe radiation-induced toxicities and maximum one in three severe postoperative complications, in patients treated with TME or local excision within 26 weeks following start of treatment. Secondary endpoints include the organ preservation rate, non-DLT, oncological outcomes, patient-reported QoL and functional outcomes up to 2 years following start of treatment. Imaging and laboratory biomarkers are explored for early response prediction. Ethics and dissemination The trial protocol has been approved by the Medical Ethics Committee of the University Medical Centre Utrecht. The primary and secondary trial results will be published in international peer-reviewed journals. Trial registration number WHO International Clinical Trials Registry (NL8997; https://trialsearch.who.int).</p

Impact of Dose-Escalated Chemoradiation on Quality of Life in Patients With Locally Advanced Rectal Cancer: 2-Year Follow-Up of the Randomized RECTAL-BOOST Trial

PURPOSE: Dose-escalated chemoradiation (CRT) for locally advanced rectal cancer did not result in higher complete response rates but initiated more tumor regression in the randomized RECTAL-BOOST trial (Clinicaltrials.gov NCT01951521). This study compared patient reported outcomes between patients who received dose-escalated CRT (5 × 3 gray boost + CRT) or standard CRT for 2 years after randomization. METHODS AND MATERIALS: Patients with locally advanced rectal cancer who were participating in the RECTAL-BOOST trial filled out European Organisation for Research and Treatment of Cancer QLQ-C30 and CR29 questionnaires on quality of life (QoL) and symptoms at baseline, 3, 6, 12, 18, and 24 months after start of treatment. Between-group differences in functional QoL domains were estimated using a linear mixed-effects model and expressed as effect size (ES). Symptom scores were compared using Mann-Whitney U test. RESULTS: Patients treated with dose-escalated CRT (boost group, n = 51) experienced a significantly stronger decline in global health at 3 and 6 months (ES -0.4 and ES -0.4), physical functioning at 6 months (ES -1.1), role functioning at 3 and 6 months (ES -0.8 and ES -0.6), and social functioning at 6 months (ES -0.6), compared with patients treated with standard CRT (control group, n = 64). The boost group reported significantly more fatigue at 3 and 6 months (83% vs 66% respectively 89% vs 76%), pain at 3 and 6 months (67% vs 36% respectively 80% vs 44%), and diarrhea at 3 months (45% vs 29%) compared with the control group. From 12 months onwards, QoL and symptoms were similar between groups, apart from more blood/mucus in stool in the boost group. CONCLUSIONS: In patients with locally advanced rectal cancer, dose-escalated CRT resulted in a transient deterioration in global health, physical, role, and social functioning and more pain, fatigue and diarrhea at 3 and 6 months after start of treatment compared with standard CRT. From 12 months onwards, the effect of dose-escalated CRT on QoL largely resolved

Impact of Dose-Escalated Chemoradiation on Quality of Life in Patients With Locally Advanced Rectal Cancer:2-Year Follow-Up of the Randomized RECTAL-BOOST Trial

Purpose: Dose-escalated chemoradiation (CRT) for locally advanced rectal cancer did not result in higher complete response rates but initiated more tumor regression in the randomized RECTAL-BOOST trial (Clinicaltrials.gov NCT01951521). This study compared patient reported outcomes between patients who received dose-escalated CRT (5 × 3 gray boost + CRT) or standard CRT for 2 years after randomization. Methods and Materials: Patients with locally advanced rectal cancer who were participating in the RECTAL-BOOST trial filled out European Organisation for Research and Treatment of Cancer QLQ-C30 and CR29 questionnaires on quality of life (QoL) and symptoms at baseline, 3, 6, 12, 18, and 24 months after start of treatment. Between-group differences in functional QoL domains were estimated using a linear mixed-effects model and expressed as effect size (ES). Symptom scores were compared using Mann-Whitney U test. Results: Patients treated with dose–escalated CRT (boost group, n = 51) experienced a significantly stronger decline in global health at 3 and 6 months (ES –0.4 and ES –0.4), physical functioning at 6 months (ES –1.1), role functioning at 3 and 6 months (ES –0.8 and ES –0.6), and social functioning at 6 months (ES –0.6), compared with patients treated with standard CRT (control group, n = 64). The boost group reported significantly more fatigue at 3 and 6 months (83% vs 66% respectively 89% vs 76%), pain at 3 and 6 months (67% vs 36% respectively 80% vs 44%), and diarrhea at 3 months (45% vs 29%) compared with the control group. From 12 months onwards, QoL and symptoms were similar between groups, apart from more blood/mucus in stool in the boost group. Conclusions: In patients with locally advanced rectal cancer, dose-escalated CRT resulted in a transient deterioration in global health, physical, role, and social functioning and more pain, fatigue and diarrhea at 3 and 6 months after start of treatment compared with standard CRT. From 12 months onwards, the effect of dose-escalated CRT on QoL largely resolved