Hitting the Target: Developing High-quality Evidence for Proton Beam Therapy Through Randomised Controlled Trials.

The National Health Service strategy for the delivery of proton beam therapy (PBT) in the UK provides a unique opportunity to deliver high-quality evidence for PBT through randomised controlled trials (RCTs). We present a summary of three UK PBT RCTs in progress, including consideration of their key design characteristics and outcome assessments, to inform and support future PBT trial development. The first three UK multicentre phase III PBT RCTs (TORPEdO, PARABLE and APPROACH), will compare PBT with photon radiotherapy for oropharyngeal squamous cell carcinoma, breast cancer and oligodendroglioma, respectively. All three studies were designed by multidisciplinary teams, which combined expertise from clinicians, clinical trialists and scientists with strong patient advocacy and guidance from national radiotherapy research networks and international collaborators. Consistent across all three studies is a focus on the reduction of long-term radiotherapy-related toxicities and an evaluation of patient-reported outcomes and health-related quality of life, which will address key uncertainties regarding the clinical benefits of PBT. Innovative translational components will provide insights into mechanisms of toxicity and help to frame the key future research questions regarding PBT. The UK radiotherapy research community is developing and delivering an internationally impactful PBT research portfolio. The combination of data from RCTs with prospectively collected data from a national PBT outcomes registry will provide an innovative, high-quality repository for PBT research and the platform to design and deliver future trials of PBT.

CT-derived measures of muscle quantity and quality predict poorer outcomes from elective colorectal surgery: a UK multicentre retrospective cohort study.

PURPOSE: To assess whether preoperative radiologically defined lean muscle measures are associated with adverse clinical outcomes in patients undergoing elective surgery for colorectal cancer. METHODS: This retrospective UK-based multicentre data collection study identified patients having had colorectal cancer resection with curative intent between January 2013 to December 2016. Preoperative computed-tomography (CT) scans were used to measure psoas muscle characteristics. Clinical records provided postoperative morbidity and mortality data. RESULTS: This study included 1122 patients. The cohort was separated into a combined group (patients with both sarcopenia and myosteatosis) and others group (either sarcopenia or myosteatosis, or neither). For the combined group, anastomotic leak was predicted on univariate (OR 4.1, 95% CI 1.43-11.79; p = 0.009) and multivariate analysis (OR 4.37, 95% CI 1.41-13.53; p = 0.01). Also for the combined group, mortality (up to 5 years postoperatively) was predicted on univariate (HR 2.41, 95% CI 1.64-3.52; p < 0.001) and multivariate analysis (HR 1.93, 95% CI 1.28-2.89; p = 0.002). A strong correlation exists between freehand-drawn region of interest-derived psoas density measurement and using the ellipse tool (R2 = 81%; p < 0.001). CONCLUSION: Measures of lean muscle quality and quantity, which predict important clinical outcomes, can be quickly and easily taken from routine preoperative imaging in patients being considered for colorectal cancer surgery. As poor muscle mass and quality are again shown to predict poorer clinical outcomes, these should be proactively targeted within prehabilitation, perioperative and rehabilitation phases to minimise negative impact of these pathological states.

A survey of patient informational preferences when choosing between medical and surgical therapy for ulcerative colitis: a sub-study from the DISCUSS project.

AIM: People living with ulcerative colitis (UC) have two broad treatment avenues, namely medical or surgical therapy. The choice between these can depend on patient preference as well as the receipt of relevant information. The aim of this study was to define the informational needs of patients with UC. METHOD: A postal survey was designed to capture respondent demographics, treatment experienced within the previous 12 months and informational preferences by rating a long list of items. It was delivered through two hospitals that provide tertiary inflammatory bowel disease services. Descriptive analyses were performed to describe demographics and experiences. Principal component analysis was carried out using a varimax rotation to investigate informational needs. RESULTS: A total of 101 responses were returned (20.1% response rate). The median age of respondents was 45 years and the median time since diagnosis was 10 years. Control preferences skewed towards shared (42.6%) or patient-led but clinician-informed (35.6%). Decision regret was low for the population (median 12.5/100, range 0-100). Key informational needs related to medical therapy were benefits and risks of long-term therapy, burden of hospital attendance, reproductive health, need for steroid treatment and impact on personal life. For surgery, these were stoma information, effect on daily life, effect on sexual and reproductive health, risks and benefits and disruption of life due to surgery. CONCLUSION: This study has identified key areas for discussion when counselling patients about treatment decisions around medical therapy and surgery for UC.

Comparing functional outcomes in minimally invasive versus open inguinal hernia repair using the army physical fitness test.

PURPOSE: The advantages of minimally invasive inguinal hernia repair (MIHR) over open hernia repair (OHR) continue to be debated. We compared MIHR to OHR by utilizing the Army Physical Fitness Test (APFT) as an outcome measure. METHODS: The APFT is a three-component test scored on a normalized 300 point scale taken semiannually by active-duty military. We identified 1119 patients who met inclusion criteria: 588 in the OHR group and 531 in the MIHR group. Changes in APFT scores, time on post-operative duty restrictions (military profile), and time interval to first post-operative APFT were compared using regression analysis. RESULTS: Postoperatively, no APFT score change difference was observed between the OHR or MIHR groups (- 7.3 ± 30 versus - 5.5 ± 27.7, p = 0.2989). Service members undergoing OHR and MIHR underwent their first post-operative APFT at equal mean timeframes (6.6 ± 5 months versus 6.7 ± 5.1, p = 0.74). No difference was observed for time in months spent on an official temporary duty restriction (military profile) for either OHR or MIHR (0.16 ± 0.16 versus 0.15 ± 0.17, p = 0.311). On adjusted regression analysis, higher pre-operative APFT scores and BMI ≥ 30 were independently associated with reduction in post-operative APFT scores. Higher-baseline APFT scores were independently associated with less time on a post-operative profile, whereas higher BMI (≥ 30) and lower rank were independently associated with longer post-operative profile duration. Higher-baseline APFT scores and lower rank were independently associated with shorter time intervals to the first post-operative APFT. CONCLUSION: Overall, no differences in post-operative APFT scores, military profile time, or time to first post-operative APFT were observed between minimally invasive or open hernioplasty in this military population.

Protocol for the ORION trial (RadiO fRequency ablatION for haemorrhoids): a randomised controlled trial.

BACKGROUND: Haemorrhoids are common and can significantly impact the personal and working lives of individuals. Those with more severe symptoms and those not responding to conservative management may require surgery. Current surgical techniques are associated with a degree of postoperative discomfort which may delay return to normal activity. Recurrence is lower in more radical procedures but resulting pain is higher. Radiofrequency ablation (RFA) is a new technique that is gaining popularity and has several hypothesised benefits, including reduced pain and recurrence. However, available evidence is limited. A recent overview from the National Institute for Health and Clinical Excellence recommended more research, in the form of randomised controlled trials, be carried out before further investment is made by national health services. Our aim is to assess whether RFA is at least as good in terms of recurrence as existing surgical interventions, but superior in terms of pain, for patients with symptomatic grade II and III haemorrhoids. METHODS: The RadiO fRequency ablatION for haemorrhoids (ORION) trial will be a pragmatic multicentre patient/assessor-blind parallel group-controlled trial with economic evaluation. The target sample size is 376 participants (188 per arm) and is based on two co-primary endpoints: (i) a non-inferiority design for recurrence and (ii) superiority design for pain at seven days. Participants with grade II or III haemorrhoids will be recruited in 16 National Health Service hospitals and randomised (1:1) to either RFA or surgeon's choice of surgery. CONCLUSIONS: Results will inform future practice for the treatment of grade II-III haemorrhoids and provide evidence for national health services on future investments in RFA. TRIAL REGISTRATION: ISRCTN14474552.

Stepped-wedge randomized controlled trial of laparoscopic ventral mesh rectopexy in adults with chronic constipation.

BACKGROUND: The effectiveness of laparoscopic ventral mesh rectopexy (LVMR) in patients with defecatory disorders secondary to internal rectal prolapse is poorly evidenced. A UK-based multicenter randomized controlled trial was designed to determine the clinical efficacy of LVMR compared to controls at medium-term follow-up. METHODS: The randomized controlled trial was conducted from March 1, 2015 TO January 31, 2019. A stepped-wedge RCT design permitted observer-masked data comparisons between patients awaiting LVMR (controls) with those who had undergone surgery. Adult participants with radiologically confirmed IRP refractory to conservative treatment were randomized to three arms with different delays before surgery. Efficacy outcome data were collected at equally stepped time points (12, 24, 36, 48, 60, and 72 weeks). Clinical efficacy of LVMR compared to controls was defined as ≥ 1.0-point reduction in Patient Assessment of Constipation-Quality of Life and/or Symptoms (PAC-QOL and/or PAC-SYM) scores at 24 weeks. Secondary outcome measures included 14-day diary data, the Generalized Anxiety Disorder scale (GAD-7), the Patient Health Questionnaire-9 (PHQ-9), St Marks incontinence score, the Pelvic Organ Prolapse/Urinary Incontinence Sexual Questionnaire (PISQ-12), the chronic constipation Behavioral Response to Illness Questionnaire (CC-BRQ), and the Brief Illness Perception Questionnaire (BIPQ). RESULTS: Of a calculated sample size of 114, only 28 patients (100% female) were randomized from 6 institutions (due mainly to national pause on mesh-related surgery). Nine were assigned to the T0 arm, 10 to T12, and 9 to T24. There were no substantial differences in baseline characteristics between the three arms. Compared to baseline, significant reduction (improvement) in PAC-QOL and PAC-SYM scores were observed at 24 weeks post-surgery (- 1.09 [95% CI - 1.76, - 0.41], p = 0.0019, and - 0.92 [- 1.52, - 0.32], p = 0.0029, respectively) in the 19 patients available for analysis (9 were excluded for dropout [n = 2] or missing primary outcome [n = 7]). There was a clinically significant long-term reduction in PAC-QOL scores (- 1.38 [- 2.94, 0.19], p = 0.0840 at 72 weeks). Statistically significant improvements in PAC-SYM scores persisted to 72 weeks (- 1.51 [- 2.87, - 0.16], p = 0.0289). Compared to baseline, no differences were found in secondary outcomes, except for significant improvements at 24 and 48 weeks on CC-BRQ avoidance behavior (- 14.3 [95% CI - 23.3, - 5.4], and - 0.92 [- 1.52, - 0.32], respectively), CC-BRQ safety behavior (- 13.7 [95% CI - 20.5, - 7.0], and - 13.0 [- 19.8, - 6.1], respectively), and BIPQ negative perceptions (- 16.3 [95% CI - 23.5, - 9.0], and - 10.5 [- 17.9, - 3.2], respectively). CONCLUSIONS: With the caveat of under-powering due to poor recruitment, the study presents the first randomized trial evidence of short-term benefit of LVMR for internal rectal prolapse. TRIAL REGISTRATION: ISRCTN Registry (ISRCTN11747152).

A mapping review of sacrococcygeal pilonidal sinus disease.

BACKGROUND: Pilonidal sinus is a hole in the natal cleft which may cause severe pain and become infected. The evidence base for management of pilonidal sinus is said to be poor quality, poorly focused and rapidly proliferating. We undertook a systematic mapping review to provide a broad overview of the field and support the identification of research priorities. METHODS: We searched MEDLINE, CINAHL, and EMBASE from inception to 22nd Nov 2020 for primary research studies focused on the management of pilonidal sinus. We extracted data on study design and categorised studies under five major headings ('non-surgical treatment', 'surgical treatment', 'aftercare' and 'other'), producing frequency counts for different study designs. Gaps in research were identified from published systematic reviews and tabulated. RESULTS: We identified 983 eligible studies, of which 36 were systematic reviews and/or meta-analyses; 121 were randomised controlled trials), and 826 observational studies of various design. The majority of studies evaluated surgical techniques (n = 665), or adjuvant medical interventions (n = 98). The literature on wound care has developed most recently, and the evidence base includes 30% randomised controlled trials. Gaps analysis highlighted comparison of surgical techniques including flaps, laser depilation, and wound care interventions as potential areas for randomised controlled trials. CONCLUSIONS: This mapping review summarises eight decades of research on the management of pilonidal sinus. Further research is needed to identify front-running interventions, understand variation in practice and patient values, and to prioritise future research.

The role of Kono-S anastomosis and mesenteric resection in reducing recurrence after surgery for Crohn's disease: a systematic review.

AIM: Recurrence after surgery for Crohn's disease is common. Anastomotic configuration may influence recurrence and the mesentery may be key. Recently the Kono-S anastomosis and radical mesenteric excision have been proposed as methods of reducing recurrence. We analysed the literature pertaining to these novel techniques. METHOD: We searched MEDLINE, Embase and the Cochrane Library for, and selected, studies evaluating Kono-S anastomosis and/or radical mesenteric excision in Crohn's disease. We assessed methodological quality and risk of bias using the Cochrane risk of bias tool for randomized controlled trials and the Joanna Briggs Institute tool for nonrandomized trials. A narrative synthesis was used to summarize the findings. RESULTS: Nine studies (896 patients) were identified. Apart from one randomized controlled trial with a low risk of bias the overall level of evidence was poor (Grade IV). The Kono-S anastomosis was associated with a lower incidence of endoscopic and surgical recurrence (0%-3.4% vs 15%-24.4% respectively). Complications, particularly anastomotic leak rate, were also lower (1.8% vs 9.3% respectively). Evidence from a single poor quality study suggested that mesenteric excision may reduce surgical recurrence rates compared with mesentery preservation. CONCLUSION: The existing literature suggests that the Kono-S anastomosis is safe and may reduce endoscopic and surgical recurrence, but level of evidence is mainly poor. One element of the Kono-S technique, preservation of the mesentery, may be detrimental to recurrence. Further, higher quality, studies are required to investigate these techniques. Such studies should consider the impact of the degree of mesenteric resection in addition to the anastomosis on disease recurrence.

Atrial fibrillation after resection: a PROGRESS III study.

AIM: Atrial fibrillation (AF) is a common cardiac arrhythmia, and is associated with worsening quality of life and complications such as stroke. Previous work showed that 8% of patients develop new-onset AF following colonic resection and highlighted factors that might predict the development of postoperative AF. The development of a new arrhythmia may have a negative effect on longer-term quality of life as well as cancer survivorship. The aim of this study is to accurately quantify the incidence of AF following colorectal cancer surgery and to validate a model to predict its development. METHOD: The Atrial Fibrillation After Resection (AFAR) study will recruit 720 patients aged 65 or over undergoing resection of colorectal cancer with curative intent. The primary outcome is development of AF within 90 days of surgery. Assessment of cardiac rhythm will be performed using 24-h Holter monitors at baseline, 30 and 90 days after surgery. An electrocardiogram (ECG) will be performed on the day of discharge. Baseline descriptors including model variables and quality of life will be recorded using EQ-5D-5L. The occurrence of complications and other key surgical outcomes will be recorded. An additional blood test for N-terminal pro B-type natriuretic peptide (NT-proBNP) will be performed prior to surgery. Statistical analysis will validate a previously derived model and will test the incremental value of added variables such as NT-proBNP. Finally, an exploratory analysis will assess whether changes in ECG measures between baseline and postoperative ECG can predict subsequent new-onset AF. CONCLUSION: This study will provide data that may allow us to stratify the risk of developing AF following colorectal cancer surgery. This may inform screening or prophylactic approaches.

A systematic review and meta-analysis of outcomes after elective surgery for ulcerative colitis.

AIM: Approximately 20%-30% of patients with ulcerative colitis (UC) will undergo surgery during their disease course, the vast majority being elective due to chronic refractory disease. The risks of elective surgery are reported variably. The aim of this systematic review and meta-analysis is to summarize the outcomes after elective surgery for UC. METHODS: A systematic review was conducted that analysed studies reporting outcomes for elective surgery in the modern era (>2002). It was prospectively registered on the PROSPERO database (ref: CRD42018115513). Searches were performed of Embase and MEDLINE on 15 January 2019. Outcomes were split by operation performed. Primary outcome was quality of life; secondary outcomes were early, late and functional outcomes after surgery. Outcomes reported in five or more studies underwent a meta-analysis of incidence using random effects. Heterogeneity is reported with I2 , and publication bias was assessed using Doi plots and the Luis Furuya-Kanamori index. RESULTS: A total of 34 studies were included (11 774 patients). Quality of life was reported in 12 studies, with variable and contrasting results. Thirteen outcomes (eight early surgical complications, five functional outcomes) were included in the formal meta-analysis, all of which were outcomes for ileal pouch-anal anastomosis (IPAA). A further 71 outcomes were reported (50 IPAA, 21 end ileostomy). Only 14 of 84 outcomes received formal definitions, with high inter-study variation of definitions. CONCLUSION: Outcomes after elective surgery for UC are variably defined. This systematic review and meta-analysis highlights the range of reported incidences and provides practical information that facilitates shared decision making in clinical practice.

Prehabilitation in elective abdominal cancer surgery in older patients: systematic review and meta-analysis.

BACKGROUND: Prehabilitation has emerged as a strategy to prepare patients for elective abdominal cancer surgery with documented improvements in postoperative outcomes. The aim of this study was to assess the evidence for prehabilitation interventions of relevance to the older adult. METHODS: Systematic searches were conducted using MEDLINE, Web of Science, Scopus, CINAHL and PsychINFO. Studies of preoperative intervention (prehabilitation) in patients undergoing abdominal cancer surgery reporting postoperative outcomes were included. Age limits were not set as preliminary searches revealed this would be too restrictive. Articles were screened and selected based on PRISMA guidelines, and assessment of bias was performed. Qualitative, quantitative and meta-analyses of data were conducted as appropriate. RESULTS: Thirty-three studies (3962 patients) were included. Interventions included exercise, nutrition, psychological input, comprehensive geriatric assessment and optimization, smoking cessation and multimodal (two or more interventions). Nine studies purposely selected high-risk, frail or older patients. Thirty studies were at moderate or high risk of bias. Ten studies individually reported benefits in complication rates, with meta-analyses for overall complications demonstrating significant benefit: multimodal (risk difference -0·1 (95 per cent c.i. -0·18 to -0·02); P = 0·01, I2  = 18 per cent) and nutrition (risk difference -0·18 (-0·26 to -0·10); P < 0·001, I2  = 0 per cent). Seven studies reported reductions in length of hospital stay, with no differences on meta-analysis. CONCLUSION: The conclusions of this review are limited by the quality of the included studies, and the heterogeneity of interventions and outcome measures reported. Exercise, nutritional and multimodal prehabilitation may reduce morbidity after abdominal surgery, but data specific to older patients are sparse.

ANTECEDENTES: La pre-habilitación ha surgido como una estrategia para preparar a los pacientes para la cirugía electiva del cáncer abdominal con mejoras documentadas en los resultados postoperatorios. El objetivo de este estudio fue evaluar la evidencia sobre las intervenciones de pre-habilitación relevantes en adultos de edad avanzada. MÉTODOS: Se realizaron búsquedas sistemáticas utilizando MEDLINE, Web of Science, Scopus, CINAHL y PsychINFO. Registro PROSPERO: CRD42019120381. Se incluyeron estudios de intervención preoperatoria (pre-habilitación) en pacientes sometidos a cirugía oncológica abdominal que describiesen resultados postoperatorios. No se fijaron límites en la edad dado que las búsquedas preliminares revelaron que ello sería demasiado restrictivo. Los artículos fueron examinados y seleccionados en base a las guías PRISMA y se realizó una evaluación del sesgo. Se llevó a cabo un análisis cualitativo, cuantitativo y metaanálisis de los datos según fuese apropiado. RESULTADOS: Se incluyeron 33 estudios (3.962 patients). Las intervenciones incluyeron ejercicio, nutrición, intervención psicológica, evaluación geriátrica global y optimización, abandono del tabaquismo y multimodal (dos o más intervenciones). Nueve estudios seleccionaron expresamente una población de pacientes de elevado riesgo, frágiles o de edad avanzada. Treinta estudios presentaban un riesgo moderado/alto de sesgo. Diez estudios describieron de forma individual beneficios en las tasas de complicaciones con metaanálisis para las complicaciones globales demostrando un beneficio significativo: multimodal (diferencia de riesgo -0,1 (i.c. del 95% −0,18 a −0,02); P = 0,01, I2 = 18%) e intervención nutricional (diferencia de riesgo −0,18 (i.c. del 95% −0,26 a −0,10); P < 0,001, I2 = 0%). Siete estudios describieron reducciones en la duración de la estancia hospitalaria, sin diferencias en el metaanálisis. CONCLUSIÓN: Las conclusiones de esta revisión están limitadas por la calidad de los estudios incluidos, heterogeneidad de las intervenciones y descripción de las medidas de resultados. Las intervenciones de pre-habilitación de ejercicio, nutricionales y multimodales puede reducir la morbilidad tras cirugía abdominal, pero los datos concretos en pacientes de edad avanzada son escasos.

Non-randomized studies should be considered for assessing surgical techniques in rectal prolapse: prospective cohort study.

AIM: Randomized trials comparing surgical techniques for rectal prolapse are not always feasible. We assessed whether non-randomized comparisons of those who have had surgery with those still waiting would be confounding baseline health status. METHOD: This was a prospective cohort study in seven UK hospitals. Participants were ≥ 18 years and listed for surgical interventions of equivalent intensity for rectal prolapse. They were defined as short or long waiters (≤ 18 or > 18 weeks, respectively). Time on the waiting list was compared with baseline comorbidity (Charlson comorbidity index) and change from baseline in health status (EQ-5D-5L) at the time of surgery. RESULTS: In all, 203 patients were analysed. Median (interquartile range) waiting time was 13.7 weeks (8.1, 20.4) varying across sites. Baseline comorbidity was not an important predictor of waiting time. Median Charlson comorbidity index was 2 (0, 3) for short and 1 (0, 3) for long waiters. A change in waiting time by a week was associated with negligible improvement in the EQ-5D-5L index of 0.001 (95% CI -0.000 to 0.003, P = 0.106). CONCLUSION: Negligible change in patient reported health status while on the waiting list and lack of effect of comorbidities in influencing waiting time support the use of non-randomized pre-/post-studies to compare the effects of surgical interventions for rectal prolapse.