Financial implications of sarcopenia in colorectal cancer surgery: a cost analysis in an Australian public hospital.

INTRODUCTION: Sarcopenia has a detrimental impact on patient outcomes following colorectal surgery, increasing financial strain on the healthcare system. Given the absence of specific Australian data, this study aimed to measure the cost of sarcopenia in the context of colorectal surgery in an Australian public hospital. METHODS: A retrospective cost analysis, following CHEERS guidelines, was conducted on major elective colorectal cancer surgical cases at the Royal Adelaide Hospital between 2018 and 2022. The cross-sectional psoas area was measured through computed tomography (CT) imaging at the level of the third lumbar vertebrae, and sarcopenia was determined using gender-specific thresholds. Hospital billing data was used to gather costings (AU$). RESULTS: Out of 271 patients, 57 (21.0%) comprised the sarcopenic group (SG). SG patients were older (74 vs. 69 years, P < 0.001), had a higher American Society of Anaesthesiologists (>II, 71.9% vs. 53.7%, P = 0.014) and a lower median body mass index (24.8 vs. 28.7 kg/m2, P < 0.001). The SG exhibited a greater likelihood of complications (84.2 vs. 68.7%, P = 0.020) and prolonged hospital stay by 1 day (median 7 vs. 6 days, P = 0.027). Despite an increased mean total cost of hospital admission, no statistically significant difference was found (AU$37 712 vs. $34 845, P = 0.296). Multivariate analysis revealed hypoalbuminemia, prolonged operative time, postoperative ileus, return to theatre, Clavien-Dindo grade ≥3 complications, and prolonged stay increased overall cost (P < 0.05). CONCLUSION: Sarcopenia was not associated with a significantly increased cost of colorectal surgery in our institution. Future studies examining the cost-effectiveness of prehabilitation programmes targeting sarcopenia should be considered.

If the peri-operative patient pathway was right, what would it look like?

BACKGROUND: Patients undergoing surgery deserve the best possible peri-operative outcomes. Each stage of the peri-operative patient journey offers opportunities to improve care delivery, with shorter lengths of stay, less complications, reduced costs and better value. METHODS: These opportunities were identified through narrative review of the literature, with consultation and consensus at the hidden pandemic (of postoperative complications) summit 2, July 2023 in Adelaide, Australia RESULTS: Before surgery: Some patients who receive timely alternative treatments may not need surgery at all. The period of waiting after listing should be a time of preparation. Risk assessment at the time of surgical listing facilitates recognition of need for comorbidity optimisation and identifies those who will most benefit from prehabilitation, particularly frail and deconditioned patients. DURING SURGERY: During the surgical admission, ERAS programs result in less postoperative complications, shorter length of stay and better patient experience but require agreement between clinicians, and coordinated monitoring of delivery of the elements in the ERAS bundle of care. AFTER SURGERY: At-risk patients need to have the appropriate levels of monitoring for cardiovascular instability, renal impairment or respiratory dysfunction, to facilitate timely, proactive management if they develop. Access to allied health in the early postoperative period is also critical for promoting mobility, and earlier discharge, particularly after joint surgery. Where appropriate, provision of rehabilitation services at home improves patient experience and adds value. The peri-operative patient journey begins and ends with primary care so there is a need for clear communication, documentation, around sharing of responsibility between practitioners at each stage. CONCLUSION: Identifying and mitigating risk to reduce complications and length of stay in hospital will improve outcomes for patients and deliver the best value for the health system.

Economic Evaluation of 'Watch and Wait' Following Neoadjuvant Therapy in Locally Advanced Rectal Cancer: A Systematic Review.

BACKGROUND: Owing to multimodal treatment and complex surgery, locally advanced rectal cancer (LARC) exerts a large healthcare burden. Watch and wait (W&W) may be cost saving by removing the need for surgery and inpatient care. This systematic review seeks to identify the economic impact of W&W, compared with standard care, in patients achieving a complete clinical response (cCR) following neoadjuvant therapy for LARC. METHODS: The PubMed, OVID Medline, OVID Embase, and Cochrane CENTRAL databases were systematically searched from inception to 26 April 2024. All economic evaluations (EEs) that compared W&W with standard care were included. Reporting and methodological quality was assessed using the Consolidated Health Economic Evaluation Reporting Standards (CHEERS), BMJ and Philips checklists. Narrative synthesis was performed. Primary and secondary outcomes were (incremental) cost-effectiveness ratios and the net financial cost. RESULTS: Of 1548 studies identified, 27 were assessed for full-text eligibility and 12 studies from eight countries (2016-2024) were included. Seven cost-effectiveness analyses (complete EEs) and five cost analyses (partial EEs) utilized model-based (n = 7) or trial-based (n = 5) analytics with significant variations in methodological design and reporting quality. W&W showed consistent cost effectiveness (n = 7) and cost saving (n = 12) compared with surgery from third-party payer and patient perspectives. Critical parameters identified by uncertainty analysis were rates of local and distant recurrence in W&W, salvage surgery, perioperative mortality and utilities assigned to W&W and surgery. CONCLUSION: Despite heterogenous methodological design and reporting quality, W&W is likely to be cost effective and cost saving compared with standard care following cCR in LARC. Clinical Trials Registration PROSPERO CRD42024513874.

Outcomes of rectal cancer treatment in rural Australia and New Zealand: analysis of the bowel cancer outcomes registry.

BACKGROUND: The demographics and geography of Australia and New Zealand (ANZ), with few metropolitan centres and vast, sparsely populated rural areas, represent a challenge to providing equal care to all patients. This study aimed to compare rectal cancer care at rural and urban hospitals in ANZ. METHODS: From the Bowel Cancer Outcomes Registry (BCOR, formerly known as the Bi-National Colorectal Cancer Audit; BCCA), rectal cancer patients treated between 2007 and 2020 were compared based on hospital location (urban versus rural). Propensity-score matching was performed to correct for differences in baseline characteristics between groups. RESULTS: A total of 9385 rectal cancer patients were identified from the BCOR: 1329 (14.2%) were treated at rural hospitals and 8056 (85.8%) at urban hospitals. Propensity-score matching resulted in 889 patients in each group, matched for age, ASA score, hospital type (public/private), tumour height from the anal verge, and pre-treatment cT- and cAJCC-stage. Rural patients had fewer pre-treatment MRIs (67.9% versus 74.7%; P = 0.002), and underwent less neoadjuvant therapy (44.7% versus 50.9%; P = 0.01). Rural patients underwent fewer ULARs (39.4% versus 45.6%; P = 0.03), and fewer anastomoses were formed (67.9% versus 74.4%; P = 0.05). CRM rates and postoperative AJCC stages (P = 0.19) were similar between groups (P = 0.87). Fewer rural patients received adjuvant chemotherapy (37.8% versus 43.3%; P = 0.02). CONCLUSION: There are significant differences in pre-treatment MRI rates, (neo)adjuvant treatment rates and surgical procedures performed between rectal cancer patients treated at rural and urban hospitals in ANZ, while CRM rates and postoperative AJCC stages are similar.

Oncological Outcomes and Response Rate After Total Neoadjuvant Therapy for Locally Advanced Rectal Cancer: A Network Meta-Analysis Comparing Induction vs. Consolidation Chemotherapy vs. Standard Chemoradiation.

TNT is now considered the preferred option for stage II-III locally advanced rectal cancer (LARC). However, the prognostic benefit and optimal sequence of TNT remains unclear. This network meta-analysis (NMA) compared short- and long-term outcomes amongst patients with LARC receiving total neoadjuvant therapy (TNT) as induction (iTNT) or consolidation chemotherapy (cTNT) with those receiving neoadjuvant chemoradiation (nCRT) alone. A systematic literature search was performed between 2012 and 2023. A Bayesian NMA was conducted using a Markov Chain Monte Carlo method with a random-effects model and vague prior distribution to calculate odds ratios (OR) with 95% credible intervals (CrI). The surface under the cumulative ranking (SUCRA) curves were used to rank treatment(s) for each outcome. In total, 11 cohorts involving 8360 patients with LARC were included. There was no significant difference in disease-free survival (DFS) and overall survival (OS) amongst the 3 treatments. Compared with nCRT, both cTNT (OR 2.36; 95% CrI, 1.57-3.66) and iTNT (OR 1.99; 95% CrI, 1.44-2.95) significantly improved complete response (CR) rate. Notably, cTNT ranked as the best treatment for CR (SUCRA 0.90) and iTNT as the best treatment for 3-year DFS and OS (SUCRA 0.72 and 0.87, respectively). Both iTNT and cTNT strategies significantly improved CR rates compared with nCRT. cTNT was ranked highest for CR rates, while iTNT was ranked highest for 3-year survival outcomes. However, no other significant differences in DFS, OS, sphincter-saving surgery, R0 resection and postoperative complications were found amongst the treatment groups.

Pyridostigmine to Reduce the duration of postoperative Ileus after Colorectal surgery (PyRICo-RCT): randomized clinical trial.

BACKGROUND: Postoperative ileus, driven by the cholinergic anti-inflammatory pathway, is the most common complication in patients undergoing colorectal surgery. By inhibiting acetylcholinesterase, pyridostigmine can potentially modulate the cholinergic anti-inflammatory pathway and accelerate gastrointestinal recovery. This study aimed to assess the efficacy of pyridostigmine in improving gastrointestinal recovery after colorectal surgery. METHODS: This double-blinded RCT enrolled adult patients undergoing elective colorectal surgery at two hospitals in South Australia. Patients were randomized to 60 mg oral pyridostigmine or placebo twice daily starting 6 h after surgery until the first passage of stool. The primary outcome was GI-2, a validated composite measure of time to first stool and tolerance of oral diet. Secondary outcomes included incidence of postoperative ileus (defined as GI-2 greater than 4 days), duration of hospital stay, and 30-day complications, evaluated by intention-to-treat univariate analysis. RESULTS: Of 130 patients recruited (mean(s.d.) age 58.4(16.4) years; 73 men, 56%), 65 were allocated to each arm. The median GI-2 was 1 day shorter with pyridostigmine compared with placebo (2 (i.q.r. 1-3) versus 3 (2-4) days; P = 0.015). However, there were no significant differences in postoperative ileus (17.2 versus 21.5%; P = 0.532) or duration of hospital stay (median 5 (i.q.r. 4-8.75) versus 5 (4-7.5) days; P = 0.921). Similarly, there were no significant differences in overall complications, anastomotic leak, cardiac complications, or patient-reported side effects. CONCLUSION: Pyridostigmine resulted in a quicker return of GI-2 and was well tolerated. Larger multicentre studies are required to determine the optimal dosing and evaluate the impact of pyridostigmine in different surgical settings. Registration number: ACTRN12621000530820 (https://anzctr.org.au).

Machine learning prediction model for postoperative ileus following colorectal surgery.

BACKGROUND: Postoperative ileus (POI) continues to be a major cause of morbidity following colorectal surgery. Despite best efforts, the incidence of POI in colorectal surgery remains high (~30%). This study aimed to investigate machine learning techniques to identify risk factors for POI in colorectal surgery patients, to help guide further preventative strategies. METHODS: A TRIPOD-guideline-compliant retrospective study was conducted for major colorectal surgery patients at a single tertial care centre (2018-2022). The primary outcome was the occurrence of POI, defined as not achieving GI-2 (outcome measure of time to first stool and tolerance of oral diet) by day four. Multivariate logistic regression, decision trees, radial basis function and multilayer perceptron (MLP) models were trained using a random allocation of patients to training/testing data sets (80/20). The area under the receiver operating characteristic (AUROC) curves were used to evaluate model performance. RESULTS: Of 504 colorectal surgery patients, 183 (36%) experienced POI. Multivariate logistic regression, decision trees, radial basis function and MLP models returned an AUROC of 0.722, 0.706, 0.712 and 0.800, respectively. The MLP model had the highest sensitivity and specificity values. In addition to well-known risk factors for POI, such as postoperative hypokalaemia, surgical approach, and opioid use, the MLP model identified sarcopenia (ranked 4/30) as a potentially modifiable risk factor for POI. CONCLUSION: MLP outperformed other models in predicting POI. Machine learning can provide valuable insights into the importance and ranking of specific predictive variables for POI. Further research into the predictive value of preoperative sarcopenia for POI is required.

Functional outcomes following anterior resection for colorectal cancer: a needs assessment and proposal of a nurse-led remote management algorithm.

AIM: With the rise of structured, remote follow-up of colorectal cancers, there is the potential risk of underdiagnosing and undermanaging low anterior resection syndrome (LARS). This cohort study aims to determine the rate of LARS and its patterns of care, with the aim of generating a risk-stratified management algorithm that can be employed for nurse-led follow-up. METHOD: Patients who underwent elective anterior resection for the management of colorectal cancer between 1 January 2017 and 31 December 2021 were sent quality-of-life questionnaires (EORTC-QLQ-CR29 and LARS score) and surveyed for LARS symptoms and management utilized. RESULTS: Out of 70 patients who completed questionnaires, 71.4% had LARS and 42.9% had major LARS. The international Delphi consensus definition identified more patients (n = 50) with LARS than the LARS score (n = 41). Tumours located <8 cm from the anal verge, ULAR, and temporary stoma were predictive of major LARS on univariate analysis. However, only temporary stoma was predictive for LARS (OR 7.89 (1.15-53.95), P = 0.035) and majors LARS (8.14 (1.79-37.01), P = 0.007) on multivariate analysis. Forty-four percent of patients with LARS did not have input from any health professional for this condition. Consultation with specialist allied health and/or colorectal surgeons ranged from 4% to 22%. CONCLUSIONS: Our study highlights that with the current remote follow-up system focused on cancer outcomes a significant proportion of patients with LARS are overlooked, resulting in the underutilization of relevant health professionals and management options. We propose a nurse-led management algorithm to address this issue while still minimizing surgical outpatient load.

Engineering tumor-colonizing E. coli Nissle 1917 for detection and treatment of colorectal neoplasia.

Bioengineered probiotics enable new opportunities to improve colorectal cancer (CRC) screening, prevention and treatment. Here, first, we demonstrate selective colonization of colorectal adenomas after oral delivery of probiotic E. coli Nissle 1917 (EcN) to a genetically-engineered murine model of CRC predisposition and orthotopic models of CRC. We next undertake an interventional, double-blind, dual-centre, prospective clinical trial, in which CRC patients take either placebo or EcN for two weeks prior to resection of neoplastic and adjacent normal colorectal tissue (ACTRN12619000210178). We detect enrichment of EcN in tumor samples over normal tissue from probiotic-treated patients (primary outcome of the trial). Next, we develop early CRC intervention strategies. To detect lesions, we engineer EcN to produce a small molecule, salicylate. Oral delivery of this strain results in increased levels of salicylate in the urine of adenoma-bearing mice, in comparison to healthy controls. To assess therapeutic potential, we engineer EcN to locally release a cytokine, GM-CSF, and blocking nanobodies against PD-L1 and CTLA-4 at the neoplastic site, and demonstrate that oral delivery of this strain reduces adenoma burden by ~50%. Together, these results support the use of EcN as an orally-deliverable platform to detect disease and treat CRC through the production of screening and therapeutic molecules.

Deep learning to predict lymph node status on pre-operative staging CT in patients with colon cancer.

INTRODUCTION: Lymph node (LN) metastases are an important determinant of survival in patients with colon cancer, but remain difficult to accurately diagnose on preoperative imaging. This study aimed to develop and evaluate a deep learning model to predict LN status on preoperative staging CT. METHODS: In this ambispective diagnostic study, a deep learning model using a ResNet-50 framework was developed to predict LN status based on preoperative staging CT. Patients with a preoperative staging abdominopelvic CT who underwent surgical resection for colon cancer were enrolled. Data were retrospectively collected from February 2007 to October 2019 and randomly separated into training, validation, and testing cohort 1. To prospectively test the deep learning model, data for testing cohort 2 was collected from October 2019 to July 2021. Diagnostic performance measures were assessed by the AUROC. RESULTS: A total of 1,201 patients (median [range] age, 72 [28-98 years]; 653 [54.4%] male) fulfilled the eligibility criteria and were included in the training (n = 401), validation (n = 100), testing cohort 1 (n = 500) and testing cohort 2 (n = 200). The deep learning model achieved an AUROC of 0.619 (95% CI 0.507-0.731) in the validation cohort. In testing cohort 1 and testing cohort 2, the AUROC was 0.542 (95% CI 0.489-0.595) and 0.486 (95% CI 0.403-0.568), respectively. CONCLUSION: A deep learning model based on a ResNet-50 framework does not predict LN status on preoperative staging CT in patients with colon cancer.

Use of Acetylcholinesterase Inhibitors in Reducing Time to Gastrointestinal Function Recovery following Abdominal Surgery: A Systematic Review.

INTRODUCTION: Postoperative ileus (POI) is a significant complication following abdominal surgery, increasing morbidity and mortality. The cholinergic anti-inflammatory response is one of the major pathways involved in developing POI, but current recommendations to prevent POI do not target this. This review aims to summarise evidence for the use of acetylcholinesterase inhibitors, neostigmine and pyridostigmine, to reduce the time to return of gastrointestinal function (GI) following abdominal surgery. METHODS: A systematic search of various databases was performed from 1946 to May 2023. Randomised controlled trials (RCTs) on acetylcholinesterase inhibitors in intra-abdominal surgery were included. Data on time to flatus and/or stool and side effects were extracted. RESULTS: Among 776 screened manuscripts, 8 RCTs (703 patients) investigating acetylcholinesterase inhibitors in intra-abdominal surgery were analysed. Five studies showed a significant reduction in time to flatus and/or stool by 17-47.6 h. Methodological variations, differing procedure types, and potential bias were observed. Limited studies reported side effects or length of stay. CONCLUSION: Acetylcholinesterase inhibitors may reduce the time for GI to return. However, current evidence is limited and biased. Further studies incorporating acetylcholinesterase inhibitors in an enhanced recovery protocol are required to address this question, especially for patients undergoing colorectal surgery.

Association Between RAS/BRAF Mutations and Complete Response Following Total Neoadjuvant Therapy in Patients with Rectal Cancer: A Prospective Multicentered Study.

BACKGROUND: The impact of RAS/BRAF mutation on primary response rates after total neoadjuvant therapy (TNT) in patients with advanced rectal cancer is unclear. The aim of this study was to assess complete response rates after TNT according to RAS/BRAF mutation status. METHODS: A prospective observational study was performed in patients with rectal cancer who underwent TNT with curative intent at three South Australian hospitals between 2019 and 2023. Patients were classified according to their mutation status: mutant RAS/BRAF (mutRAS) or wild-type RAS/BRAF (wtRAS). The primary endpoint was overall complete response (oCR) rate, defined as the proportion of patients who achieved clinical complete response (cCR) and/or pathological complete response (pCR). RESULTS: Of the 150 patients eligible for inclusion, 80 patients with RAS/BRAF status available were identified. Of these, 43 (53.8%) patients were classified as mutRAS and 37 (46.3%) patients as wtRAS. Patients with mutRAS had significantly lower cCR and oCR rates after TNT than patients with wtRAS (14% vs. 37.8%, p = 0.014; 11.6% vs. 43.2%, p = 0.001, respectively). There was no significant difference in pCR rate between the groups. Of the 80 rectal cancer patients tested, 35 (43.8%) had metastatic disease (M1). There was no significant difference in complete M1 response rates between the groups (17.6% vs. 38.9%, p = 0.254). CONCLUSION: RAS/BRAF mutations negatively impact primary tumor response rates after TNT in patients with advanced rectal cancer. Large-scale national studies are needed to determine whether RAS/BRAF status could be used to select optimal oncologic therapy in rectal cancer patients.

Management of rectal cancer in the era of total neoadjuvant therapy and watch and wait: A multidisciplinary team discussion at the Australasian Gastro-Intestinal Trials Group (AGITG) Annual Scientific Meeting 2022.

Rectal cancer is a common malignancy. The management of rectal cancer has recently evolved and has undergone a paradigm shift with the advent of treatment approaches such as total neoadjuvant therapy and the watch-and-wait approach. However, despite the recently available evidence, there is no consensus on the optimal management approach in the setting of locally advanced rectal cancer. To address some of the controversies, a joint multidisciplinary panel discussion was conducted at the Australasian Gastro-Intestinal Trials Group (AGITG) Annual Scientific Meeting in November 2022. Members from different subspecialties formed two panels and discussed three clinical cases in a debate format. Each case represented some of the complex issues faced by clinicians in this setting. The discussion is now presented in this manuscript, which depicts the different available management approaches and reiterates the importance of a multidisciplinary approach.