Current perioperative care in patients undergoing a beyond total mesorectal excision procedure for rectal cancer: What are the differences with the colorectal enhanced recovery after surgery protocol?

AIM: Patients requiring a beyond total mesorectal excision (bTME) procedure for locally advanced rectal cancer (LARC) and locally recurrent rectal cancer (LRRC) will probably benefit from enhanced recovery after surgery (ERAS) protocols. However, implementation of ERAS protocols in such groups of patients is considered challenging. The aims of this study were to evaluate ERAS-related outcomes of patients with LARC or LRRC undergoing bTME and to investigate the possibility of designing a tailored ERAS protocol. METHOD: This study was divided into four phases. Phase one consisted of a literature study to compare functional recovery and postoperative outcomes in patients undergoing bTME. In phase two, outcomes on ERAS care elements in bTME were retrospectively evaluated. In phase three, differences in ERAS-related outcomes and compliance of the colorectal ERAS protocol in patients who had undergone bTME were studied. In phase four, multidisciplinary team meetings were held to develop an ERAS protocol for bTME patients. RESULTS: Seven studies reported on ERAS-related outcomes in patients undergoing bTME. Median length of hospital stay was 9-19 days, median stay in the intensive care unit was 2-4 days and 30-day postoperative major complication rates were 22.6%-61.3%. Seventy-five bTME patients were included for retrospective analysis. In these patients, length of stay was 9.0 days and major postoperative complications were observed in 40.0%. The overall ERAS compliance was 44.4%. Compared with the colorectal ERAS protocol, the largest differences in management were observed in the use of epidural anaesthesia, the postoperative use of urethral catheters, oral intake and mobilization. CONCLUSION: Patients undergoing bTME for LARC or LRRC are substantially different from patients treated with the colorectal ERAS protocol, regarding ERAS-related outcomes. A tailored, multimodal ERAS protocol with specific modifications was developed by an expert multidisciplinary team for patients undergoing bTME for LARC or LRRC.

Patient-reported outcomes during first-line palliative systemic therapy alternated with pressurized intraperitoneal aerosol chemotherapy for unresectable colorectal peritoneal metastases: a single-arm phase II trial (CRC-PIPAC-II).

BACKGROUND: The CRC-PIPAC-II study prospectively assessed bidirectional therapy (BT) consisting of first-line palliative systemic therapy and electrostatic precipitation oxaliplatin-based pressurized intraperitoneal aerosol chemotherapy (ePIPAC-OX) in patients with unresectable colorectal peritoneal metastases (CPM). This study describes the exploration of patient-reported outcomes (PROs). METHODS: In this phase II trial, 20 patients with isolated CPM were treated with up to three cycles of BT, each cycle consisting of two to three courses of systemic therapy, followed by ePIPAC-OX (92 mg/m2). Patients were asked to complete the EuroQoL EQ-5D-5L, EORTC QLQ-C30, and EORTC QLQ-CR29 questionnaires at baseline, during the first cycle of BT, and one and four weeks after each consecutive BT cycle. PRO scores were calculated and compared between baseline and each subsequent time point using linear-mixed modeling (LMM). PROs were categorized into symptom scales and function scales. Symptom scales ranged from 0 to 100, with 100 representing the maximum symptom load. Function scales ranged from 0 to 100, with 100 representing optimal functioning. RESULTS: Twenty patients underwent a total of 52 cycles of bidirectional therapy. Most PROs (29 of 37, 78%) were not significantly affected during trial treatment. In total, only eight PROs (22%) were significantly affected during trial treatment: Six PROs (index value, global health status, emotional functioning, C30, appetite, and insomnia) showed transient improvement at different time points. Two PROs transiently deteriorated: pain initially improved during the first BT cycle [- 16, p < 0.001] yet worsened temporarily one week after the first two BT cycles (+ 20, p < 0.001; + 17, p = 0.004; respectively). Abdominal pain worsened temporarily one week after the first BT cycle (+ 16, p = 0.004), before improving again four weeks after treatment ended (- 10, p = 0.004). All significant effects on Pros were clinically significant and all deteriorations in PROs were of temporary nature. DISCUSSION: Patients undergoing BT for unresectable CPM had significant, but reversible alterations in several PROs. Most affected PROs concerned improvements and only two PROs showed deteriorations. Both deteriorated PROs returned to baseline after trial treatment and were of a temporary nature. These outcomes help to design future studies on the role of ePIPAC in the palliative setting.

Indocyanine green near-infrared fluorescence bowel perfusion assessment to prevent anastomotic leakage in minimally invasive colorectal surgery (AVOID): a multicentre, randomised, controlled, phase 3 trial.

BACKGROUND: Anastomotic leakage is a severe postoperative complication in colorectal surgery and compromised bowel perfusion is considered a major contributing factor. Conventional methods to assess bowel perfusion have a low predictive value for anastomotic leakage. We therefore aimed to evaluate the efficacy of real-time assessment with near-infrared (NIR) fluorescence imaging with indocyanine green (ICG) in the prevention of anastomotic leakage. METHODS: This multicentre, randomised, controlled, phase 3 trial was done in eight hospitals in the Netherlands. We included adults (aged >18 years) who were scheduled for laparoscopic or robotic colorectal surgery (with planned primary anastomosis) for benign and malignant diseases. Preoperatively, patients were randomly assigned (1:1) to fluorescence-guided bowel anastomosis (FGBA) or conventional bowel anastomosis (CBA) by variable block randomisation (block sizes 4, 6, and 8) and stratified by site. The operating surgeon and investigators analysing the data were not masked to group assignment. Patients were unmasked after the surgical procedure or after study end. In the FGBA group, surgeons marked anastomosis levels per conventional perfusion assessment and then administered 5 mg of ICG by 2 mL intravenous bolus. They assessed bowel perfusion using NIR fluorescence imaging and adjusted (or kept) transection lines accordingly. Only conventional methods for bowel perfusion assessment were used in the CBA group. The primary outcome was the difference in the rate of clinically relevant anastomotic leakage (ie, requiring active therapeutic intervention but manageable without reoperation [grade B] or requiring reoperation [grade C], per the International Study Group of Rectal Cancer) between the FGBA group and the CBA group within 90 days post-surgery. The primary outcome and safety were assessed in the intention-to-treat population. This study was registered with ToetsingOnline.nl (NL7502) and ClinicalTrials.gov (NCT04712032) and is complete. FINDINGS: Between July 2, 2020, and Feb 21, 2023, 982 patients were enrolled, of whom 490 were assigned to FGBA and 492 were assigned to CBA. After excluding 51 patients, the intention-to-treat population comprised 931 (463 assigned FGBA and 468 assigned CBA). Patients had a median age of 68·0 years (IQR 59·0-75·0) and 485 (52%) were male and 446 (48%) were female. Ethnicity data were not available. The overall 90-day rate of clinically relevant anastomotic leakage was not significantly different between the FGBA group (32 [7%] of 463 patients) and the CBA group (42 [9%] of 468 patients; relative risk 0·77 [95% CI 0·50-1·20]; p=0·24). No adverse events related to ICG use were observed. 313 serious adverse events in 229 (25%) patients were at 90-day follow-up (159 serious adverse events in 113 [24%] patients in the FGBA group and 154 serious adverse events in 116 [25%] patients in the CBA group). 18 (2%) people died by 90 days (ten in the FGBA group and eight in the CBA group). INTERPRETATION: ICG NIR fluorescence imaging did not reduce 90-day anastomotic leakage rates in this trial across all types of colorectal surgeries. Further research should be done in subgroups, such as rectosigmoid resections, for which evidence suggests ICG NIR might be beneficial. FUNDING: Olympus Medical, Diagnostic Green, and Intuitive Foundation.

Effects of a perioperative educational pathway on ostomy self-care, level of independence and need for visiting nurse services: a comparative observational cohort study.

AIM: Most new ostomy patients are not able to manage ostomy self-care when they are discharged and rely on visiting nurse services for ostomy care. The aim of this study was to determine if a perioperative ostomy educational pathway increases the level of independence and decreases the need for visiting nurse services in new ostomy patients. METHOD: A prospective longitudinal study was conducted between July 2018 and February 2020. Patients who received a colostomy or ileostomy and were treated on the surgery ward were included. Patients who followed a perioperative ostomy educational pathway were compared to a historical control group. The primary outcome measure was the level of independence in ostomy care and the need for visiting nurse services. RESULTS: After discharge, 67.6% of patients in the intervention group (n = 244) were able to independently perform ostomy care and were therefore not relying on visiting nurse services, compared to 15.2% of the patients in the control group (n = 33). The need for visiting nurse services was higher in patients aged ≥70 years (OR 3.20, P < 0.001), those who did not attend the preoperative practice session (OR 3.02, P = 0.002), those with a history of transient ischaemic attack (OR 10.22, P = 0.045) and those with mild cognitive impairment (OR 28.98, P = 0.002). CONCLUSION: A perioperative ostomy educational pathway effectively increased the level of independence and decreased the need for visiting nurse services in new ostomy patients.

Post-operative complications following dose adaptation of intra-operative electron beam radiation therapy in locally advanced or recurrent rectal cancer.

Purpose: The benefit of intra-operative radiotherapy (IORT) in the treatment of locally advanced rectal cancer (LARC) or locally recurrent rectal cancer (LRRC) lie in its ability to provide high-dose of radiation to limited at-risk volume, thereby eliminating microscopic disease and decreasing toxicity. A comparative study between high-dose-rate (HDR) brachytherapy, named intra-operative brachytherapy (IOBT), and intra-operative electron radiotherapy (IOERT) was performed showing favorable LRFS after IOBT, possibly due to a higher surface dose that is inherent in IOBT technique. The IOERT technique in Catharina Hospital Eindhoven was adapted to increase the surface dose, aiming to improve local control. Post-operative complications due to an increased radiation dose remain the matter of concern. This retrospective study was performed to compare complication rates before and after adapted IOERT dose. Material and methods: All patients undergoing surgery with IOERT for LARC or LRRC from September 2019 until July 2023, were considered. Patients selected until August 31, 2021 were included in control cohort (n = 108), and those chosen from September 1, 2021 onwards were included in intervention cohort (n = 92). Perioperative and (major) post-operative complications were classified retrospectively, during admission, at 30 days, and at 90 days. Results: In LARC patients, a decrease in post-operative complications was observed (p = 0.009). 19% of LARC patients experienced major post-operative surgical complications, i.e., Clavien-Dindo grade 3b-5, regardless of treatment group. No difference in major 90-day complications was noted (p = 0.142). In LRRC patients, the use of induction chemotherapy decreased from 78% to 29% (p < 0.001), which complicated comparison. However, no difference in major post-operative complications was observed at 30 days (p = 0.222) or 90 days (p = 0.977) after surgery. Conclusions: Increased surface dose of IOERT does not seem to lead to an increase in post-operative complications. Further research is needed to evaluate the efficacy of dose adaptation in IOERT to improve local oncological control rates. Routine evaluation of CTCAE scores in follow-up will help uncover possible long-term radiation-induced toxicity.

Dutch national guidelines for locally recurrent rectal cancer.

Due to improvements in treatment for primary rectal cancer, the incidence of LRRC has decreased. However, 6-12% of patients will still develop a local recurrence. Treatment of patients with LRRC can be challenging, because of complex and heterogeneous disease presentation and scarce - often low-grade - data steering clinical decisions. Previous consensus guidelines have provided some direction regarding diagnosis and treatment, but no comprehensive guidelines encompassing all aspects of the clinical management of patients with LRRC are available to date. The treatment of LRRC requires a multidisciplinary approach and overarching expertise in all domains. This broad expertise is often limited to specific expert centres, with dedicated multidisciplinary teams treating LRRC. A comprehensive, narrative literature review was performed and used to develop the Dutch National Guideline for management of LRRC, in an attempt to guide decision making for clinicians, regarding the complete clinical pathway from diagnosis to surgery.

Intraperitoneal pharmacokinetics of systemic oxaliplatin, 5-fluorouracil and bevacizumab in patients with colorectal peritoneal metastases.

BACKGROUND: Peritoneal metastases (PM) commonly occur in colorectal cancer patients. Systemic chemotherapy yields poor outcomes for these patients. It is hypothesised that traditional systemic chemotherapy is not very effective for this patient population. This study investigates to what extent systemic anti-cancer therapy crosses the peritoneal barrier. METHODS: In a Phase I study, eighteen patients received systemic oxaliplatin, 5-FU, and bevacizumab. Plasma and peritoneal fluid samples were collected to measure drug concentrations. A non-compartmental analysis determined the Area Under the Curve (AUC) for oxaliplatin and 5-FU in both matrices. Intraperitoneal (IP) and intravenous (IV) exposure ratios were calculated, along with the bevacizumab concentration IP/IV ratio. The relationship between tumour load and IP/IV ratios and the correlation between the IP/IV ratios of different treatments were assessed statistically. RESULTS: A total of 438 5-FU samples and 578 oxaliplatin samples were analysed in plasma and peritoneal fluid. Bevacizumab was quantified with 17 measurements in plasma and 15 measurements IP. Median IP/IV ratios were 0.143, 0.352 and 0.085 for 5-FU, oxaliplatin and bevacizumab, respectively. Oxaliplatin exhibited a longer IP half-life than 5-FU. A correlation was found between oxaliplatin and bevacizumab IP/IV ratios (R=0.69, p=0.01). No statistical correlations were found between the other investigated drugs. CONCLUSIONS: Our findings indicate that only a small percentage of systemically administered anti-cancer treatment reaches the IP cavity, questioning their efficacy against PM. This strengthens the hypothesis for repeated intraperitoneal chemotherapy to reach adequate anti-cancer drug levels.

Population pharmacokinetics of intraperitoneal irinotecan and SN-38 in patients with peritoneal metastases from colorectal origin.

Peritoneal metastases (PM) are common in patients with colorectal cancer. Patients with PM have a poor prognosis, and for those who are not eligible for cytoreductive surgery (CRS) with or without hyperthermic intraperitoneal chemotherapy (HIPEC), palliative chemotherapy is currently the only option. Recently, we conducted a phase I trial (INTERACT) in which irinotecan was administered intraperitoneally (IP) to 18 patients ineligible for CRS-HIPEC. The primary objective was to evaluate covariates influencing the PK profile of irinotecan and SN-38 after IP administration. Secondly, a population PK model was developed to support the further development of IP irinotecan by improving dosing in patients with PM. Patients were treated with IP irinotecan every 2 weeks in combination with systemic FOLFOX-bevacizumab. Irinotecan and SN-38 were measured in plasma (588 samples) and SN-38 was measured in peritoneal fluid (267 samples). Concentration-Time data were log-transformed and analyzed using NONMEM version 7.5 using FOCE+I estimation. An additive error model described the residual error, with inter-individual variability in PK parameters modeled exponentially. The final structural model consisted of five compartments. Weight was identified as a covariate influencing the SN-38 plasma volume of distribution and GGT was found to influence the SN-38 plasma clearance. This population PK model adequately described the irinotecan and SN-38 in plasma after IP administration, with weight and GGT as predictive factors. Irinotecan is converted intraperitoneal to SN-38 by carboxylesterases and the plasma bioavailability of irinotecan is low. This model will be used for the further clinical development of IP irinotecan by providing dosing strategies.

Factors associated with one-year mortality after curative surgery for primary clinical T4 and locally recurrent rectal cancer in elderly patients.

INTRODUCTION: Despite advancements in colorectal cancer care, one-year post-operative mortality rates remain high for elderly patients who have undergone curative surgery for primary clinical T4 rectal cancer (cT4RC) or locally recurrent rectal cancer (LRRC). This study aimed to identify factors associated with one-year mortality and to evaluate the causes of death. MATERIALS & METHODS: This retrospective cohort study included patients aged ≥70 years who underwent surgery with curative intent for cT4RC or LRRC between January 2013 and December 2020. Clinical and follow-up data were collected and analyzed to determine survival rates and investigate factors associated with mortality within one year after surgery. RESULTS: A total of 183 patients (94 cT4RC, 89 LRRC) were included. One-year mortality rates were 16.0% for cT4RC and 28.1% for LRRC (P = 0.064). In cT4RC patients, factors associated with one-year mortality were preoperative anemia (OR 3.83, P = 0.032), total pelvic exenteration (TPE) (OR 7.18, P = 0.018), multivisceral resections (OR 5.73, P = 0.028), pulmonary complications (OR 13.31, P < 0.001) and Clavien-Dindo grade ≥ III complications (OR 5.19, P = 0.025). In LRRC patients, factors associated with one-year mortality were TPE (OR 27.00, P = 0.008), the need for supported care after discharge (OR 3.93, P = 0.041) and Clavien-Dindo grade ≥ III complications (OR 3.95, P = 0.006). The main causes of death in cT4RC and LRRC patients were failure to recover (cT4RC 26.6%, LRRC 28.0%) and disease recurrence (cT4RC 26.6%, LRRC 60.0%). CONCLUSION: In order to tailor treatment in elderly with cT4RC and LRRC, factors associated with increased one-year mortality (e.g. pre-operative anemia, TPE) should be incorporated in the decision-making process. CLINICAL TRIAL REGISTRATION: Not applicable.

Intraperitoneal irinotecan with concomitant FOLFOX and bevacizumab for patients with unresectable colorectal peritoneal metastases: protocol of the multicentre, open-label, phase II, INTERACT-II trial.

INTRODUCTION: The peritoneum is the second most affected organ for the dissemination of colorectal cancer (CRC). Patients with colorectal peritoneal metastases (CPM) face a poor prognosis, despite the majority of patients being treated with palliative systemic therapy. The efficacy of palliative systemic therapy is limited due to the plasma-peritoneum barrier. The poor prognosis of unresectable CPM patients has resulted in the development of new treatment strategies where systemic therapy is combined with local, intraperitoneal chemotherapy. In the recently published phase I study, the maximum tolerated dose and thus the recommended phase II dose of intraperitoneal irinotecan was investigated and determined to be 75 mg. In the present study, the overall survival after treatment with 75 mg irinotecan with concomitant mFOLFOX4 and bevacizumab will be investigated. MATERIALS AND METHODS: In this single-arm phase II study in two Dutch tertiary referral centres, 85 patients are enrolled. Eligibility criteria are an adequate performance status and organ function, histologically confirmed microsatellite stable and unresectable CPM, no previous palliative therapy for CRC, no systemic therapy<6 months for CRC prior to enrolment and no previous cytoreductive surgery and hyperthermic intraperitoneal chemotherapy (CRS and HIPEC). Patients will undergo a diagnostic laparoscopy as standard work-up for CPM and if the peritoneal disease is considered unresectable (eg, Peritoneal Cancer Index (PCI)>20, too extensive small bowel involvement), a peritoneal access port and a port-a-cath are placed for administration of intraperitoneal and intravenous chemotherapy, respectively. Patients may undergo up to 12 cycles of study treatment. Each cycle consists of intravenous mFOLFOX4 with bevacizumab and concomitant intraperitoneal irinotecan (75 mg), which is repeated every 2 weeks, with a maximum of 12 cycles. Modified FOLFOX-4 regimen consists of 85 mg/m2 oxaliplatin plus 200 mg/m2 LV and 5-FU 400 mg/m2 bolus on day 1 followed by 1600 mg/m2 5-FU as a 46 hours infusion. Study treatment ends after the 12th cycle, or earlier in case of disease progression or unacceptable toxicity. The primary outcome is overall survival and key secondary outcomes are progression-free survival, safety (measured by the amount of grade ≥3 adverse events (Common Terminology Criteria for Adverse Events V.5.0)), patient-reported outcomes and pharmacokinetics of irinotecan. It is hypothesised that the trial treatment will lead to a 4 month increase in overall survival; from a median of 12.2 to 16.2 months. ETHICS AND DISSEMINATION: This study is approved by the Dutch Authority (CCMO, the Hague, the Netherlands), by a central medical ethics committee (MEC-U, Nieuwegein, the Netherlands) and by the institutional research boards of both research centres. Results will be submitted for publication in peer-reviewed medical journals and presented to patients and healthcare professionals. TRIAL REGISTRATION NUMBER: NCT06003998.

Abandonment of Routine Radiotherapy for Nonlocally Advanced Rectal Cancer and Oncological Outcomes.

Importance: Neoadjuvant short-course radiotherapy was routinely applied for nonlocally advanced rectal cancer (cT1-3N0-1M0 with >1 mm distance to the mesorectal fascia) in the Netherlands following the Dutch total mesorectal excision trial. This policy has shifted toward selective application after guideline revision in 2014. Objective: To determine the association of decreased use of neoadjuvant radiotherapy with cancer-related outcomes and overall survival at a national level. Design, Setting, and Participants: This multicenter, population-based, nationwide cross-sectional cohort study analyzed Dutch patients with rectal cancer who were treated in 2011 with a 4-year follow-up. A similar study was performed in 2021, analyzing all patients that were surgically treated in 2016. From these cohorts, all patients with cT1-3N0-1M0 rectal cancer and radiologically unthreatened mesorectal fascia were included in the current study. The data of the 2011 cohort were collected between May and October 2015, and the data of the 2016 cohort were collected between October 2020 and November 2021. The data were analyzed between May and October 2022. Main Outcomes and Measures: The main outcomes were 4-year local recurrence and overall survival rates. Results: Among the 2011 and 2016 cohorts, 1199 (mean [SD] age, 68 [11] years; 430 women [36%]) of 2095 patients (57.2%) and 1576 (mean [SD] age, 68 [10] years; 547 women [35%]) of 3057 patients (51.6%) had cT1-3N0-1M0 rectal cancer and were included, with proportions of neoadjuvant radiotherapy of 87% (2011) and 37% (2016). Four-year local recurrence rates were 5.8% and 5.5%, respectively (P = .99). Compared with the 2011 cohort, 4-year overall survival was significantly higher in the 2016 cohort (79.6% vs 86.4%; P < .001), with lower non-cancer-related mortality (13.8% vs 6.3%; P < .001). Conclusions and Relevance: The results of this cross-sectional study suggest that an absolute 50% reduction in radiotherapy use for nonlocally advanced rectal cancer did not compromise cancer-related outcomes at a national level. Optimizing clinical staging and surgery following the Dutch total mesorectal excision trial has potentially enabled safe deintensification of treatment.

Optimisation of Organ Preservation treatment strategies in patients with rectal cancer with a good clinical response after neoadjuvant (chemo)radiotherapy: Additional contact X-ray brachytherapy versus eXtending the observation period and local excision (OPAXX) - protocol for two multicentre, parallel, single-arm, phase II studies.

INTRODUCTION: Standard treatment for patients with intermediate or locally advanced rectal cancer is (chemo)radiotherapy followed by total mesorectal excision (TME) surgery. In recent years, organ preservation aiming at improving quality of life has been explored. Patients with a complete clinical response to (chemo)radiotherapy can be managed safely with a watch-and-wait approach. However, the optimal organ-preserving treatment strategy for patients with a good, but not complete clinical response remains unclear. The aim of the OPAXX study is to determine the rate of organ preservation that can be achieved in patients with rectal cancer with a good clinical response after neoadjuvant (chemo)radiotherapy by additional local treatment options. METHODS AND ANALYSIS: The OPAXX study is a Dutch multicentre study that investigates the efficacy of two additional local treatments aiming at organ preservation in patients with a good, but not complete response to neoadjuvant treatment (ie near-complete response or a small residual tumour mass <3 cm). The sample size will be 168 patients in total. Patients will be randomised (1:1) between two parallel single-arm phase II studies: study arm 1 involves additional contact X-ray brachytherapy (an intraluminal radiation boost), while in study arm 2 the observation period is extended followed by a second response evaluation and optional transanal local excision. The primary endpoint of the study is the rate of successful organ preservation at 1 year following randomisation. Secondary endpoints include toxicity, morbidity, oncological and functional outcomes at 1 and 2 years of follow-up. Finally, an observational cohort study for patients who are not eligible for randomisation is conducted. ETHICS AND DISSEMINATION: The trial protocol has been approved by the medical ethics committee of the Netherlands Cancer Institute (METC20.1276/M20PAX). Informed consent will be obtained from all participants. The trial results will be published in an international peer-reviewed journal. TRIAL REGISTRATION NUMBER: NCT05772923.

Comparing patient reported abdominal pain between patients treated with oxaliplatin-based pressurized intraperitoneal aerosol chemotherapy (PIPAC-OX) and primary colorectal cancer surgery.

Oxaliplatin-based pressurized intraperitoneal aerosol chemotherapy (PIPAC-OX) is an emerging palliative treatment for patients with unresectable colorectal peritoneal metastases. Previously, our study group reported that patients experienced abdominal pain for several weeks after PIPAC-OX. However, it is unknown how this compares to abdominal pain after regular colorectal cancer surgery. To provide some perspective, this study compared the presence of abdominal pain after PIPAC-OX to the presence of abdominal pain after primary tumor surgery. Patient reported abdominal pain scores (EORTC QLQ-CR-29), from two prospective, Dutch cohorts were used in this study. Scores ranged from 0 to 100, a higher score represents more abdominal pain. Abdominal pain at baseline and at four weeks after treatment were compared between the two groups. Twenty patients who underwent PIPAC-OX and 322 patients who underwent primary tumor surgery were included in the analysis. At baseline, there were no differences in abdominal pain between both groups (mean 20 vs. 18, respectively; p = 0.688). Four weeks after treatment, abdominal pain was significantly worse in the PIPAC group (39 vs 15, respectively; p < 0.001; Cohen's d = 0.99). The differential effect over time for abdominal pain differed significantly between both groups (mean difference: 19 vs - 3, respectively; p = 0.004; Cohen's d = 0.88). PIPAC-OX resulted in significantly worse postoperative abdominal pain than primary tumor surgery. These results can be used for patient counseling and stress the need for adequate analgesia during and after PIPAC-OX. Further research is required to prevent or reduce abdominal pain after PIPAC-OX.Trial registration CRC-PIPAC: Clinicaltrails.gov NCT03246321 (01-10-2017).

An evaluation of postoperative outcomes and treatment changes after frailty screening and geriatric assessment and management in a cohort of older patients with colorectal cancer.

INTRODUCTION: Adequate patient selection is crucial within the treatment of older patients with colorectal cancer (CRC). While previous studies report increased morbidity and mortality in older patients screened positive for frailty, improvements in the perioperative care and postoperative outcomes have raised the question of whether older patients screened positive for frailty still face worse outcomes. This study aimed to investigate the postoperative outcomes of older patients with CRC screened positive for frailty, and to evaluate changes in treatment after frailty screening and geriatric assessment. MATERIALS AND METHODS: Patients ≥70 years with primary CRC who underwent frailty screening between 1 January 2019 and 31 October 2021 were included. Frailty screening was performed by the Geriatric-8 (G8) screening tool. If the G8 indicated frailty (G8 ≤ 14), patients were referred for a comprehensive geriatric assessment (CGA). Postoperative outcomes and changes in treatment based on frailty screening and CGA were evaluated. RESULTS: A total of 170 patients were included, of whom 74 (43.5%) screened positive for frailty (G8 ≤ 14). Based on the CGA, the initially proposed treatment plan was altered to a less intensive regimen in five (8.9%) patients, and to a more intensive regimen in one (1.8%) patient. Surgery was performed in 87.8% of patients with G8 ≤ 14 and 96.9% of patients with G8 > 14 (p = 0.03). Overall postoperative complications were similar between patients with G8 ≤ 14 and G8 > 14 (46.2% vs. 47.3%, p = 0.89). Postoperative delirium was observed in 7.7% of patients with G8 ≤ 14 and 1.1% of patients with G8 > 14 (p = 0.08). No differences in 30-day mortality (1.1% vs. 1.5%, p > 0.99) or one-year and two-year survival rates were observed (log rank, p = 0.26). DISCUSSION: Although patients screened positive for frailty underwent CRC surgery less often, those considered eligible for surgery can safely undergo CRC resection within current clinical care pathways, without increased morbidity and mortality. Efforts to optimise perioperative care and minimise the risk of postoperative complications, in particular delirium, seem warranted. A multidisciplinary onco-geriatric pathway may support tailored decision-making in patients at risk of frailty.

A Deep Learning Framework with Explainability for the Prediction of Lateral Locoregional Recurrences in Rectal Cancer Patients with Suspicious Lateral Lymph Nodes.

Malignant lateral lymph nodes (LLNs) in low, locally advanced rectal cancer can cause (ipsi-lateral) local recurrences ((L)LR). Accurate identification is, therefore, essential. This study explored LLN features to create an artificial intelligence prediction model, estimating the risk of (L)LR. This retrospective multicentre cohort study examined 196 patients diagnosed with rectal cancer between 2008 and 2020 from three tertiary centres in the Netherlands. Primary and restaging T2W magnetic resonance imaging and clinical features were used. Visible LLNs were segmented and used for a multi-channel convolutional neural network. A deep learning model was developed and trained for the prediction of (L)LR according to malignant LLNs. Combined imaging and clinical features resulted in AUCs of 0.78 and 0.80 for LR and LLR, respectively. The sensitivity and specificity were 85.7% and 67.6%, respectively. Class activation map explainability methods were applied and consistently identified the same high-risk regions with structural similarity indices ranging from 0.772-0.930. This model resulted in good predictive value for (L)LR rates and can form the basis of future auto-segmentation programs to assist in the identification of high-risk patients and the development of risk stratification models.

Towards patient-led follow-up after curative surgical resection of stage I, II and III colorectal cancer (DISTANCE-trial): a study protocol for a stepped-wedge cluster-randomised trial.

BACKGROUND: Colorectal cancer (CRC) is among the most frequently diagnosed cancers. Approximately 20-30% of stage I-III CRC patients develop a recurrent tumour or metastases after curative surgical resection. Post-operative follow-up is indicated for the first five years after curative surgical resection. As intensified follow-up after curative surgical resection has shown no effect on survival, patient organisations and policy makers have advocated for a more patient-centred approach to follow-up. The objective of this study is to successfully implement patient-led, home-based follow-up (PHFU) in six hospitals in The Netherlands, with as ultimate aim to come to a recommendation for a patient-centred follow-up schedule for stage I-III CRC patients treated with surgical resection with curative intent. METHODS: This study is designed as a stepped-wedge cluster-randomised trial (SW-CRT) in six participating centres. During the trial, three centres will implement PHFU after six months; the other three centres will implement PHFU after 12 months of inclusion in the control group. Eligible patients are those with pT2-4N0M0 or pT1-4N1-2M0 CRC, who are 18 years or older and have been free of disease for 12 months after curative surgical resection. The studied intervention is PHFU, starting 12 months after curative resection. The in-hospital, standard-of-care follow-up currently implemented in the participating centres functions as the comparator. The proportion of patients who had contact with the hospital regarding CRC follow-up between 12-24 months after curative surgical resection is the primary endpoint of this study. Quality of life, fear of cancer recurrence, patient satisfaction, cost-effectiveness and survival are the secondary endpoints. DISCUSSION: The results of this study will provide evidence on whether nationwide implementation of PHFU for CRC in The Netherlands will be successful in reducing contact between patient and health care provider. Comparison of PROMs between in-hospital follow-up and PHFU will be provided. Moreover, the cost-effectiveness of PHFU will be assessed. TRIAL REGISTRATION: Dutch Trail Register (NTR): NL9266 (Registered on January 1st, 2021).

Implementation of an Enhanced Recovery after Surgery Protocol in Advanced and Recurrent Rectal Cancer Patients after beyond Total Mesorectal Excision Surgery: A Feasibility Study.

INTRODUCTION: The implementation of an Enhanced Recovery After Surgery (ERAS) protocol in patients with locally advanced rectal cancer (LARC) and locally recurrent rectal cancer (LRRC) has been deemed unfeasible until now because of the heterogeneity of this disease and low caseloads. Since evidence and experience with ERAS principles in colorectal cancer care are increasing, a modified ERAS protocol for this specific group has been developed. The aim of this study is to evaluate the implementation of a tailored ERAS protocol for patients with LARC or LRRC, requiring beyond total mesorectal excision (bTME) surgery. METHODS: Patients who underwent a bTME for LARC or LRRC between October 2021 and December 2022 were prospectively studied. All patients were treated in accordance with the ERAS LARRC protocol, which consisted of 39 ERAS care elements specifically developed for patients with LARC and LRRC. One of the most important adaptations of this protocol was the anaesthesia procedure, which involved the use of total intravenous anaesthesia with intravenous (iv) lidocaine, iv methadone, and iv ketamine instead of epidural anaesthesia. The outcomes showed compliance with ERAS care elements, complications, length of stay, and functional recovery. A follow-up was performed at 30 and 90 days post-surgery. RESULTS: Seventy-two patients were selected, all of whom underwent bTME for either LARC (54.2%) or LRRC (45.8%). Total compliance with the adjusted ERAS protocol was 73.6%. Major complications were present in 12 patients (16.7%), and the median length of hospital stay was 9 days (IQR 6.0-14.0). Patients who received multimodal anaesthesia (75.0%) stayed in the hospital for a median of 7.0 days (IQR 6.8-15.5). These patients received fewer opioids on the first three postoperative days than patients who received epidural analgesia (p < 0.001). CONCLUSIONS: The implementation of the ERAS LARRC protocol seemed successful according to its compliance rate of >70%. Its complication rate was substantially reduced in comparison with the literature. Multimodal anaesthesia is feasible in beyond TME surgery with promising effects on recovery after surgery.

Phase I study of intraperitoneal irinotecan combined with palliative systemic chemotherapy in patients with colorectal peritoneal metastases.

BACKGROUND: Patients with colorectal peritoneal metastases who are not eligible for cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) owing to extensive peritoneal disease have a poor prognosis. It was hypothesized that these patients may benefit from the addition of intraperitoneal irinotecan to standard palliative systemic chemotherapy. METHODS: This was a classical 3 + 3 phase I dose-escalation trial in patients with colorectal peritoneal metastases who were not eligible for CRS-HIPEC. Intraperitoneal irinotecan was administered every 2 weeks, concomitantly with systemic FOLFOX (5-fluorouracil, folinic acid, oxaliplatin)-bevacizumab. The primary objective was to determine the maximum tolerated dose and dose-limiting toxicities. Secondary objectives were to elucidate the systemic and intraperitoneal pharmacokinetics, safety profile, and efficacy. RESULTS: Eighteen patients were treated. No dose-limiting toxicities were observed with 50 mg (4 patients) and 75 mg (9 patients) intraperitoneal irinotecan. Two dose-limiting toxicities occurred with 100 mg irinotecan among five patients. The maximum tolerated dose of intraperitoneal irinotecan was established to be 75 mg, and it was well tolerated. Intraperitoneal exposure to SN-38 (active metabolite of irinotecan) was high compared with systemic exposure (median intraperitoneal area under the curve (AUC) to systemic AUC ratio 4.6). Thirteen patients had a partial radiological response and five had stable disease. Four patients showed a complete response during post-treatment diagnostic laparoscopy. Five patients underwent salvage resection or CRS-HIPEC. Median overall survival was 23.9 months. CONCLUSION: Administration of 75 mg intraperitoneal irinotecan concomitantly with systemic FOLFOX-bevacizumab was safe and well tolerated. Intraperitoneal SN-38 exposure was high and prolonged. As oncological outcomes were promising, intraperitoneal administration of irinotecan may be a good alternative to other, more invasive and costly treatment options. A phase II study is currently accruing.

Patients with extensive colorectal peritoneal metastases who are not eligible for surgery and heated intraperitoneal chemotherapy have poor survival. The authors tried to improve the survival of these patients by adding intraperitoneal (inside the abdominal cavity) chemotherapy to standard palliative chemotherapy which is administered into the bloodstream. In this trial, irinotecan (a type of chemotherapy) was administered into the abdomen of patients with extensive colorectal peritoneal metastases. The authors investigated which dose could be administered safely in combination with standard palliative chemotherapy. They also looked into toxicity, safety, benefit, and movement of the drug in the body. Eighteen patients were treated in this study. The maximum tolerated dose of intraperitoneal irinotecan was 75 mg. It was well tolerated and could be administered safely. The intra-abdominal amount of irinotecan was high, whereas the amount of irinotecan in the blood remained low. The benefits of intra-abdominal irinotecan were promising. Because of this, a new study has been started to further investigate this new combination chemotherapy for colorectal cancer.