Use of patient-derived explants as a preclinical model for precision medicine in colorectal cancer: A scoping review.

PURPOSE: Whilst the treatment paradigm for colorectal cancer has evolved significantly over time, there is still a lack of reliable biomarkers of treatment response. Treatment decisions are based on high-risk features such as advanced TNM stage and histology. The role of the tumour microenvironment, which can influence tumour progression and treatment response, has generated considerable interest. Patient-derived explant cultures allow preservation of native tissue architecture and tumour microenvironment. The aim of the scoping review is to evaluate the utility of patient-derived explant cultures as a preclinical model in colorectal cancer. METHODS: A search was conducted using Ovid MEDLINE, EMBASE, Web of Science, and Cochrane databases from start of database records to September 1, 2022. We included all peer-reviewed human studies in English language which used patient-derived explants as a preclinical model in primary colorectal cancer. Eligible studies were grouped into the following categories: assessing model feasibility; exploring tumour microenvironment; assessing ex vivo drug responses; discovering and validating biomarkers. RESULTS: A total of 60 studies were eligible. Fourteen studies demonstrated feasibility of using patient-derived explants as a preclinical model. Ten studies explored the tumour microenvironment. Thirty-eight studies assessed ex vivo drug responses of chemotherapy agents and targeted therapies. Twenty-four studies identified potential biomarkers of treatment response. CONCLUSIONS: Given the preservation of tumour microenvironment and tumour heterogeneity, patient-derived explants has the potential to identify reliable biomarkers, treatment resistance mechanisms, and novel therapeutic agents. Further validation studies are required to characterise, refine and standardise this preclinical model before it can become a part of precision medicine in colorectal cancer.

The Impact of Neoadjuvant Chemotherapy on the Surgical Management of Colorectal Peritoneal Metastases: A Systematic Review and Meta-Analysis.

BACKGROUND: Cytoreductive surgery (CRS) with or without hyperthermic intraperitoneal chemotherapy (HIPEC) is a well-recognised treatment option for the management of colorectal peritoneal metastases (CRPM). However, incorporating the routine use of neoadjuvant chemotherapy (NAC) into this management plan is controversial. METHODS: A systematic review and meta-analysis were conducted to evaluate the impact of neoadjuvant chemotherapy on perioperative morbidity and mortality, and long-term survival of patients with CRPM undergoing CRS and HIPEC. RESULTS: Twelve studies met the inclusion criteria (n = 2,463 patients). Ten were retrospective cohort, one was prospective cohort, and one was a prospective randomised by design. Patients who received NAC followed by CRS and HIPEC experienced no difference in major perioperative morbidity and mortality compared with patients who underwent surgery first (SF). There was no difference in overall survival at 3 years, but at 5 years NAC patients had superior survival (relative risk [RR] 1.31; 95% confidence interval [CI] 1.11-1.54, P < 0.001). There were no differences in 1- and 3-year, disease-free survival (DFS) between groups. Study heterogeneity was generally high across all outcome measures. CONCLUSIONS: Patients who received neoadjuvant chemotherapy did not experience any increase in perioperative morbidity or mortality. The potential improvement in 5-year overall survival in patients receiving NAC is based on limited confidence due to several limitations in the data, but not sufficiently enough to curtail its use. The practice of NAC in this setting will remain heterogeneous and guided by retrospective evidence until prospective, randomised data are reported.

Effect of Surgical Humidification on Inflammation and Peritoneal Trauma in Colorectal Cancer Surgery: A Randomized Controlled Trial.

BACKGROUND: Pre-clinical studies indicate that dry-cold-carbon-dioxide (DC-CO2) insufflation leads to more peritoneal damage, inflammation and hypothermia compared with humidified-warm-CO2 (HW-CO2). Peritoneum and core temperature in patients undergoing colorectal cancer (CRC) surgery were compared. METHODS: Sixty-six patients were randomized into laparoscopic groups; those insufflated with DC-CO2 or HW-CO2. A separate group of nineteen patients undergoing laparotomy were randomised to conventional surgery or with the insertion of a device delivering HW-CO2. Temperatures were monitored and peritoneal biopsies and bloods were taken at the start of surgery, at 1 and 3 h. Further bloods were taken depending upon hospital length-of-stay (LOS). Peritoneal samples were subjected to scanning electron microscopy to evaluate mesothelial damage. RESULTS: Laparoscopic cases experienced a temperature drop despite Bair-HuggerTM use. HW-CO2 restored normothermia (≥ 36.5 °C) by 3 h, DC-CO2 did not. LOS was shorter for colon compared with rectal cancer cases and if insufflated with HW-CO2 compared with DC-CO2; 5.0 vs 7.2 days, colon and 11.6 vs 15.4 days rectum, respectively. Unexpectedly, one third of patients had pre-existing damage. Damage increased at 1 and 3 h to a greater extent in the DC-CO2 compared with the HW-CO2 laparoscopic cohort. C-reactive protein levels were higher in open than laparoscopic cases and lower in both matched HW-CO2 groups. CONCLUSIONS: This prospective RCT is in accord with animal studies while highlighting pre-existing damage in some patients. Peritoneal mesothelium protection, reduced inflammation and restoration of core-body temperature data suggest benefit with the use of HW-CO2 in patients undergoing CRC surgery.

Patient-Related Functional Outcomes After Robotic-Assisted Rectal Surgery Compared With a Laparoscopic Approach: A Systematic Review and Meta-analysis.

BACKGROUND: Robotic surgery has gained significant momentum in rectal cancer surgery. Most studies focus on short-term and oncological outcomes, showing similar outcomes to laparoscopic surgery. Increasing survivorship mandates greater emphasis on quality of life and long-term function. OBJECTIVE: This study aimed to compare quality of life and urinary, sexual, and lower GI functions between robotic and laparoscopic rectal surgeries. DATA SOURCES: A systematic search of Medline, PubMed, Embase, Clinical Trials Register, and Cochrane Library-identified articles comparing robotic with laparoscopic rectal resections was performed. MAIN OUTCOME MEASURES: The outcome measures were quality of life and urinary, sexual, and GI functions between robotic and laparoscopic rectal resection patient groups. Where comparable data were available, results were pooled for analysis. RESULTS: The initial search revealed 1777 papers; 101 were reviewed in full, and 14 studies were included for review. Eleven assessed male sexual function; 7 favored robotic surgery, and the remaining studies showed no significant difference. Pooled analysis of 5 studies reporting rates of male sexual dysfunction at 12 months showed significantly lower rates after robotic surgery (OR, 0.51; p = 0.043). Twelve studies compared urinary function. Six favored robotic surgery, but in 2 studies, a difference was seen at 6 months but not sustained at 12 months. Pooled analysis of 4 studies demonstrated significantly better urinary function scores at 12 months after robotic surgery (OR, 0.26; p = 0.016). Quality of life and GI function were equivalent, but very little data exist for these parameters. LIMITATIONS: A small number of studies compare outcomes between these groups; only 2 are randomized. Different scoring systems limit comparisons and pooling of data. CONCLUSIONS: The limited available data suggest that robotic rectal cancer resection improves male sexual and urinary functions when compared with laparoscopy, but there is no difference in quality of life or GI function. Future studies should report all facets of functional outcomes using standardized scoring systems.

Exercise and colorectal cancer survival: an updated systematic review and meta-analysis.

PURPOSE: The benefit of exercise to colorectal cancer patients has been advocated. However, comparative data to quantify the survival benefit is lacking. The aim of this review was to assess the effect of exercise on colorectal cancer survival. METHODS: An up-to-date systematic review was performed on the available literature between 2000 and 2021 on PubMed, EMBASE, Medline, and Cochrane Library databases. All studies reporting on the impact of exercise and colorectal cancer outcomes in patients treated for non-metastatic colorectal cancer were analysed. The main outcome measures were the overall survival (OS), cancer specific survival (CSS) and disease free survival (DFS). RESULTS: A total of 13 prospective observational studies were included, accounting for 19,135 patients. Compared to negligible physical activity, overall survival (OS) was significantly increased for both moderate and highest activity group (HR 0.82, 95% CI: 0.74-0.90, p < 0.001 and HR 0.64, 0.56-0.72, p < 0.001 respectively). This was also reflected in cancer specific survival (CSS) analysis, but not disease-free survival (DFS) analysis. CONCLUSION: Exercise was associated with an increased in overall survival after a colorectal cancer resection. This would support the promotion of exercise interventions amongst colorectal cancer patients.

Total Neoadjuvant Therapy in Locally Advanced Rectal Cancer: A Systematic Review and Metaanalysis of Oncological and Operative Outcomes.

BACKGROUND: Total neoadjuvant therapy in rectal cancer refers to the administration of chemoradiotherapy plus chemotherapy before surgery. Recent studies have shown improved pathological complete response and disease-free survival with this approach. However, survival benefits remain unproven. Our objective is to present a metaanalysis of oncological outcomes of total neoadjuvant therapy in locally advanced rectal cancer. PATIENTS AND METHODS: A comprehensive search was performed on PubMed, Medline, and Google Scholars. Studies comparing total neoadjuvant therapy with standard neoadjuvant chemoradiotherapy were included. Data extracted from the individual studies were pooled and a metaanalysis performed. The outcomes of interest are the rate of complete pathological response, nodal response, resection margin, anal preservation, anastomotic leak, local recurrence, distant recurrence, disease-free survival, and overall survival. RESULTS: There were 15 comparative studies with 2437 patients in the neoadjuvant chemoradiotherapy group and 2284 in the total neoadjuvant therapy group. The pooled complete pathological response was 22.3% in the total neoadjuvant therapy group, compared with 14.2% in the standard neoadjuvant chemoradiotherapy group (p < 0.001). Even though there was no difference in local recurrence rate, there was a significantly lower rate of distant recurrence (OR 0.81, p = 0.02), and better 3-year disease-free survival (70.6% vs. 65.3%, respectively, p < 0.001) and overall survival (84.9% vs. 82.3%, respectively, p = 0.006), favoring the total neoadjuvant therapy group. Due to significant heterogeneity in the study protocols, there remains uncertainty on the ideal chemotherapy/radiotherapy sequence. CONCLUSIONS: This study provides supporting evidence on the favorable immediate and intermediate oncological outcomes with the use of total neoadjuvant therapy for locally advanced rectal cancer.

Neoadjuvant chemotherapy in locally advanced colon cancer: a systematic review and meta-analysis.

BACKGROUND: There is increasing evidence to support the use of neoadjuvant chemotherapy (NAC) in locally advanced colon cancer (LACC). However, its safety, efficacy and side effect profile is yet to be completely elucidated. This review aims to assess NAC regimens, duration, compare completion rates, intra-operative and post-operative complication profiles and oncological outcomes, in order to provide guidance for clinical practice and further research. METHODS: PubMed, EMBASE and MEDLINE were searched for a systematic review of the literature from 2000 to 2020. Eight eligible studies were included, with a total of 1213 patients, 752 (62%) of whom received NAC. Of the eight studies analysed, two were randomised controlled trials comparing neoadjuvant chemotherapy followed by oncological resection to upfront surgery and adjuvant chemotherapy, three were prospective single-arm phase II trials analysing neoadjuvant chemotherapy followed by surgery only, one was a retrospective study comparing neoadjuvant chemotherapy followed by surgery versus surgery first followed by adjuvant chemotherapy and the remaining two were single-arm retrospective studies of neoadjuvant chemotherapy followed by surgery. RESULTS: All cases of LACC were determined and staged by computed tomography; majority of the studies defined LACC as T3 with extramural depth of 5 mm or more, T4 and/or nodal positivity. NAC administered was either folinic acid, fluorouracil and oxaliplatin (FOLFOX) or capecitabine and oxaliplatin (XELOX) with the exception of one study which utilised 5-fluorouracil and mitomycin. Most studies had NAC completion rates of above 83% with two notable exceptions being Zhou et al. and The Colorectal Cancer Chemotherapy Study Group of Japan who both recorded a completion rate of 52%. Time to surgery from completion of NAC ranged on average from 16 to 31 days. The anastomotic leak rate in the NAC group ranged from 0 to 4.5%, with no cases of postoperative mortality. The R0 resection rate in the NAC group was 96.1%. Meta-analysis of both RCTs included in this study showed that neoadjuvant chemotherapy increased the likelihood of a negative resection margin T3/4 advanced colon cancer (pooled relative risk of 0.47 with a 95% confidence interval) with no increase in adverse consequence of anastomotic leak, wound infection or return to theatre. CONCLUSIONS: Our systematic review and meta-analysis show that NAC is safe with an acceptable side effect profile in the management of LACC. The current data supports an oncological benefit for tumour downstaging and increased in R0 resection rate.

Robotic versus laparoscopic ventral mesh rectopexy: a systematic review and meta-analysis.

INTRODUCTION: Ventral mesh rectopexy is frequently performed as a means of improving the quality of life for sufferers of rectal prolapse. The minimally invasive approach is highly desirable but can be technically difficult to achieve in the narrow confines of the pelvis. The robotic platform is becoming a more common means of overcoming these difficulties, but evidence of an objective benefit over standard laparoscopy is scarce. This study seeks to review and analyse the data comparing outcomes after robotic and laparoscopic ventral mesh rectopexy. METHOD: We searched MEDLINE, EMBASE and the Cochrane database for papers comparing robotic to laparoscopic ventral mesh rectopexy. Comparable data was pooled for meta-analysis. RESULTS: Six studies compared outcomes between robotic and laparoscopic ventral mesh rectopexy. Sample sizes were relatively small, and only two of the studies were randomised. Pooled analysis was possible for data on operating time, complication rates, conversion rates and length of stay in hospital. This showed a non-significant trend towards longer operating times and a statistically significant reduction in length of stay after robotic procedures. There was no significant difference in complication and conversion rates. CONCLUSION: The frequent finding of longer operating time for robotic surgery was not confirmed in this study. Shorter length of stay in hospital was seen, with other post-operative outcomes showing no significant difference. More data is needed with cost-benefit analyses to show whether the robotic platform is justified.

Does rectal tube/transanal stent placement after an anterior resection for rectal cancer reduce anastomotic leak? A systematic review and meta-analysis.

BACKGROUND: There is increasing evidence that either a transanal stent (TAS) or rectal tube (RT) can decrease the risk of anastomotic leakage (AL) after anterior resection for rectal cancer, in which a diverting stoma may not be required. OBJECTIVES: The aim of this review was to investigate the efficacy and safety of RT/TAS in preventing AL after anterior resections. DATA SOURCES: An up-to-date systematic review was performed on the available literature between 2000 and 2020 on PubMed, EMBASE, Medline and Cochrane Library databases. STUDY SELECTION: All studies reporting on anterior resections in adults, comparing transanal tube/stent versus non-tube/stent, were analysed. MAIN OUTCOME MEASURE: The primary outcome was rates of AL, whereas secondary outcomes compared associated unplanned re-operation for AL and hospital length of stay (LOS). RESULTS: Two randomized controlled trials and 13 observational studies were included, with 1714 patients receiving RT/TAS and 1741 patients without. There were 119 (7%) patients with AL in the RT/TAS group compared to 216 (12.3%) patients in the non-RT/TAS group (OR: 0.48, 95% CI: 0.38-0.62, p < 0.001). There were 47 (2.9%) patients with AL complications requiring surgery in the RT/TAS group compared to 132 (8%) patients in the non-RT/TAS group (OR: 0.29, 95% CI: 0.20-0.42, p < 0.001) and no significant difference identified with the standardized mean difference (SMD) favouring the RT/TAS group for hospital LOS (SMD: -0.23, 95% CI: -0.51 to 0.06, p = 0.115). CONCLUSION: The use of RT/TAS post restorative anterior resection for rectal cancer should be considered, given the benefits shown from this meta-analysis.

Robotic versus laparoscopic ileal pouch-anal anastomosis (IPAA): a systematic review and meta-analysis.

BACKGROUND: Restorative proctocolectomy with ileal-pouch anal anastomosis (IPAA) is a curative and cancer preventative procedure in patients with ulcerative colitis (UC) and familial adenomatous polyposis (FAP). It can be technically difficult laparoscopically, and hence the robotic platform has been suggested as a way to enable minimally invasive surgery in more patients. This systematic review examines robotic proctectomy or proctocolectomy with IPAA. A limited meta-analysis was performed on data comparing the robotic approach to laparoscopy. METHODS: We searched MEDLINE, EMBASE and the Cochrane database for case series of robotic IPAA procedures and studies comparing the robotic to laparoscopic or open procedures. Data examined includes operating time, conversion to open, length of stay, complications, blood loss, return of bowel function, reoperation rate and functional outcomes. RESULTS: Five non-randomised studies compared robotic to laparoscopic techniques; one compared robotic to open surgery and three case series are included. Operating time was significantly longer in robotic cases. Estimated blood loss was significantly less in three of four studies which reported this; hospital stay was significantly less in two. There were nonsignificant reductions in complications and readmission rates. Pooled analysis of four papers with adequate data showed a nonstatistically significant trend to less complications in robotic procedures. Three studies assessed functional and quality of life outcomes, with little difference between the platforms. CONCLUSIONS: Available data suggests that the robotic platform is safe to use for IPAA procedures. There is minimal evidence for clinical advantages, but with little data to base decisions and significant potential for improvements in technique and cost-effectiveness, further use of the platform for this operation is warranted. It is vital that this occurs within an evaluation framework.