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Effects of Community-based Exercise Prehabilitation for Patients Scheduled for Colorectal Surgery With High Risk for Postoperative Complications: Results of a Randomized Clinical Trial.
Berkel, AEM, Bongers, BC, Kotte, H, Weltevreden, P, de Jongh, FHC, Eijsvogel, MMM, Wymenga, M, Bigirwamungu-Bargeman, M, van der Palen, J, van Det, MJ, et al
Annals of surgery. 2022;(2):e299-e306
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OBJECTIVE To assess the effects of a 3-week community-based exercise program on 30-day postoperative complications in high-risk patients scheduled for elective colorectal resection for (pre)malignancy. SUMMARY BACKGROUND DATA Patients with a low preoperative aerobic fitness undergoing colorectal surgery have an increased risk of postoperative complications. It remains, however, to be demonstrated whether prehabilitation in these patients reduces postoperative complications. METHODS This 2-center, prospective, single-blinded randomized clinical trial was carried out in 2 large teaching hospitals in the Netherlands. Patients (≥60 years) with colorectal (pre)malignancy scheduled for elective colorectal resection and with a score ≤7 metabolic equivalents on the veterans-specific activity questionnaire were randomly assigned to the prehabilitation group or the usual care group by using block-stratified randomization. An oxygen uptake at the ventilatory anaerobic threshold <11 mL/kg/min at the baseline cardiopulmonary exercise test was the final inclusion criterion. Inclusion was based on a power analysis. Patients in the prehabilitation group participated in a personalized 3-week (3 sessions per week, nine sessions in total) supervised exercise program given in community physical therapy practices before colorectal resection. Patients in the reference group received usual care. The primary outcome was the number of patients with one or more complications within 30 days of surgery, graded according to the Clavien-Dindo classification. Data were analyzed on an intention-to-treat basis. RESULTS Between February 2014 and December 2018, 57 patients [30 males and 27 females; mean age 73.6 years (standard deviation 6.1), range 61-88 years] were randomized to either prehabilitation (n = 28) or usual care (n = 29). The rate of postoperative complications was lower in the prehabilitation group (n = 12, 42.9%) than in the usual care group (n = 21, 72.4%, relative risk 0.59, 95% confidence interval 0.37-0.96, P = 0.024). CONCLUSIONS Exercise prehabilitation reduced postoperative complications in high-risk patients scheduled to undergo elective colon resection for (pre)malignancy. Prehabilitation should be considered as usual care in high-risk patients scheduled for elective colon, and probably also rectal, surgery.
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Irreversible Electroporation to Treat Unresectable Colorectal Liver Metastases (COLDFIRE-2): A Phase II, Two-Center, Single-Arm Clinical Trial.
Meijerink, MR, Ruarus, AH, Vroomen, LGPH, Puijk, RS, Geboers, B, Nieuwenhuizen, S, van den Bemd, BAT, Nielsen, K, de Vries, JJJ, van Lienden, KP, et al
Radiology. 2021;(2):470-480
Abstract
Background Irreversible electroporation (IRE), an ablative technique that uses high-voltage electrical pulses, has shown promise for eradicating tumors near critical structures, including blood vessels and bile ducts. Purpose To investigate the efficacy and safety of IRE for colorectal liver metastases (CRLMs) unsuitable for resection or thermal ablation because of proximity to critical structures and for further systemically administered treatments. Materials and Methods Between June 2014 and November 2018, participants with fluorine 18 (18F) fluorodeoxyglucose (FDG) PET-avid CRLMs measuring 5.0 cm or smaller, unsuitable for partial hepatectomy and thermal ablation, underwent percutaneous or open IRE (ClinicalTrials.gov identifier: NCT02082782). Follow-up included tumor marker assessment and 18F-FDG PET/CT imaging. For the primary end point to be met, at least 50% of treated participants had to be alive without local tumor progression (LTP) at 12 months, defined as LTP-free survival. Secondary aims were safety, technical success, local control allowing for repeat procedures, disease-free status, and overall survival. Results A total of 51 participants (median age, 67 years [interquartile range, 62-75 years]; 37 men) underwent IRE. Of these 51 participants, 50 with a total of 76 CRLMs (median tumor size, 2.2 cm; range, 0.5-5.4 cm) were successfully treated in 62 procedures; in one participant, treatment was stopped prematurely because of pulse-induced cardiac arrhythmia. With a per-participant 1-year LTP-free survival of 68% (95% CI: 59, 84) according to competing risk analysis, the primary end point was met. Local control following repeat procedures was achieved in 74% of participants (37 of 50). Median overall survival from first IRE was 2.7 years (95% CI: 1.6, 3.8). Twenty-three participants experienced a total of 34 adverse events in 25 of the 62 procedures (overall complication rate, 40%). One participant (2%), who had an infected biloma after IRE, died fewer than 90 days after the procedure (grade 5 adverse event). Conclusion Irreversible electroporation was effective and relatively safe for colorectal liver metastases 5.0 cm or smaller that were unsuitable for partial hepatectomy, thermal ablation, or further systemic treatment. © RSNA, 2021 Online supplemental material is available for this article. See also the editorial by Goldberg in this issue.
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Plasma deoxyuridine as a surrogate marker for toxicity and early clinical response in patients with metastatic colorectal cancer after 5-FU-based therapy in combination with arfolitixorin.
Taflin, H, Odin, E, Carlsson, G, Tell, R, Gustavsson, B, Wettergren, Y
Cancer chemotherapy and pharmacology. 2021;(1):31-41
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PURPOSE The aim was to explore the correlation between increasing doses of [6R]-5,10-methylenetetrahydrofolate (arfolitixorin) and plasma concentrations of deoxyuridine (dUr) in patients with metastatic colorectal cancer (mCRC), subjected to 5-fluorouracil (5-FU)-based chemotherapy. The aim was further to investigate the possibility to predict toxicity and clinical response during treatment using gender, age, and plasma dUr as explanatory variables. METHODS Thirty-three patients from the ISO-CC-005 phase I/IIa study, which investigated safety and tolerability of arfolitixorin at four dose levels, were included. Toxicity and clinical response were evaluated after 4 cycles of chemotherapy. Plasma dUr was quantified before (0 h) and 24 h after 5-FU administration at the first (C1) and fourth (C4) cycle using LC-MS/MS. Fit modelling was used to predict toxicity and clinical response. RESULTS The dUr levels increased with increasing arfolitixorin dose. Females had higher total and haematological toxicity scores (p = 0.0004 and 0.0089, respectively), and needed dose reduction more often than males (p = 0.012). Fit modeling showed that gender and the dUr levels at C1-0 h and C4-24 h predicted total toxicity (p = 0.0011), whereas dUr C4-0 h alone was associated with gastrointestinal toxicity (p = 0.026). Haematological toxicity was predicted by gender and age (p = 0.0071). The haematological toxicity score in combination with the dUr levels at C1-24 h and C4-24 h predicted early clinical response (p = 0.018). CONCLUSION The dUr level before and during administration of 5-FU and arfolitixorin was predictive for toxicity and early clinical response and could be a potential surrogate marker for thymidylate synthase inhibition in patients with mCRC. TRIAL REGISTRATION NCT02244632, first posted on ClinicalTrials.gov on September 19, 2014.
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WASh multicentre randomised controlled trial: water-assisted sigmoidoscopy in English NHS bowel scope screening.
Rutter, MD, Evans, R, Hoare, Z, Von Wagner, C, Deane, J, Esmaily, S, Larkin, T, Edwards, R, Yeo, ST, Spencer, LH, et al
Gut. 2021;(5):845-852
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OBJECTIVES The English Bowel Cancer Screening Programme invites 55 year olds for a sigmoidoscopy (Bowel Scope Screening (BSS)), aiming to resect premalignant polyps, thus reducing cancer incidence. A national patient survey indicated higher procedural pain than anticipated, potentially impacting on screening compliance and effectiveness. We aimed to assess whether water-assisted sigmoidoscopy (WAS), as opposed to standard CO2 technique, improved procedural pain and detection of adenomatous polyps. DESIGN The WASh (Water-Assisted Sigmoidoscopy) trial was a multicentre, single-blind, randomised control trial for people undergoing BSS. Participants were randomised to either receive WAS or CO2 from five sites across England. The primary outcome measure was patient-reported moderate/severe pain, as assessed by patients on a standard Likert scale post procedure prior to discharge. The key secondary outcome was adenoma detection rate (ADR). The costs of each technique were also measured. RESULTS 1123 participants (50% women, mean age 55) were randomised (561 WAS, 562 CO2). We found no difference in patient-reported moderate/severe pain between WAS and CO2 (14% in WAS, 15% in CO2; p=0.47). ADR was 15% in the CO2 arm and 11% in the WAS arm (p=0.03); however, it remained above the minimum national performance standard in both arms. There was no statistical difference in mean number of adenomas nor overall polyp detection rate. There was negligible cost difference between the two techniques. CONCLUSION In the context of enema-prepared unsedated screening sigmoidoscopies performed by screening-accredited endoscopists, no difference in patient-reported pain was seen when using either a CO2 or WAS intubation technique. TRIAL REGISTRATION NUMBER ISRCTN81466870.
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Transcutaneous electrical acupoint stimulation applied in lower limbs decreases the incidence of paralytic ileus after colorectal surgery: A multicenter randomized controlled trial.
Gao, W, Li, W, Yan, Y, Yang, R, Zhang, Y, Jin, M, Luo, Z, Xie, L, Ma, Y, Xu, X, et al
Surgery. 2021;(6):1618-1626
Abstract
BACKGROUND Postoperative paralytic ileus prolongs hospitalization duration, increases medical expenses, and is even associated with postoperative mortality; however, effective prevention of postoperative paralytic ileus is not yet available. This trial aimed to assess the preventative effectiveness of transcutaneous electrical acupoint stimulation applied in the lower limbs on postoperative paralytic ileus incidence after colorectal surgery. METHODS After ethics approval and written informed consent, 610 patients from 10 hospitals who were scheduled for colorectal surgery between May 2018 and September 2019 were enrolled. Patients were randomly allocated into the transcutaneous electrical acupoint stimulation (stimulated on bilateral Zusanli, Shangjuxu, and Sanyinjiao acupoints in lower limbs for 30 minutes each time, total 4 times) or sham (without currents delivered) group with 1:1 ratio. The primary outcome was postoperative paralytic ileus incidence, defined as no flatus for >72 hours after surgery. RESULTS Compared to the sham treatment, transcutaneous electrical acupoint stimulation lowered the postoperative paralytic ileus incidence by 8.7% (32.3% vs 41.0%, P = .026) and decreased the risk of postoperative paralytic ileus by 32% (OR, 0.68; P = .029). Transcutaneous electrical acupoint stimulation also shortened the recovery time to flatus, defecation, normal diet, and bowel sounds. Transcutaneous electrical acupoint stimulation treatment significantly increased median serum acetylcholine by 55% (P = .007) and interleukin-10 by 88% (P < .001), but decreased interleukin-6 by 47% (P < .001) and inducible nitric oxide synthase by 42% (P = .002) at 72 hours postoperatively. CONCLUSION Transcutaneous electrical acupoint stimulation attenuated the postoperative paralytic ileus incidence and enhanced gastrointestinal functional recovery, which may be associated with increasing parasympathetic nerve tone and its anti-inflammatory actions.
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Prospective multicentre study of a new bowel obstruction treatment in colorectal surgery: Reduced morbidity and mortality.
Fahim, M, Dijksman, LM, Derksen, WJM, Bloemen, JG, Biesma, DH, Smits, AB
European journal of surgical oncology : the journal of the European Society of Surgical Oncology and the British Association of Surgical Oncology. 2021;(9):2414-2420
Abstract
INTRODUCTION Bowel obstruction patients are at increased risk of emergency surgery and have poor nutritional and physical conditions. These patients could benefit from prehabilitation and prevention of emergency surgery. This study assessed the effect of a multimodal obstruction treatment for bowel obstruction patients in colorectal surgery on the risk of emergency surgery and postoperative morbidity and mortality. MATERIALS AND METHODS This multicenter observational cohort study included all consecutive bowel obstruction patients who received obstruction treatment (obstruction protocol) in the period 2019-2020 in two Dutch hospitals. Benign and malignant causes of bowel obstruction were included. Treatment consisted of 1. dietary adjustments, 2. postponing surgery for three weeks, 3. laxatives, and 4. prehabilitation. We compared emergency surgery and postoperative morbidity and mortality rates to known rates from the literature. RESULTS Eighty-nine patients were included: obstruction treatment was successful in 77 patients (87%) who underwent elective surgery and unsuccessful in 12 patients (13%) who underwent emergency surgery. Sixty-six (74%) had colorectal cancer, and 22 (25%) had benign disease. Thirty-day mortality of 0% in our study was significantly lower than the national average of 4% in colorectal cancer patients in the Netherlands (p = 0.049). Anastomotic leakage rate was 3%, severe complications (Clavien-Dindo ≥ III) 8%, and bowel perforation 0%. These rates did not differ significantly from rates reported in literature. CONCLUSION The obstruction treatment prevented emergency surgery in most patients with bowel obstruction and reduced postoperative morbidity and mortality. The obstruction treatment seems to be a safe and efficient alternative to emergency surgery.
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Serological Biomarkers and Diversion Colitis: Changes after Stimulation with Probiotics.
Rodríguez-Padilla, Á, Morales-Martín, G, Pérez-Quintero, R, Gómez-Salgado, J, Ruiz-Frutos, C
Biomolecules. 2021;(5)
Abstract
Diversion colitis is a non-specific inflammation of a defunctionalised segment of the colon after a temporary stoma has been performed. This inflammation is associated with an alteration of certain inflammatory serum markers. The aims of this study were, firstly, to evaluate the modification of inflammatory biomarkers after stimulation with probiotics prior to closure of the protective ileostomy. Secondly, to identify if a relationship could be established between the severity of diversion colitis and the alteration of inflammatory biomarkers in the blood. A prospective, randomized, double-blind, controlled study was conducted. Patients who underwent surgery for colorectal carcinoma with protective ileostomy between January 2017 and December 2018 were included, pending reconstructive surgery and with diversion colitis as diagnosis. The sample was randomly divided into a group stimulated with probiotics (SG) (n = 34) and a control group (CG) (n = 35). Histological and endoscopic changes were evaluated after stimulation, after restorative surgery and during the short-term follow-up after surgery, including the correlation with pro-inflammatory biomarkers in blood. As main findings, a significant decrease in C-reactive protein (CRP), Neutrophil/lymphocyte ratio (NLR ratio), and monocyte/lymphocyte ratio (LMR ratio) was observed in the SG versus the CG with a p < 0.001. A significant increase in transferrin values and in the platelet/lymphocyte ratio (PLR) was observed in the SG versus CG after stimulation with probiotics with a p < 0.001. A normalisation of CRP and transferrin levels was observed in the third month of follow-up after closure ileostomy, and NLR, LMR and PLR ratios were equal in both groups. Decreased modified Glasgow prognostic score was found in SG compared to CG after probiotic stimulation (p < 0.001). The endoscopic and histological severity of diversion colitis is associated with a greater alteration of blood inflammatory biomarkers. The stimulation with probiotics prior to reconstructive surgery promotes an early normalization of these parameters.
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Efficacy and Safety of Proposed Bevacizumab Biosimilar BE1040V in Patients With Metastatic Colorectal Cancer: A Phase III, Randomized, Double-blind, Noninferiority Clinical Trial.
Rezvani, H, Mortazavizadeh, SM, Allahyari, A, Nekuee, A, Najafi, SN, Vahidfar, M, Ghadyani, M, Khosravi, A, Qarib, S, Sadeghi, A, et al
Clinical therapeutics. 2020;(5):848-859
Abstract
PURPOSE The purpose of this study was to compare the efficacy and safety of a proposed bevacizumab biosimilar to those of the reference product in patients with metastatic colorectal cancer (mCRC). METHODS This Phase III, multicenter, randomized, double-blind (patient- and assessor-blind), active-controlled, 2-armed, parallel-group, noninferiority trial was conducted in patients with histologically verified colorectal cancer with evidence of at least 1 metastasis. Patients with mCRC were randomized 2:1 to receive 5 mg/kg IV of either study drug plus FOLFIRI-3 (with repeated irinotecan 100 mg/m2 60-min infusion on day 3) or the reference drug plus FOLFIRI-3 every 2 weeks for 1 year. Progression-free survival (PFS) was the primary end point, and overall survival, objective response rate, and time to treatment failure as well as safety and immunogenicity were secondary end points. The population assessable for PFS was per protocol, and the intention-to-treat population was used for sensitivity analysis. Safety was assessed based on reports of adverse events, laboratory test results, and vital sign measurements. FINDINGS A total of 126 patients were enrolled; PFS values in the biosimilar and reference arms were 232 days (7.7 months) and 210 days (7 months), respectively (P = 0.47). The hazard ratio of the biosimilar arm versus the reference arm was 0.79 in the per-protocol population (90% CI, 0.46-1.35; P = 0.47). The upper limit for the 2-sided 90% CI was lower than the margin of 1.44, indicating that the biosimilar drug was noninferior to the reference drug. The hazard ratio for overall survival in the intent-to-treat population was 0.99 (95% CI, 0.55-1.80; P = 0.99). The difference between other efficacy end points among the groups was not statistically significant. No significant difference was observed in the comparison of the two arms for safety. The antidrug antibody was positive in 1 patient in each arm. IMPLICATIONS The proposed biosimilar BE1040V was noninferior to the reference product in terms of efficacy in the treatment of mCRC, and tolerability was comparable between the 2 drugs. ClinicalTrials.gov identifier: NCT03288987.
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Cumulative Burden of Colorectal Cancer-Associated Genetic Variants Is More Strongly Associated With Early-Onset vs Late-Onset Cancer.
Archambault, AN, Su, YR, Jeon, J, Thomas, M, Lin, Y, Conti, DV, Win, AK, Sakoda, LC, Lansdorp-Vogelaar, I, Peterse, EFP, et al
Gastroenterology. 2020;(5):1274-1286.e12
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BACKGROUND & AIMS Early-onset colorectal cancer (CRC, in persons younger than 50 years old) is increasing in incidence; yet, in the absence of a family history of CRC, this population lacks harmonized recommendations for prevention. We aimed to determine whether a polygenic risk score (PRS) developed from 95 CRC-associated common genetic risk variants was associated with risk for early-onset CRC. METHODS We studied risk for CRC associated with a weighted PRS in 12,197 participants younger than 50 years old vs 95,865 participants 50 years or older. PRS was calculated based on single nucleotide polymorphisms associated with CRC in a large-scale genome-wide association study as of January 2019. Participants were pooled from 3 large consortia that provided clinical and genotyping data: the Colon Cancer Family Registry, the Colorectal Transdisciplinary Study, and the Genetics and Epidemiology of Colorectal Cancer Consortium and were all of genetically defined European descent. Findings were replicated in an independent cohort of 72,573 participants. RESULTS Overall associations with CRC per standard deviation of PRS were significant for early-onset cancer, and were stronger compared with late-onset cancer (P for interaction = .01); when we compared the highest PRS quartile with the lowest, risk increased 3.7-fold for early-onset CRC (95% CI 3.28-4.24) vs 2.9-fold for late-onset CRC (95% CI 2.80-3.04). This association was strongest for participants without a first-degree family history of CRC (P for interaction = 5.61 × 10-5). When we compared the highest with the lowest quartiles in this group, risk increased 4.3-fold for early-onset CRC (95% CI 3.61-5.01) vs 2.9-fold for late-onset CRC (95% CI 2.70-3.00). Sensitivity analyses were consistent with these findings. CONCLUSIONS In an analysis of associations with CRC per standard deviation of PRS, we found the cumulative burden of CRC-associated common genetic variants to associate with early-onset cancer, and to be more strongly associated with early-onset than late-onset cancer, particularly in the absence of CRC family history. Analyses of PRS, along with environmental and lifestyle risk factors, might identify younger individuals who would benefit from preventive measures.
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Clinical impact of first-line bevacizumab plus chemotherapy in metastatic colorectal cancer of mucinous histology: a multicenter, retrospective analysis on 685 patients.
Catalano, V, Bergamo, F, Cremolini, C, Vincenzi, B, Negri, F, Giordani, P, Alessandroni, P, Intini, R, Stragliotto, S, Rossini, D, et al
Journal of cancer research and clinical oncology. 2020;(2):493-501
Abstract
PURPOSE In metastatic colorectal cancer (MCRC), mucinous histology has been associated with poor response rate and prognosis. We investigated whether bevacizumab combined with different chemotherapy regimens may have an impact on clinical outcomes of MCRC patients with mucinous histology. METHODS 685 MCRC patients were classified in mucinous adenocarcinoma (MC) and non-mucinous adenocarcinoma (NMC) and were treated with first-line bevacizumab plus fluoropyrimidine (FP)-based, oxaliplatin (OXA)-based, irinotecan (IRI)-based, or FOLFOXIRI. RESULTS Ninety-four (13.7%) patients had MC. With a median follow-up of 50 months, MC patients had a median overall survival (OS) of 28.2 months compared with 27.7 months for the NMC group [hazard ratio (HR) = 0.92; 95% confidence interval (CI) 0.70-1.19, P = 0.530]. The overall response rates for MC and NMC were 41.5% (95% CI 31.5-51.4) and 62.4% (95% CI 58.4-66.3), respectively (Chi-square test, P <0.003). After correcting for significant prognostic factors by multivariate Cox regression analysis, age, resection of the primary tumour, and number of metastatic sites were found to be associated with poorer OS, but not mucinous histology. CONCLUSION Compared with NMC, MCRC patients with mucinous histology treated with bevacizumab plus chemotherapy had comparable OS despite lower overall response rate.