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1.
Protective effect of the oral administration of cystine and theanine on oxaliplatin-induced peripheral neuropathy: a pilot randomized trial.
Kobayashi, M, Sato, R, Komura, T, Ichikawa, H, Hirashima, T, Otake, S, Akazawa, N, Yazawa, T, Abe, T, Okada, T, et al
International journal of clinical oncology. 2020;(10):1814-1821
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Abstract
BACKGROUND Oxaliplatin, one of the key cytotoxic drugs for colorectal cancer, frequently causes peripheral neuropathy which leads to dose modification and decreased patients' quality of life. However, prophylactic or therapeutic measures have not yet been established. Orally administered amino acids, cystine and theanine, promoted the synthesis of glutathione which was one of the potential candidates for preventing the neuropathy. The aim of this study was to determine whether daily oral administration of cystine and theanine attenuated oxaliplatin-induced peripheral neuropathy (OXLIPN). METHODS Twenty-eight colorectal cancer patients who received infusional 5-fluorouracil, leucovorin, and oxaliplatin (mFOLFOX6) therapy were randomly and evenly assigned to the cystine and theanine group and the control group. OXLIPN was assessed up to the sixth course using original 7-item questionnaire as well as Common Terminology Criteria for Adverse Events (CTCAE) grading scale. RESULTS Neuropathy scores according to our original questionnaire were significantly smaller in the cystine and theanine group at the fourth (p = 0.026), fifth (p = 0.029), and sixth course (p = 0.038). Furthermore, significant differences were also observed in CTCAE neuropathy grades at the fourth (p = 0.037) and the sixth course (p = 0.017). There was one patient in each group who required dose reduction due to OXLIPN. Except for neurotoxicity, no significant differences were noted in the incidence of adverse events, and the total amount of administered oxaliplatin. CONCLUSION The results demonstrated the daily oral administration of cystine and theanine attenuated OXLIPN.
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S-Adenosylmethionine Treatment of Colorectal Cancer Cell Lines Alters DNA Methylation, DNA Repair and Tumor Progression-Related Gene Expression.
Zsigrai, S, Kalmár, A, Nagy, ZB, Barták, BK, Valcz, G, Szigeti, KA, Galamb, O, Dankó, T, Sebestyén, A, Barna, G, et al
Cells. 2020;(8)
Abstract
Global DNA hypomethylation is a characteristic feature of colorectal carcinoma (CRC). The tumor inhibitory effect of S-adenosylmethionine (SAM) methyl donor has been described in certain cancers including CRC. However, the molecular impact of SAM treatment on CRC cell lines with distinct genetic features has not been evaluated comprehensively. HT-29 and SW480 cells were treated with 0.5 and 1 mmol/L SAM for 48 h followed by cell proliferation measurements, whole-genome transcriptome and methylome analyses, DNA stability assessments and exome sequencing. SAM reduced cell number and increased senescence by causing S phase arrest, besides, multiple EMT-related genes (e.g., TGFB1) were downregulated in both cell lines. Alteration in the global DNA methylation level was not observed, but certain methylation changes in gene promoters were detected. SAM-induced γ-H2AX elevation could be associated with activated DNA repair pathway showing upregulated gene expression (e.g., HUS1). Remarkable genomic stability elevation, namely, decreased micronucleus number and comet tail length was observed only in SW480 after treatment. SAM has the potential to induce senescence, DNA repair, genome stability and to reduce CRC progression. However, the different therapeutic responses of HT-29 and SW480 to SAM emphasize the importance of the molecular characterization of CRC cases prior to methyl donor supplementation.
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[Meta-analysis of laparoscopic versus open surgery for palliative resection of the primary tumor in stage IV colorectal cancer].
Tan, SJ, Jiang, Y, Xi, QL, Meng, QY, Zhuang, QL, Han, YS, Wu, GH
Zhonghua wei chang wai ke za zhi = Chinese journal of gastrointestinal surgery. 2020;(6):589-596
Abstract
Objective: To systematically evaluate the safety and efficacy of laparoscopic versus open surgery for palliative resection of the primary tumor in stage IV colorectal cancer. Methods: The databases of CNKI, Wanfang, VIP, PubMed, EMBASE and Cochrane Library were searched to retrieve randomized controlled trials (RCT) or clinical controlled trials (CCT) comparing laparoscopic surgery with open surgery for palliative resection of the primary tumor in stage IV colorectal cancer published from January 1991 to May 2019. Chinese search terms included "colorectum/colon/rectum" , "cancer/malignant tumor" , "laparoscopy" , "metastasis" , " IV" ; English search terms included "laparoscop*" , "colo*" , "rect*" , "cancer/tumor/carcinoma/neoplasm" , " IV" , "metasta*" . Inclusion criteria: (1) RCT or CCT, with or without allocation concealment or blinding; (2) patients with stage IV colorectal cancer that was diagnosed preoperatively and would receive resection of the primary tumor; (3) the primary tumor that was palliatively resected by laparoscopic or open procedure. Exclusion criteria: (1) no valid data available in the literature; (2) single study sample size ≤20; (3) subjects with colorectal benign disease; (4) metastatic resection or lymph node dissection was performed intraoperatively in an attempt to perform radical surgery; (5) duplicate publication of the literature. Two researchers independently evaluated the quality of the included studies. In case of disagreement, the evaluation was performed by discussion or a third researcher was invited to participate. The data were extracted from the included studies, and the Cochrane Collaboration RevMan 5.1.0 version software was used for this meta-analysis. Results: Four CCTs with a total of 864 patients were included in this study, including 216 patients in the laparoscopic group and 648 patients in the open group. Compared with the open group, except for longer operation time (WMD=37.60, 95% CI: 26.11 to 49.08, P<0.05), laparoscopic group had less intraoperative blood loss (WMD=-74.89, 95% CI: -144.78 to -5.00, P<0.05), earlier first flatus and food intake after surgery (WMD=-1.00, 95% CI: -1.12 to -0.87, P<0.05; WMD=-1.61, 95%CI: -2.16 to -1.06, P<0.05), shorter hospital stay (WMD=-2.01, 95% CI: -2.21 to -1.80, P<0.05) and lower morbidity of postoperative complication (OR=0.52, 95% CI: 0.35 to 0.77, P<0.05). However, no significant differences were found in time to start postoperative chemotherapy, postoperative chemotherapy rate, and mortality (P > all 0.05). Conclusion: Laparoscopic surgery for palliative resection of the primary tumor is safe and feasible to enhance recovery after surgery by promoting postoperative bowel function recovery, shortening hospital stay and reducing postoperative complication in stage IV colorectal cancer.
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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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Abstract
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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Associations between nutritional factors and KRAS mutations in colorectal cancer: a systematic review.
El Asri, A, Zarrouq, B, El Kinany, K, Bouguenouch, L, Ouldim, K, El Rhazi, K
BMC cancer. 2020;(1):696
Abstract
BACKGROUND Between 30 and 50% of colon tumors have mutations in the Kirsten-ras (KRAS) gene, which have a large nutritional attributable risk. Despite its high frequency in colorectal cancer (CRC), data to support specific associations between KRAS mutations in CRC and diet are sparse. Here, we conducted a systematic review to summarize the current epidemiological evidence on the association between various dietary factors and KRAS mutations. METHODS PubMed, Science Direct, and Cochrane databases were searched for relevant studies published until December 31, 2019, using inclusion and exclusion criteria in accordance with PRISMA guidelines. We analyzed the studies to find associations between nutritional factors and CRC tumors with KRAS mutations in humans. RESULTS We identified 28 relevant studies to include in this systematic review. In-depth analyses showed unclear associations between nutritional factors and KRAS mutations in CRC. Most epidemiological studies in the same nutrient or food often reported conflicting and/or inconclusive findings, whereas for some dietary factors, the results were homogeneous. CONCLUSIONS Further research using a more robust prospective cohort study is needed to lend more credence to the epidemiological associations found between KRAS mutations and dietary factors.
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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.
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Non-randomized preliminary study of an education and elastic-band resistance exercise program on severity of neuropathy, physical function, muscle strength and endurance & quality of life in colorectal cancer patients experiencing oxaliplatin-induced peripheral neuropathy.
Chen, SC, Huang, HP, Huang, WS, Lin, YC, Chu, TP, Beaton, RD, Jane, SW
European journal of oncology nursing : the official journal of European Oncology Nursing Society. 2020;:101834
Abstract
PURPOSE Many colorectal cancer (CRC) patients report having Oxaliplatin-induced peripheral neuropathy (OXAIPN), compromising their overall quality of life (QoL). Yet, the existing studies on examining the effects of elastic-band resistance exercise yielded inconsistent results and there was a scare study with CRC population employing a longitudinal research design. The purpose of this non-randomized preliminary study was to examine the effects of an educational program providing skills and knowledge about OXAIPN along with home-based lower extremity elastic-band exercise training in a sample (n = 42) of Taiwanese patients with CRC. METHOD A quasi-experimental study with one-group, pretest-posttest repeated measures and longitudinal design was employed. The 4.5-month interventional protocol included 8 sessions of face-to-face education from the 3rd to the 7th cycles of chemotherapy. Physical exams, muscle strength and endurance, and self-reports regarding adverse impacts of OXAIPN and QoL were obtained at three time points throughout chemotherapy course. RESULTS The most consistently significant increase was the participants' muscle strength and endurance measured with one-repetition maximum and 6-min walk distance, respectively (both P < .001). The participants' OXAIPN-related QoL showed significant improvements at some time points of the chemotherapy cycles, but not others. CONCLUSION Study findings indicated that an educational program combined with knowledge about OXAIPN symptom management and skills with lower extremity resistance training had potential benefits over time on muscle strength and endurance and autonomic dimension of CIPN-related QoL. These preliminarily results may assist healthcare providers to incorporate self-management strategies such as lower extremity exercise for patients with OXAIPN to partially mitigate its negative effects.
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Considering anticipated regret may reduce colorectal cancer screening intentions: a randomised controlled trial.
Hunkin, H, Turnbull, D, Zajac, IT
Psychology & health. 2020;(5):555-572
Abstract
Objective: Regular screening for colorectal cancer (CRC) can substantially improve outcomes. This study investigated how measuring regret expected from failing to screen might lead to stronger screening intentions. Five potential moderators were evaluated: perceived threat, psychological reactance, prior screening participation, concurrently measuring faecal aversion (FA) and anticipated regret (AR). Design: A 2 (AR measured pre/post intention) × 2 (FA measured pre/post intention) single blind parallel randomised controlled trial was used. Australians aged 45 and over completed an online survey measuring AR, FA, intention, theory of planned behaviour variables and potential moderators. Main outcome measures: The primary outcome was CRC screening intention. Results: Eight hundred and three participants were randomised, with 666 analysed. Measuring AR prior to intention unexpectedly resulted in a significantly lower intention to screen (d = 0.18, 95% CI [0.03, 0.33]) compared to measuring after intention. Trait reactance predicted a significantly lower intention when it was at least 0.52 SD above the mean; other moderators were not supported. Conclusion: The processes underlying anticipated regret manipulations must be better understood in order to have practical value in health promotion. More research is required to determine how to minimise or avoid the apparent negative effects of psychological reactance in CRC screening communication. Trial registration: Australian New Zealand Clinical Trials Registry: ACTRN12618001098224 http://www.ANZCTR.org.au/ACTRN12618001098224.aspx.
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Maintenance treatment with fluoropyrimidine plus bevacizumab versus fluoropyrimidine alone after induction chemotherapy for metastatic colorectal cancer: The BEVAMAINT - PRODIGE 71 - (FFCD 1710) phase III study.
Manfredi, S, Turpin, A, Malka, D, Barbier, E, Laurent-Puig, P, Zaanan, A, Dahan, L, Lièvre, A, Phelip, JM, Michel, P, et al
Digestive and liver disease : official journal of the Italian Society of Gastroenterology and the Italian Association for the Study of the Liver. 2020;(10):1143-1147
Abstract
BACKGROUND Maintenance treatments with fluoropyrimidine alone or combined with bevacizumab after induction chemotherapy are two standard options in first-line metastatic colorectal cancer (mCRC). However, no trial has compared these two maintenance regimens. METHODS BEVAMAINT is a multicenter, open-label, randomized phase III trial comparing fluoropyrimidine alone or plus bevacizumab as maintenance treatment after induction polychemotherapy in mCRC. The primary endpoint is the time-to-treatment failure (TTF), calculated from date of randomization to first radiological progression, death, start of a new chemotherapy regimen (different from induction or maintenance chemotherapy) or end of maintenance treatment without introduction of further chemotherapy. We expect a 2-month TTF improvement from 6 months in the monotherapy arm to 8 months in the combination arm (hazard ratio [HR], 0.75). Based on a two-sided α risk of 5% and a power of 80%, using Schoenfeld method, 379 events are required (planned enrolment, 400 patients). Patients with mCRC, whose disease is measurable according to RECIST 1.1 criteria and controlled (objective response or stable disease) - but remains unresectable - after 4 to 6 months of induction polychemotherapy (doublet or triplet chemotherapy with or without anti-EGFR or bevacizumab), and who have recovered from limiting adverse events of induction polychemotherapy are eligible for randomization. Randomization is stratified according to center, response to induction chemotherapy (objective response vs stable disease), ECOG performance status (0-1 vs 2), maintenance fluoropyrimidine (5-fluorouracil vs capecitabine) and primary tumor status (resected vs not). Capecitabine or bolus and infusional 5-fluorouracil plus folinic acid (simplified LV5FU2 regimen) are both accepted for maintenance chemotherapy, at investigator's discretion. Clinical evaluation, tumor imaging, carcinoembryonic antigen and circulating tumor DNA dosages are planned at enrolment and every 9 weeks. The maintenance treatment will be discontinued in the event of unbearable toxicity, progression or patient refusal. After maintenance discontinuation, reintroduction of induction polychemotherapy is recommended; otherwise a second-line treatment is started. The enrolment has begun in January 2020.