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Background: The significance of resection of para-aortic lymph node metastasis in colorectal cancer is controversial., Objective: To clarify the prognosis of colorectal cancer after para-aortic lymph node metastasis resection., Design: Multicenter retrospective study., Settings: Thirty-six institutions in Japan participated in this study. Database and medical records at each institution were used for data collection., Patients: Patients with resected and pathologically proven para-aortic lymph node metastasis of colorectal cancer between 2010 and 2015 were included., Main Outcome Measures: Overall survival after para-aortic lymph node metastasis resection, recurrence-free survival, and recurrence patterns after R0 resection of para-aortic lymph node metastasis., Results: A total of 133 patients were included in the primary analysis population in this study. The 5-year overall survival rate (95% CI) was 41.0% (32.0-49.8), and the median survival (95% CI) was 4.1 (3.4-4.7) years. Independent prognostic factors for overall survival were the pathological T stage (pT4 vs pT1- 3, adjusted HR: 1.91, p = 0.006), other organ metastasis (present vs absent, adjusted HR: 1.98, p = 0.005), time to metastases (synchronous vs metachronous adjusted HR: 2.02, p = 0.02), and the number of para-aortic lymph node metastasis (3 or more vs less than 3, adjusted HR: 2.13, p = 0.001). The 5-year recurrence-free survival rate (95% CI) was 21.1% (13.5-29.7), with a median (95% CI) of 1.2 (0.9-1.4) years. The primary tumor location (left- vs right-sided colon, adjusted HR: 4.77, p = 0.01; rectum vs right-sided colon, adjusted HR: 5.27, p = 0.006), other organ metastasis (present vs absent, adjusted HR: 1.90, p = 0.03), number of para-aortic lymph node metastases (3 or more vs less than 3, adjusted HR: 2.20, p = 0.001), and hospital volume (less than 10 vs 10 or more, adjusted HR: 2.18, p = 0.02) were identified as independent prognostic factors for recurrence-free survival. Para-aortic lymph node recurrence was the most common at 33.3%., Limitations: Selection bias cannot be ruled out because of the retrospective nature of the study., Conclusions: Less than 3 para-aortic lymph node metastases were a favorable prognostic factor for overall and recurrence-free survival. However, para-aortic lymph node metastases were considered to be a systemic disease, and the significance of resection was limited. See Video Abstract ., Resultado a Largo Plazo Posterior a La Reseccin Quirrgica De Metstasis En Ganglios Linfticos Paraarticos De Cncer Colorrectal Un Estudio Retrospectivo Multicntrico: ANTECEDENTES:La importancia de la resección de metástasis en los ganglios linfáticos paraaórticos (PALNM) en el cáncer colorrectal (CCR) es controvertida.OBJETIVO:Aclarar el pronóstico del CCR después de la resección PALNM.DISEÑO:Estudio retrospectivo multicéntrico.ENTORNO CLINICO:Treinta y seis instituciones en Japón participaron en este estudio.PACIENTES:Pacientes con PALNM de CCR resecado y patológicamente probado entre 2010 y 2015.FUENTES DE DATOS:Base de datos y registros médicos de cada institución.PRINCIPALES MEDIDAS DE RESULTADO:Supervivencia general (SG) después de la resección PALNM, supervivencia libre de recurrencia (SLR) y patrones de recurrencia después de la resección R0 de PALNM.RESULTADOS:Se incluyó un total de 133 pacientes en la población de análisis primario de este estudio. La tasa de SG a 5 años (intervalo de confianza [IC] del 95 %) fue del 41,0 % (32,0, 49,8) y la mediana de supervivencia (IC del 95 %) fue de 4,1 (3,4, 4,7) años. Los factores de pronóstico independientes para la SG fueron el estadio T patológico (pT4 vs. pT1-3, índice de riesgo ajustado [aHR]: 1,91, p = 0,006), metástasis en otros órganos (presente vs. ausente, aHR: 1,98, p = 0,005), tiempo hasta las metástasis (síncronas vs. metacrónicas, aHR: 2,02, p = 0,02) y número de PALNM (≥3 vs. <3, aHR: 2,13, p = 0,001). La tasa de SLR a 5 años (IC del 95%) fue del 21,1% (13,5, 29,7), con una mediana (IC del 95%) de 1,2 (0,9, 1,4) años. La ubicación del tumor primario (colon del lado izquierdo vs. derecho, aHR: 4,77, p = 0,01; recto vs. colon del lado derecho, aHR: 5,27, p = 0,006), metástasis en otros órganos (presente vs. ausente, aHR: 1,90, p = 0,03), el número de PALNM (≥3 vs. <3, aHR: 2,20, p = 0,001) y el volumen hospitalario (<10 vs. ≥10, aHR: 2,18, p = 0,02) se identificaron como independientes factores pronósticos del SLR. La recurrencia de los ganglios linfáticos paraaórticos fue la más común con un 33,3%.LIMITACIONES:No se puede descartar un sesgo de selección debido a la naturaleza retrospectiva del estudio.CONCLUSIONES:Menos de tres PALNM fue un factor pronóstico favorable tanto para la SG como para la SLR. Sin embargo, las PALNM se consideraron una enfermedad sistémica y la importancia de la resección fue limitada. (Traducción- Dr. Francisco M. Abarca-Rendon )., (Copyright © The ASCRS 2024.)

Although phase III randomized controlled trials (RCTs) represent the most robust statistical approach for answering clinical questions, they require massive expenditures in terms of time, labor, and funding. Ancillary and supplementary analyses using RCTs are sometimes conducted as alternative approaches to answering clinical questions, but the available integrated databases of RCTs are limited. In this background, the Colorectal Cancer Study Group (CCSG) of the Japan Clinical Oncology Group (JCOG) established a database of ancillary studies integrating four phase III RCTs (JCOG0212, JCOG0404, JCOG0910 and JCOG1006) conducted by the CCSG to investigate specific clinicopathological factors in pStage II/III colorectal cancer (JCOG2310A). This database will be updated by adding another clinical trial data and accelerating several analyses that are clinically relevant in the management of localized colorectal cancer. This study describes the details of this database and planned and ongoing analyses as an initiative of JCOG cOlorectal Young investigators (JOY)., Competing Interests: Declaration of competing interest None declared., (© 2024 Published by Elsevier Ltd.)

Colorectal cancer (CRC) is a heterogeneous disease that develops through stepwise accumulation of genetic alterations and progresses via several distinct pathways. However, the tumorigenesis of CRCs with BRAF non-V600E mutations remains unclear. Here, we aimed to elucidate the tumorigenesis of CRCs with BRAF non-V600E mutations, focusing on differences in mucin phenotype and genetic alterations between CRCs with non-V600E and V600E mutations. We investigated 201 patients with CRC and performed panel testing of 415 genes to identify BRAF mutations. Patients were classified into five mucin phenotypes - large-intestinal, small-intestinal, gastric, mixed, and unclassified - using immunohistochemistry for CD10, MUC2, MUC5AC, and MUC6. BRAF mutations were identified in 24 of 201 patients' samples, of which 13 (6.5%) had a V600E mutation (V600E-mutant) and 11 (5.5%) had non-V600E mutations (non-V600E-mutant). MUC5AC expression was significantly associated with V600E mutations (P = 0.040), while CD10 expression was significantly associated with non-V600E mutations (P = 0.010). The small-intestinal mucin phenotype was significantly associated with non-V600E mutations (P = 0.031), while the mixed mucin phenotype was significantly associated with V600E mutations (P = 0.027). Regarding genetic alterations, focusing on the WNT signaling pathway, APC mutation was significantly associated with non-V600E mutations (P < 0.001), while RNF43 mutation was significantly associated with V600E mutations (P = 0.020). Considering the differences in mucin phenotype and genetic alterations, different modes of tumorigenesis are assumed for CRC with BRAF V600E mutation and non-V600E mutations. These findings are important in understanding the biology and treatment strategies for BRAF-mutant CRC., Competing Interests: Declaration of competing interest All authors have no conflicts of interest regarding this manuscript., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Objective: The aim of this study was to determine the genuine prognostic relevance of primary tumor sidedness (PTS) in patients with early-stage colorectal cancer (CRC)., Background: The prognostic relevance of PTS in early-stage CRC remains a topic of debate. Several large epidemiological studies investigated survival only and did not consider the risk of recurrence so far., Methods: Patients with stage II/III adenocarcinoma of the colon and upper rectum from 4 randomized controlled trials were analyzed. Survival outcomes were compared according to the tumor location: right-sided (cecum to transverse colon) or left-sided (descending colon to upper rectum)., Results: A total of 4113 patients were divided into a right-sided group (N=1349) and a left-sided group (N=2764). Relapse-free survival after primary surgery was not associated with PTS in all patients and each stage [hazard ratio (HR) adjusted =1.024 (95% CI: 0.886-1.183) in all patients; 1.327 (0.852-2.067) in stage II; and 0.990 (0.850-1.154) in stage III]. Also, overall survival after primary surgery was not associated with PTS in all patients and each stage [HR adjusted =0.879 (95% CI: 0.726-1.064) in all patients; 1.517 (0.738-3.115) in stage II; and 0.840 (0.689-1.024) in stage III]. In total, 795 patients (right-sided, N=257; left-sided, N=538) developed recurrence after primary surgery. PTS was significantly associated with overall survival after recurrence (HR adjusted =0.773, 95% CI: 0.627-0.954)., Conclusions: PTS had no impact on the risk of recurrence for stage II/III CRC. Treatment stratification based on PTS is unnecessary for early-stage CRC., Competing Interests: Y.K. received consulting or advisory role from Covidien; honoraria from Chugai Pharma, Ethicon, Covidien, and Intuitive Surgical. T.H. received honoraria from Chugai Pharma, Merck Serono, Takeda, Taiho Pharmaceutical, Ono Pharmaceutical, Yakult Pharmaceutical, Lilly, Bristol-Myers Squibb Japan, Bayer, and Daiichi Sankyo/UCB Japan; research funding from Taiho Pharmaceutical, Ono Pharmaceutical, Chugai Pharma, BeiGene, Astellas Pharma, AstraZeneca, and Pfizer. Y.S. received honoraria from Ono Pharmaceutical, Novartis, Yakult Honsha, and Daiichi Sankyo/UCB Japan. M.O. received speakers’ bureau from Chugai Pharma: research funding from Taiho Pharmaceutical. J.W. received speakers’ bureau from Covidien, Johnson & Johnson/Janssen, and Lilly Japan; research funding from Medtronic, and TERUMO. T.K. received honoraria from Ethicon: research funding from Chugai Pharma, and Taiho Pharmaceutical. The remaining authors report no conflicts of interest., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

Large-scale genomic sequencing of colorectal cancers has been reported mainly for Western populations. Differences by stage and ethnicity in the genomic landscape and their prognostic impact remain poorly understood. We investigated 534 Japanese stage III colorectal cancer samples from the Phase III trial, JCOG0910. Targeted-capture sequencing of 171 potentially colorectal cancer-associated genes was performed, and somatic single-nucleotide variants and insertion-deletions were determined. Hypermutated tumors were defined as tumors with MSIsensor score >7 and ultra-mutated tumors with POLE mutations. Genes with alterations associated with relapse-free survival were analyzed using multivariable Cox regression models. In all patients (184 right-sided, 350 left-sided), mutation frequencies were TP53, 75.3%; APC, 75.1%; KRAS, 43.6%; PIK3CA, 19.7%; FBXW7, 18.5%; SOX9, 11.8%; COL6A3, 8.2%; NOTCH3, 4.5%; NRAS, 4.1%; and RNF43, 3.7%. Thirty-one tumors were hypermutated (5.8%; 14.1% right-sided, 1.4% left-sided). Modest associations were observed: poorer relapse-free survival was seen with mutant KRAS (hazard ratio 1.66; p = 0.011) and mutant RNF43 (2.17; p = 0.055), whereas better relapse-free survival was seen with mutant COL6A3 (0.35; p = 0.040) and mutant NOTCH3 (0.18; p = 0.093). Relapse-free survival tended to be better for hypermutated tumors (0.53; p = 0.229). In conclusion, the overall spectrum of mutations in our Japanese stage III colorectal cancer cohort was similar to that in Western populations, but the frequencies of mutation for TP53, SOX9, and FBXW7 were higher, and the proportion of hypermutated tumors was lower. Multiple gene mutations appeared to impact relapse-free survival, suggesting that tumor genomic profiling can support precision medicine for colorectal cancer., (© 2023 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.)

Purpose: Despite marked recent advances in chemotherapy, few reports have focused on the prognosis for patients with metastatic colorectal cancer (mCRC) achieving complete response (CR) after systemic chemotherapy. This study investigated the clinical course of mCRC patients achieving CR and evaluated the role of chemotherapy in CR., Methods: This retrospective study searched a prospectively maintained database at the author's institute to identify medical records for mCRC patients achieving CR after systematic chemotherapy from January 2007 to March 2020., Results: The search yielded 23 patients with confirmed CR to systemic chemotherapy. Median time to CR from treatment initiation was 6.8 months. Maintenance chemotherapy was continued for 22 of 23 patients. Median duration of maintenance chemotherapy was 11.1 months. Disease progression occurred for 17 (73.9%) patients at a median 48.1-month follow-up. Median progression-free survival was 26.6 months. Median overall survival was 91.7 months., Conclusions: Patients with CR to chemotherapy had a high probability of disease progression, but a relatively long-term prognosis. Treatment strategies after achievement of CR should be based an understanding of the high potential that tumor cells will remain. Use of maintenance chemotherapy after achievement of CR is still unclear, and the recent data do not demonstrate a negative impact for continuing maintenance chemotherapy after CR., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Bevacizumab(BV)combination chemotherapy in colorectal cancer under subcutaneously implanted central venous port (CVP)implantation may cause complications after the implantation. Measurement of D-dimer is recommended to predict thromboembolism and other complications, but its relevance to complications after CVP implantation remains unclear. In this study, we investigated the association between D-dimer and complications after CVP implantation in 93 patients with colorectal cancer who received BV combination chemotherapy. Complications after CVP implantation occurred in 26 patients (28%), and those with VTE showed higher D-dimer values at the onset of the complication. The D-dimer values of the patients with VTE displayed a sharp increase at the onset of the disease, while those with an abnormal CVP implantation site showed a more variable course. Measurement of D-dimer levels appeared useful in estimating the incidence of VTE and abnormal CVP implantation sites in post-CVP implantation complications of BV combination chemotherapy for colorectal cancer. Further, monitoring not only the quantitative values but also the fluctuations over time is also important.

Background: Primary tumor location is considered a predictor of overall survival (OS) in RAS wild-type (WT) metastatic colorectal cancer (mCRC) treated with bevacizumab (BEV) or an anti-epidermal growth factor antibody (cetuximab or panitumumab [CET/PAN]) as first-line molecularly targeted therapy. BEV is recommended for right-sided mCRC and CET/PAN for left-sided mCRC based on post-hoc analyses of clinical trial data, but real-world evidence is lacking., Methods: We retrospectively collected data of patients who started BEV or CET/PAN plus 5-fluorouracil-based doublet chemotherapy between January 2013 and December 2016 as first-line treatment for RAS WT mCRC at any of 24 Japanese institutions. OS was compared between the BEV and CET/PAN groups according to primary tumor location by Cox multivariate regression analysis in the full cohort and in a propensity score-matched cohort., Results: In total, 935 patients were enrolled. Median OS was 24.6 months with BEV and 20.9 months with CET/PAN in right-sided mCRC (n = 213; adjusted hazard ratio [HR] 0.73, 95% confidence interval [CI] 0.50-1.06) and 35.7 months and 30.0 months, respectively, in left-sided mCRC (n = 722; adjusted HR 0.92, 95% CI 0.74-1.13). In the propensity score-matched cohort, OS was significantly better in the BEV group than in the CET/PAN group in right-sided mCRC (HR 0.52, 95% CI 0.28-0.96) but was not significantly different in left-sided mCRC (HR 0.78, 95% CI 0.53-1.07)., Conclusion: Real-world data showed that OS was better with BEV than with CET/PAN in right-sided mCRC. However, there was no significant difference in OS in left-sided mCRC., (© 2022. The Author(s) under exclusive licence to Japan Society of Clinical Oncology.)

Neuroendocrine neoplasms of the colon and rectum are colorectal epithelial neoplasms with neuroendocrine differentiation. A platinum regimen used for small cell lung cancer is the currently recommended chemotherapy for gastroenteropancreatic neuroendocrine carcinomas (GEP-NECs), regardless of the organ. The BRAF V600E mutation has been recently reported as a druggable driver mutation in colorectal NECs. In BRAF V600E mutant colorectal cancer, a combination of BRAF inhibitor and anti-epidermal growth factor receptor (EGFR) antibody, with or without a MEK inhibitor, is recommended. Here, we report the case of 77-year-old man who had lymph node recurrence after surgery for primary ascending colonic NEC. Two cytotoxic regimens, cisplatin plus irinotecan and modified FOLFOX6, were administered as first- and second-line chemotherapies with no remarkable response observed. At this point, genetic analysis confirmed the tumor harbored a BRAF V600E mutation. Thus, a regimen of BRAF inhibitor plus anti-EGFR antibody was administered. After commencing this regimen, carcinoembryonic antigen levels decreased within normal range, and there was dramatic shrinkage of the lymph node metastases observed by chest and abdominal computed tomography scans. To our knowledge, this is the first reported case of a colorectal NEC responding to a BRAF inhibitor and anti-EGFR antibody., (© 2022. Japanese Society of Gastroenterology.)

JCOG-CCSG has been conducting several surgical trials and experienced several challenges. The first point is the appropriate timing of conducting the trial. Once a certain number of surgeons acquire the new technique and its utility is accepted, it suddenly becomes difficult to maintain 'equipoise' between the standard and new treatment, which may lead to poor patient accrual. Smooth preparation and commencement of the trial at an appropriate timing is necessary for its success. Second is the appropriate quality assurance of surgery. High-level quality assurance will strengthen the comparability of randomized control trials and minimize the heterogeneity among hospitals. On the other hand, it may impair the generalizability of the trial. Large observational studies help to bridge the gap of heterogeneity among hospitals. Third is the selection of an appropriate endpoint. Overall survival (OS) is the gold-standard primary endpoint; however, the number of events is much less due to more effective treatment. JCOG0212 and JCOG0404 were unable to demonstrate the non-inferiority of omission of lateral lymph node dissection and laparoscopic surgery partly due to a lack of power. Disease-free survival (DFS) is also a promising candidate for primary endpoint, but as in JCOG0603, special attention must be paid when DFS does not correlate with OS. Although careful discussion is required because the precision of the hazard ratio depends on the number of events, an alternative population-level summary of variables, including restricted mean survival time, can be considered as the primary endpoint. Future surgical trials should be planned considering these points., (© The Author(s) 2021. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permission@oup.com.)

Purpose: Adjuvant chemotherapy after hepatectomy is controversial in liver-only metastatic colorectal cancer (CRC). We conducted a randomized controlled trial to examine if adjuvant modified infusional fluorouracil, leucovorin, and oxaliplatin (mFOLFOX6) is superior to hepatectomy alone for liver-only metastasis from CRC., Patients and Methods: In this phase II or III trial (JCOG0603), patients age 20-75 years with confirmed CRC and an unlimited number of liver metastatic lesions were randomly assigned to hepatectomy alone or 12 courses of adjuvant mFOLFOX6 after hepatectomy. The primary end point of phase III was disease-free survival (DFS) in intention-to-treat analysis., Results: Between March 2007 and January 2019, 300 patients were randomly assigned to hepatectomy alone (149 patients) or hepatectomy followed by chemotherapy (151 patients). At the third interim analysis of phase III with median follow-up of 53.6 months, the trial was terminated early according to the protocol because DFS was significantly longer in patients treated with hepatectomy followed by chemotherapy. With median follow-up of 59.2 months, the updated 5-year DFS was 38.7% (95% CI, 30.4 to 46.8) for hepatectomy alone compared with 49.8% (95% CI, 41.0 to 58.0) for chemotherapy (hazard ratio, 0.67; 95% CI, 0.50 to 0.92; one-sided P = .006). However, the updated 5-year overall survival (OS) was 83.1% (95% CI, 74.9 to 88.9) with hepatectomy alone and 71.2% (95% CI, 61.7 to 78.8) with hepatectomy followed by chemotherapy. In the chemotherapy arm, the most common grade 3 or higher severe adverse event was neutropenia (50% of patients), followed by sensory neuropathy (10%) and allergic reaction (4%). One patient died of unknown cause after three courses of mFOLFOX6 administration., Conclusion: DFS did not correlate with OS for liver-only metastatic CRC. Adjuvant chemotherapy with mFOLFOX6 improves DFS among patients treated with hepatectomy for CRC liver metastasis. It remains unclear whether chemotherapy improves OS., Competing Interests: Yukihide KanemitsuHonoraria: Chugai Pharma, Ethicon, Covidien, Intuitive SurgicalConsulting or Advisory Role: Covidien Junki MizusawaHonoraria: Chugai Pharma, Taiho Pharmaceutical Tetsuya HamaguchiHonoraria: Chugai Pharma, Merck Serono, Takeda, Ono Pharmaceutical, Yakult Pharmaceutical, Lilly, Sanofi, Bristol Myers Squibb Japan, Bayer, Fujifilm, NovartisResearch Funding: Taiho Pharmaceutical, Ono Pharmaceutical, Chugai Pharma, BeiGene, Astellas Pharma, AstraZeneca Masayuki OhueHonoraria: Chugai PharmaResearch Funding: Taiho Pharmaceutical Jun WatanabeSpeakers' Bureau: Covidien Japan, Johnson & Johnson/Janssen, Lilly Japan Yusuke KinugasaHonoraria: Jonthon and Jonthon, Intuitive Surgical Takaya KobatakeHonoraria: EthiconResearch Funding: Chugai Pharma, Taiho Pharmaceutical Yasuhiro ShimadaHonoraria: Chugai Pharma, Ono Pharmaceutical, Taiho Pharmaceutical, Lilly Japan, SanofiResearch Funding: Taiho Pharmaceutical, MSD K.K. Haruhiko FukudaHonoraria: Chugai PharmaNo other potential conflicts of interest were reported.

Background: Tumor mutational burden-high (TMB-H), which is detected with gene panel testing, is a promising biomarker for immune checkpoint inhibitors (ICIs) in colorectal cancer (CRC). However, in clinical practice, not every patient is tested for TMB-H using gene panel testing. We aimed to identify the histopathological characteristics of TMB-H CRC for efficient selection of patients who should undergo gene panel testing. Moreover, we attempted to develop a convolutional neural network (CNN)-based algorithm to predict TMB-H CRC directly from hematoxylin and eosin (H&E) slides., Methods: We used two CRC cohorts tested for TMB-H, and whole-slide H&E digital images were obtained from the cohorts. The Japanese CRC (JP-CRC) cohort (N = 201) was evaluated to detect the histopathological characteristics of TMB-H using H&E slides. The JP-CRC cohort and The Cancer Genome Atlas (TCGA) CRC cohort (N = 77) were used to develop a CNN-based TMB-H prediction model from the H&E digital images., Results: Tumor-infiltrating lymphocytes (TILs) were significantly associated with TMB-H CRC (P < 0.001). The area under the curve (AUC) for predicting TMB-H CRC was 0.910. We developed a CNN-based TMB-H prediction model. Validation tests were conducted 10 times using randomly selected slides, and the average AUC for predicting TMB-H slides was 0.934., Conclusions: TILs, a histopathological characteristic detected with H&E slides, are associated with TMB-H CRC. Our CNN-based model has the potential to predict TMB-H CRC directly from H&E slides, thereby reducing the burden on pathologists. These approaches will provide clinicians with important information about the applications of ICIs at low cost.

Purpose: It remains controversial whether primary tumor resection (PTR) before chemotherapy improves survival in patients with colorectal cancer (CRC) with asymptomatic primary tumor and synchronous unresectable metastases., Patients and Methods: This randomized phase III study investigated the superiority of PTR followed by chemotherapy versus chemotherapy alone in relation to overall survival (OS) in patients with unresectable stage IV asymptomatic CRC and three or fewer unresectable metastatic diseases confined to the liver, lungs, distant lymph nodes, or peritoneum. Chemotherapy regimens of either mFOLFOX6 plus bevacizumab or CapeOX plus bevacizumab were decided before study entry. The primary end point was OS, which was analyzed by intention-to-treat., Results: Between June 2012 and September 2019, a total of 165 patients were randomly assigned to either chemotherapy alone (84 patients) or PTR plus chemotherapy (81 patients). When the first interim analysis was performed in September 2019 with 50% (114/227) of the expected events observed among 160 patients at the data cutoff date of June 5, 2019, the Data and Safety Monitoring Committee recommended early termination of the trial because of futility. With a median follow-up of 22.0 months, median OS was 25.9 months (95% CI, 19.9 to 31.5) in the PTR plus chemotherapy arm and 26.7 (95% CI, 21.9 to 32.5) in the chemotherapy-alone arm (hazard ratio, 1.10; 95% CI, 0.76 to 1.59; one-sided P = .69). Three postoperative deaths occurred in the PTR plus chemotherapy arm., Conclusion: Given that PTR followed by chemotherapy showed no survival benefit over chemotherapy alone, PTR should no longer be considered a standard of care for patients with CRC with asymptomatic primary tumors and synchronous unresectable metastases.

Right-sided colorectal cancer (RCRC) demonstrates worse survival outcome compared with left-sided CRC (LCRC). Recently, the importance of RNF43 mutation and BRAF V600E mutation has been reported in the serrated neoplasia pathway, which is one of the precancerous lesions in RCRC. It was hypothesized that the clinical significance of RNF43 mutation differs according to primary tumor sidedness. To test this hypothesis, the clinicopathological characteristics and survival outcome of patients with RNF43 mutation in RCRC and LCRC were investigated. Stage I-IV CRC patients (n=201) were analyzed. Genetic alterations including RNF43 using a 415-gene panel were investigated. Clinicopathological characteristics between RNF43 wild-type and RNF43 mutant-type were analyzed. Moreover, RNF43 mutant-type was classified according to primary tumor sidedness, i.e., right-sided RNF43 mutant-type or left-sided RNF43 mutant-type, and the clinicopathological characteristics between the two groups were compared. RNF43 mutational prevalence, spectrum and frequency between our cohort and TCGA samples were compared. RNF43 mutation was observed in 27 out of 201 patients (13%). Multivariate analysis revealed that age (≥65), absence of venous invasion, and BRAF V600E mutation were independently associated with RNF43 mutation. Among the 27 patients with RNF43 mutation, 12 patients were right-sided RNF43 mutant-type and 15 left-sided RNF43 mutant-type. Right-sided RNF43 mutant-type was significantly associated with histopathological grade 3, presence of lymphatic invasion, APC wild, BRAF V600E mutation, microsatellite instability-high (MSI-H), and RNF43 nonsense/frameshift mutation compared with left-sided RNF43 mutant-type. Similarly, RNF43 nonsense/frameshift mutations were more frequently observed in RCRC compared with LCRC in the TCGA cohort (P=0.042). Right-sided RNF43 mutant-type exhibited significantly worse overall survival than RNF43 wild-type and left-sided RNF43 mutant-type (P=0.001 and P=0.023, respectively) in stage IV disease. RNF43 mutation may be a distinct molecular subtype which is associated with aggressive tumor biology along with BRAF V600E mutation in RCRC.

Colorectal cancer is a major public health concern in Japan. While early-stage colorectal adenocarcinoma treatment entails radical resection of the primary tumor, the importance of perioperative treatment is growing as physicians seek to further improve treatment outcomes. For anal squamous cell carcinoma, definitive chemoradiotherapy is superior to radical surgery in terms of improved patient quality of life. The Colorectal Cancer Study Group of the Japanese Clinical Oncology Group was established in 2001 and has worked to provide answers to common clinical questions and improve treatment outcomes for colorectal and anal cancers through 15 large-scale prospective clinical trials. Here, we discuss the current state of perioperative treatment for early-stage colon, rectal and anal cancers in Japan and approaches taken by the Colorectal Cancer Study Group/the Japanese Clinical Oncology Group to improve treatment outcomes for these cancers., (© The Author(s) 2020. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

We investigated the incidence of thromboembolism in patients receiving combination chemotherapy with bevacizumab (BV)for colorectal cancer and examined its association with clinical factors. Between July 2007 and April 2014, 250 patients with colorectal cancer received combination chemotherapy with BV. Thromboembolism occurred in 24 cases(9.6%). Five predictive risk factors(platelet count B350,000/µL, hemoglobin <10 g/dL, leukocyte count>11,000/mL, body mass index B25.3 kg/m2, and D-dimer B1.44 µg/mL)were set based on a previous report, and the corresponding number of risk factors for thromboembolism and incidence of thromboembolism were examined. The results of multivariate analysis showed that the occurrence of 3 or more risk factors conferred a significant risk for the incidence of thromboembolism. Due to the increased risk of developing thromboembolism in such patients, special attention during management is required.

Aims: SMAD4 acts as a tumour suppressor, and the loss of SMAD4 is associated with poor prognosis in colorectal cancer (CRC) patients. Although next-generation sequencing (NGS) enabled us to detect numerous genetic alterations in a single assay, the clinical significance of SMAD4 alteration detected with NGS has not been fully investigated. The aim of this study was to evaluate the clinicopathological characteristics and clinical significance of SMAD4 alteration detected with NGS in CRC., Methods and Results: We retrospectively investigated 201 patients with stage I-IV CRC, by using a 415-gene panel. To analyse the relationship between SMAD4 alteration and other clinicopathological characteristics, we evaluated clinicopathological variables, including invasive-front pathological markers: tumour budding, poorly differentiated cluster, and Crohn-like lymphoid reaction. Fifty-six patients (28%) had SMAD4 alteration: 24 and 32 patients had SMAD4 mutation and deletion, respectively. SMAD4 alteration was significantly associated with T category (P = 0.027), N category (P = 0.037), M category (P = 0.028), and invasive-front pathological markers, such as poorly differentiated cluster grade 3 (P = 0.020) and absence of Crohn-like lymphoid reaction (P = 0.004). Immunohistochemistry revealed that SMAD4 alteration was significantly associated with loss of SMAD4 (P = 0.023). In 90 patients with stage I-III disease, SMAD4 alteration was significantly associated with poor prognosis for relapse-free and overall survival (P = 0.047; P = 0.022, respectively). Conversely, in 111 patients with stage IV disease, SMAD4 alteration was not significantly associated with overall survival., Conclusion: SMAD4 alteration is associated with invasive-front pathological markers and poor prognosis in stage I-III CRC patients., (© 2019 The Authors. Histopathology Published by John Wiley & Sons Ltd.)

Comprehensive genomic sequencing (CGS) enables us to detect numerous genetic alterations in a single assay. We aimed to identify molecular markers for predicting prognosis and conversion surgery in Stage IV colorectal cancer (CRC) using CGS. One-hundred eleven patients with Stage IV CRC who underwent primary tumor resection were analyzed. We retrospectively investigated genetic alterations using CGS of a 415-gene panel. Clinicopathological variables and genetic alterations were analyzed to identify independent prognostic factors of overall survival (OS). Forty-five of 111 patients had R0 resection; of these, 11 patients underwent conversion surgery. Univariate and multivariate analyses identified histopathological grade 3, R0 resection, BRAF V600E mutation, and SRC mutation as independent prognostic factors for OS (P = 0.041, P = 0.013, P = 0.005, and P = 0.023, respectively). BRAF V600E and SRC mutations were mutually exclusive, and SRC mutation was significantly associated with left-sided tumor and liver metastasis compared to BRAF V600E mutation (P = 0.016 and P = 0.025, respectively). Eleven of the 74 initially unresectable patients underwent conversion surgery for R0 resection, yet none harbored BRAF V600E or SRC mutations. BRAF V600E and SRC mutations are important molecular markers which can predict prognosis and conversion surgery in Stage IV CRC.

A 78-year-old man was admitted with diarrhea. Colonoscopy and computed tomography(CT)revealed rectal cancer with multiple liver metastases. Low anterior resection was performed for local control. After the operation, 5 courses of mFOLFOX6 plus bevacizumab chemotherapy were administered as first-line systemic therapy, but CT showed progressive disease with liver metastases. After the first-line systemic therapy, 2 courses of FOLFIRI plus bevacizumab chemotherapy were performed as second-line systemic therapy, but CT also revealed progressive disease with liver metastases. We retrospectively performed comprehensive genomic sequencing with a 415-gene panel and found that the patient had a hypermutation subtype. Interestingly, the panel also revealed that he had mismatch-repair(MMR)deficiency with MSH2 mutation, which is reported as a possible cause of resistance to 5-fluorouracil in colorectal cancer.

Background: Adjuvant chemotherapy with oral fluoropyrimidine alone after D3/D2 lymph node dissection improves disease-free survival and overall survival in patients with stage III colon cancer. Adjuvant S-1 has been shown to be non-inferior to uracil and tegafur plus leucovorin in terms of disease-free survival. This study aims to confirm the non-inferiority of S-1 compared with capecitabine as adjuvant treatment in patients with stage III colorectal cancer., Methods: This study was an open-label, non-inferiority, randomised, phase 3, multicentre trial done in 56 Japanese centres to assess the non-inferiority of S-1 to capecitabine as adjuvant chemotherapy. Eligible patients were aged 20-80 years with stage III colorectal adenocarcinoma, as defined by the presence of an inferior margin of the primary tumour above the peritoneal reflection; R0 resection; and colectomy with D3 or D2 lymph node dissection. Patients were randomly assigned (1:1) to receive eight courses of capecitabine (1250 mg/m 2 orally twice daily, days 1-14, every 21 days) or four courses of S-1 (40 mg/m 2 orally twice daily, days 1-28, every 42 days). Randomisation was done via phone call, fax, or web-based systems to the Japan Clinical Oncology Group Data Center and used a minimisation method with a random component adjusted by institution, tumour location (colon vs rectosigmoid and upper rectum), number of positive lymph node metastases (≤3 vs ≥4), and surgical technique (conventional vs non-touch isolation). The primary endpoint was disease-free survival with a non-inferiority margin for the hazard ratio (HR) set at 1·24, analysed by intention to treat. This trial was registered with UMIN Clinical Trial Registry, number UMIN000003272., Findings: Between March 1, 2010, and Aug 23, 2013, 1564 patients were randomly assigned to capecitabine (n=782) or S-1 (n=782), all of whom were included in the efficacy analysis; 777 patients in the capecitabine group and 768 in the S-1 group were included in the safety analysis. At the prespecified second interim analysis after final accrual, 258 (48%) of 535 required events were reported, and the Data and Safety Monitoring Committee recommended early publication because S-1 could not show non-inferiority compared with capecitabine for disease-free survival. With a median follow-up of 23·7 months (IQR 14·1-35·2), 3-year disease-free survival was 82·0% (95% CI 78·5-85·0) for the capecitabine group and 77·9% (74·1-81·1) for the S-1 group (HR 1·23, 99·05% CI 0·89-1·70; one-sided p non-inferiority =0·46). The most frequent grade 3 or higher adverse events in the capecitabine group were hand-foot skin reactions (123 [16%] of 777 patients), and in the S-1 group were diarrhoea (64 [8%] of 768 patients) and neutropenia (61 [8%]). There was one (<1%) treatment-related death in each group., Interpretation: Adjuvant capecitabine remains one of the standard treatments for stage III colorectal cancer in Japan; S-1 is not recommended., Funding: National Cancer Center and Ministry of Health, Labour and Welfare of Japan., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

HER2-targeted therapy is considered effective for KRAS codon 12/13 wild-type, HER2-positive metastatic colorectal cancer (CRC). In general, HER2 status is determined by the use of immunohistochemistry (IHC) and fluorescence in situ hybridization (FISH). Comprehensive genomic sequencing (CGS) enables the detection of gene mutations and copy number alterations including KRAS mutation and HER2 amplification; however, little is known about the utility of CGS for detecting HER2-positive CRC. To assess its utility, we retrospectively investigated 201 patients with stage I-IV CRC. The HER2 status of the primary site was assessed using IHC and FISH, and HER2 amplification of the primary site was also assessed using CGS, and the findings of these approaches were compared in each patient. CGS successfully detected alterations in 415 genes including KRAS codon 12/13 mutation and HER2 amplification. Fifty-nine (29%) patients had a KRAS codon 12/13 mutation. Ten (5%) patients were diagnosed as HER2 positive because of HER2 IHC 3+, and the same 10 (5%) patients had HER2 amplification evaluated using CGS. The results of HER2 status and HER2 amplification were completely identical in all 201 patients (P < .001). Nine of the 10 HER2-positive patients were KRAS 12/13 wild-type and were considered possible candidates for HER2-targeted therapy. CGS has the same utility as IHC and FISH for detecting HER2-positive patients who are candidates for HER2-targeted therapy, and facilitates precision medicine and tailor-made treatment., (Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.)

Recently, targeted drugs have been developed for the treatment of colorectal cancer(CRC). Among targets, it is well known that KRAS mutations are associated with resistance to epidermal growth factor receptor(EGFR)monoclonal antibodies. However, response rates using anti-EGFR monotherapy for CRC were less than 20-30% in previous clinical studies. Thus, because the RAS/MAP2K/MAPK and PI3K/AKT pathways are associated with CRC resistance to chemotherapy, we analyzed gene mutations in Stage IV CRC patients using a genomic test(CancerPlex®). Medical records were reviewed for 112 patients who received treatment for CRC between 2007 and 2015 in Niigata University Medical and Dental Hospital or Niigata Cancer Center Hospital. There were 66 male and 46 female patients, and their median age was 62.5(range, 30-86) years. Cluster analyses were performed in 110 non-hypermutated Japanese CRC patients using Euclidean distance and Ward's clustering method, and 6 typical groups were identified. Among these, patients with all wild-type actionable genes benefited from anti-EGFR therapies. The expense of targeted drugs warrants consideration of cost-effectiveness during treatment decision-making for advanced CRC patients. To this end, based on the genetic information on CRC, it is possible to develop precision medicine using CancerPlex®.

Purposes: Recently, the serum p53 antibody (S-p53Ab) has been used widely in clinical practice as a tumor marker for colorectal cancer (CRC). However, no large-scale studies have examined the usefulness of serial measurements of S-p53Ab or have established the relationship of this parameter with the clinicopathological factors of CRC., Methods: An ELISA for S-p53Ab was performed for 1384 primary CRC patients, and the results were categorized by the clinicopathological factors., Results: The S-p53Ab positivity rate was 24.1 %, and was significantly higher in Stage III-IV than in Stage 0-II cases. However, no relationship was seen with the serum carcinoembryonic antigen (CEA) or carbohydrate antigen 19-9 (CA19-9) levels. The addition of the S-p53Ab assay to the CEA and CA19-9 measurements increased the overall diagnostic sensitivity to 50.9 % (CEA and/or CA19-9: 37.3 %). In patients who had undergone complete resection, S-p53Ab positivity was associated with a decrease in the relapse-free survival (p = 0.012), but it was not independent prognostic indicator. S-p53Ab positivity had no influence on the cancer-specific survival., Conclusions: The S-p53Ab positivity rate was higher than the positivity rates for CEA and/or CA19-9 in Stage 0-I CRC patients. Combining the use of the three tumor marker tests is a potentially effective method for detecting even early-stage CRC.

A randomized controlled trial is currently being conducted in Japan to demonstrate the superiority of the no-touch isolation technique over the conventional technique for patients with potentially curative colon and rectosigmoid cancer. The conventional technique procedure gives first priority to mobilization of the tumor-bearing segment of the colon, which is followed by central vascular ligation and ligation of other vasculature. Conversely, the no-touch isolation technique gives first priority to central vascular ligation, which is followed by mobilization of the tumor-bearing segment of the colon. A total of 850 patients will be enrolled in this trial. The primary endpoint is disease-free survival. Secondary endpoints are overall survival, relapse-free survival, liver metastasis-free survival, mode of recurrence, surgical morbidity, adverse events due to postoperative chemotherapy, serious adverse events and short-term clinical outcomes.

We evaluated the predictive relevance of several biomarkers on the survival of patients with stage III colorectal cancer treated with adjuvant chemotherapy of oral fluoropyrimidines. This was a multicenter phase II trial on adult patients with histologically confirmed resected stage III (Dukes' C) colorectal cancer. Patients received oral doxifluridine (800 mg/m2/day) in 3 divided doses, or oral uracil/tegafur (UFT) (400 mg/m2/day) in 2 divided doses for 5 days, every 7 days for 12 months with a 5-year follow-up. Outcome measures were disease-free survival and tissue markers [thymidine phosphorylase (TP), dihydropyrimidine dehydrogenase (DPD) protein levels and TP, DPD, thymidylate synthase (TS) and orotate phosphoribosyltransferase (OPRT) mRNA levels in tumor samples and TS tandem-repeat type in blood samples]. There was a significant association between the intratumoral TP/DPD enzyme ratio and disease-free survival when the model included the drug, the parameter and the interactions between them [hazard ratio (HR)=2.76; P=0.00469]. The 5-year disease-free survival rate was statistically significantly higher in patients with high TP/DPD ratios [median ≥2.63: 71.9%; 95% confidence interval (CI) 61.4-80.0] compared to patients with low TP/DPD ratios (<2.63: 57.0%; 95% CI 46.3-66.3) (log-rank P=0.0277) following adjuvant therapy with oral fluoropyrimidines. No significant association was observed between the intratumoral TP/DPD enzyme ratio (cut-off value 2.0) and the disease-free survival rate in the doxifluridine group; primary endpoint (log-rank P=0.6850). The magnitude of the intratumoral TP/DPD enzyme ratio may be a potential indicator for the individualization of postoperative adjuvant chemotherapy with oral fluoropyrimidines for stage III colorectal cancer.

Aim: The aim of this retrospective study was to show the efficacy and safety of modified FOLFOX6 plus high-dose bevacizumab (10 mg/kg/2 weeks) in the second-line or later treatment of metastatic colorectal cancer., Methods: A total of 24 consecutive patients treated between August 2007 and August 2009 were included in this retrospective study. None of the patients had received bevacizumab as part of prior treatment., Results: All 24 patients received modified FOLFOX6 plus high-dose bevacizumab and were followed for a median of 36.9 months. Overall response rate was 29%. Median progression-free survival was 7.5 months, and median overall survival was 17.3 months. Grade 3/4 adverse events were: neutropenia (54.2%), leukopenia (25.0%), neuropathy (12.5%), hypertension (12.5%), thrombocytopenia (8.3%), and decreased haemoglobin, gastrointestinal haemorrhage, wound complications, nausea, diarrhoea, mucositis and fatigue (each 4.2%)., Conclusion: Modified FOLFOX6 plus high-dose bevacizumab may be useful in the second-line treatment of patients with metastatic colorectal cancer who have not received bevacizumab., (Copyright © 2013 S. Karger AG, Basel.)

Background: This study attempted to determine the therapeutic dosage of irinotecan and S-1 (IRIS) as a second-line treatment for colorectal cancer (CRC)., Methods: S-1 was administered on days 1-14 of a 28-day cycle. Irinotecan was administered on days 1 and 15. The irinotecan dose was then escalated to determine the maximum-tolerated dose and the recommended dose at a fixed dosage of S-1 (80 or 65 mg·m(-2)·day(-1)). The S-1 dose was reduced to 65 mg·m(-2)·day(-1) when dose-limiting toxicities were observed at 80 mg·m(-2)· day(-1) and the irinotecan dose was increased., Results: The recommended dose was 65 mg/m(2) for S-1 and 75 mg/m(2) for irinotecan. Twenty-one patients were treated at the recommended dose. The overall response rate was 28.6%., Conclusion: This modified IRIS regimen is considered effective with acceptable toxicities for advanced CRC resistant to treatment with 5-fluorouracil/leucovorin or uracil and tegafur/leucovorin.

We report three cases of complete response (CR) after treatment with UFT/LV for recurrent colorectal cancer. Case 1: A 44-year-old man was diagnosed with multiple liver metastases after resection of cecal cancer. UFT (500 mg/day)/Leucovorin (75 mg/day) was administered. Metastatic lesions of the liver completely disappeared on computed tomography(CT)one month after chemotherapy. Grade 2 hyperbilirubinemia and grade 1 diarrhea, pigmentation and rash were recognized. No signs of recurrence were observed for 35 months. Case 2: A 66-year-old man who underwent left colectomy and partial hepatectomy for transverse colon cancer and descending colon cancer with liver metastasis was determined to have multiple lung metastases. UFT/LV therapy was started. The lung lesions became only scars 7 months later. Adverse events were not seen. No other recurrence was found over 20 months. Case 3: A 66- year-old woman was detected with a lymph node recurrence after surgery for rectal cancer. CT revealed the disappearance of the tumor after 7 courses of UFT/LV therapy. Grade 2 hyperbilirubinemia appeared. Recurrence was not observed for 22 months, and the treatment has been discontinued.