Colorectal cancer is a major cause of death in Japan, where it accounts for the largest number of deaths from malignant neoplasms in women and the third largest number in men. Many new treatment methods have been developed over the last few decades. The Japanese Society for Cancer of the Colon and Rectum (JSCCR) guidelines 2010 for the treatment of colorectal cancer (JSCCR Guidelines 2010) have been prepared to show standard treatment strategies for colorectal cancer, to eliminate disparities among institutions in terms of treatment, to eliminate unnecessary treatment and insufficient treatment, and to deepen mutual understanding between health-care professionals and patients by making these Guidelines available to the general public. These Guidelines have been prepared by consensuses reached by the JSCCR Guideline Committee, based on a careful review of the evidence retrieved by literature searches and in view of the medical health insurance system and actual clinical practice settings in Japan. Therefore, these Guidelines can be used as a tool for treating colorectal cancer in actual clinical practice settings. More specifically, they can be used as a guide to obtaining informed consent from patients and choosing the method of treatment for each patient. As a result of the discussions held by the Guideline Committee, controversial issues were selected as Clinical Questions, and recommendations were made. Each recommendation is accompanied by a classification of the evidence and a classification of recommendation categories based on the consensus reached by the Guideline Committee members. Here we present the English version of the JSCCR Guidelines 2010.

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Japanese Society for Cancer of the Colon and Rectum (JSCCR) guidelines 2010 for the treatment of colorectal cancer

Cetuximab Monotherapy and Cetuximab plus Irinotecan in Irinotecan-Refractory Metastatic Colorectal Cancer

Purpose To investigate the prevalence, distribution, and prognostic role of BRAF mutations in a large cohort of white patients with non–small-cell lung cancer (NSCLC). Patients and Methods A retrospective series of 1,046 NSCLCs—comprising 739 adenocarcinomas (ADCs) and 307 squamous cell carcinomas (SCCs)—was investigated for BRAF mutations. High-resolution melting analysis followed by sequencing and strip hybridization assay were used. All patients were also analyzed for KRAS and EGFR mutations. Results BRAF mutations were present in 36 ADCs (4.9%) and one SCC (0.3%; P = .001). Twenty-one of the mutations (56.8%) were V600E, and 16 (43.2%) were non-V600E. V600E mutations were significantly more prevalent in females (16 of 187 patients; 8.6%) than in males (five of 552 patients; 0.9%), as indicated by multivariate logistic regression analysis (hazard ratio [HR], 11.29; P < .001). V600E-mutated tumors showed an aggressive histotype characterized by micropapillary features in 80% of patients and were signifi...

https://ascopubs.org/doi/pdf/10.1200/jco.2011.35.9638

Clinical Features and Outcome of Patients With Non–Small-Cell Lung Cancer Harboring BRAF Mutations

Purpose To evaluate dabrafenib, a selective BRAF inhibitor, combined with trametinib, a selective MEK inhibitor, in patients with BRAF V600–mutant metastatic colorectal cancer (mCRC). Patients and Methods A total of 43 patients with BRAF V600–mutant mCRC were treated with dabrafenib (150 mg twice daily) plus trametinib (2 mg daily), 17 of whom were enrolled onto a pharmacodynamic cohort undergoing mandatory biopsies before and during treatment. Archival tissues were analyzed for microsatellite instability, PTEN status, and 487-gene sequencing. Patient-derived xenografts were established from core biopsy samples. Results Of 43 patients, five (12%) achieved a partial response or better, including one (2%) complete response, with duration of response > 36 months; 24 patients (56%) achieved stable disease as best confirmed response. Ten patients (23%) remained in the study > 6 months. All nine evaluable during-treatment biopsies had reduced levels of phosphorylated ERK relative to pretreatment biopsies (avera...

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Combined BRAF and MEK inhibition with dabrafenib and trametinib in BRAF V600-Mutant colorectal cancer

Pan-Asian adapted ESMO consensus guidelines for the management of patients with metastatic colorectal cancer: a JSMO-ESMO initiative endorsed by CSCO, KACO, MOS, SSO and TOS.

Activating mutation of KRAS and BRAF are focused on as potential prognostic and predictive biomarkers in patients with colorectal cancer (CRC) treated with anti-EGFR therapies This study investigated the clinicopathological features and prognostic impact of KRAS/BRAF mutation in advanced and recurrent CRC patients Patients with advanced and recurrent CRC treated with systemic chemotherapy (n=229) were analysed for KRAS/BRAF genotypes by cycleave PCR Prognostic factors associated with survival were identified by univariate and multivariate analyses using the Cox proportional hazards model KRAS and BRAF mutations were present in 345% and 65% of patients, respectively BRAF mutated tumours were more likely to develop on the right of the colon, and to be of the poorly differentiated adenocarcinoma or mucinous carcinoma, and peritoneal metastasis The median overall survival (OS) for BRAF mutation-positive and KRAS 13 mutation-positive patients was 110 and 277 months, respectively, which was significantly worse than that for patients with wild-type (wt) KRAS and BRAF (406 months) (BRAF; HR=425, P<0001, KRAS13; HR=203, P=0024) After adjustment for significant features by multivariate Cox regression analysis, BRAF mutation was associated with poor OS (HR=423, P=0019) Presence of mutated BRAF is one of the most powerful prognostic factors for advanced and recurrent CRC The KRAS13 mutation showed a trend towards poor OS in patients with advanced and recurrent CRC

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BRAF mutation is a powerful prognostic factor in advanced and recurrent colorectal cancer

This randomised phase II trial compared dose-escalated weekly paclitaxel (wPTX) vs standard-dose wPTX for patients with previously treated advanced gastric cancer (AGC). Ninety patients were randomised to a standard dose of wPTX (80 mg m−2) or an escalated dose of wPTX (80–120 mg m−2) to assess the superiority of overall survival (OS) with a one-sided alpha error of 0.3 and a power of 0.8. The median OS showed a trend towards longer survival in the dose-escalated arm (11.8 vs 9.6 months; hazard ratio (HR), 0.75; one-sided P=0.12), although it was statistically not significant. The median progression-free survival (PFS) was significantly longer in the dose-escalated arm (4.3 vs 2.5 months, HR, 0.55; P=0.017). Objective response rate was 30.3% with dose escalation and 17.1% with standard dose (P=0.2). The frequency of all grades of neutropenia was significantly higher with dose escalation (88.7% vs 60.0%, P=0.002); however, no significant difference was observed in the proportion of patients experiencing grade 3 or more (40.9% vs 31.1%, P=0.34). Dose-escalated wPTX in patients with pretreated AGC met our predefined threshold of primary end point, OS (P<0.3); however, it did not show a significantly longer OS. Progression-free survival was significantly better with dose escalation.

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Randomised phase II study comparing dose-escalated weekly paclitaxel vs standard-dose weekly paclitaxel for patients with previously treated advanced gastric cancer.

The aim of this study is to prospectively evaluate the efficacy of combination chemotherapy with every second week cetuximab and irinotecan in patients with pretreated metastatic colorectal cancer harboring wild-type KRAS. Patients with wild-type KRAS metastatic colorectal cancer that had progressed after chemotherapy with irinotecan, oxaliplatin, and fluoropyrimidine were included. Cetuximab was administered at 500 mg/m2 biweekly with irinotecan. The primary endpoint was response rate. The pharmacokinetics of cetuximab was also evaluated in 5 patients. From May 2009 to February 2010, a total of 31 patients were enrolled from five institutions. One patient was not eligible. Among the 30 patients who were treated with biweekly cetuximab plus irinotecan, partial response was observed in 9 patients. The objective response rate was 30.0% (95% confidence interval [CI], 14.7%–49.4%) and the disease control rate (complete response, partial response, or stable disease) was 76.7% (95% CI, 57.7%–90.0%). The median progression-free survival was 5.3 months and median overall survival was 10.8 months. Grade 3 skin toxicity was observed in 3 patients (10.0%) and one treatment related death due to pneumonia was observed. Combination chemotherapy with biweekly cetuximab and irinotecan was effective for pretreated metastatic colorectal cancer with wild-type KRAS.

Phase II study of combination chemotherapy with biweekly cetuximab and irinotecan for wild-type KRAS metastatic colorectal cancer refractory to irinotecan, oxaliplatin, and fluoropyrimidines

The aim of this study was to prospectively evaluate the efficacy of combination irinotecan and cetuximab chemotherapy in patients with pretreated metastatic colorectal cancer harboring wild-type KRAS. Patients with metastatic colorectal cancer that had progressed after chemotherapy with irinotecan, oxaliplatin, and fluoropyrimidine were included. KRAS status was evaluated using the Cycleave PCR method; only patients without KRAS mutations were included. Cetuximab was administered initially at 400 mg/m2 followed by weekly 250 mg/m2 infusions. Irinotecan was administered biweekly. From October 2008 to April 2009, a total of 30 patients were enrolled. The objective response rate was 30.0% (95% confidence interval [CI], 14.7–49.4%) and the disease control rate (complete response, partial response, or stable disease) was 80.0% (95% CI, 61.4–92.3%). Among the 15 patients with stable disease, 11 patients experienced >10% tumor shrinkage. Median progression-free survival was 5.8 months (95% CI, 4.1–7.6). Median overall survival was not reached at a median follow-up of 10.1 months. Grade 2 skin toxicity was observed in 23 patients, while no grade 3 skin toxicity was observed. Combined irinotecan and cetuximab is effective for pretreated metastatic wild-type KRAS colorectal cancer.

Setsuo Utsunomiya

Papers

BRAF mutation is a powerful prognostic factor in advanced and recurrent colorectal cancer

Randomised phase II study comparing dose-escalated weekly paclitaxel vs standard-dose weekly paclitaxel for patients with previously treated advanced gastric cancer.

Phase II study of combination chemotherapy with biweekly cetuximab and irinotecan for wild-type KRAS metastatic colorectal cancer refractory to irinotecan, oxaliplatin, and fluoropyrimidines

Phase II study of combination chemotherapy with irinotecan and cetuximab for pretreated metastatic colorectal cancer harboring wild-type KRAS

Cetuximab for patients with colon cancer and hepatic metastasis complicated by liver dysfunction and icterus.