Megumi Ishiguro

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

Colorectal cancer is a major cause of death in Japan, where it accounts for the largest number of deaths from malignant neoplasms among women and the third largest number among men. Many new methods of treatment have been developed during recent decades. The Japanese Society for Cancer of the Colon and Rectum Guidelines 2014 for treatment of colorectal cancer (JSCCR Guidelines 2014) have been prepared as standard treatment strategies for colorectal cancer, to eliminate treatment disparities among institutions, to eliminate unnecessary treatment and insufficient treatment, and to deepen mutual understanding among health-care professionals and patients by making these guidelines available to the general public. These guidelines have been prepared as a result of consensuses reached by the JSCCR Guideline Committee on the basis of careful review of evidence retrieved by literature searches and taking into consideration the medical health insurance system and actual clinical practice in Japan. They can, therefore, be used as a guide for treating colorectal cancer in clinical practice. 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 of 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, on the basis of consensus reached by Guideline Committee members. Here we present the English version of the JSCCR Guidelines 2014.

Potential Prognostic Benefit of Lateral Pelvic Node Dissection for Rectal Cancer Located Below the Peritoneal Reflection

Objective:To identify the parameters related to the effective selection of patients who could receive prognostic benefit from lateral pelvic node dissection. Background:Accurate preoperative diagnosis of lateral nodal involvement (LNI) remains difficult, and the indications for lateral lymph node dissection have been controversial. Patients and Methods:A total of 244 consecutive patients who underwent potentially curative surgery with lateral dissection for advanced lower rectal cancer (1985–2000) were reviewed. Patients were stratified into groups based on various parameters, and the therapeutic value index for survival benefit was compared among groups. The therapeutic index of lateral dissection was calculated by multiplying the frequency of metastasis to the lateral area and the cancer-related 5-year survival rate of patients with metastasis to the lateral area, irrespective of metastasis to other areas (mesorectal, superior rectal artery [SRA], and inferior mesenteric artery [IMA] areas). Results:LNI was observed in 41 patients (17%); and 88% of them had nodal involvement in the region along the internal iliac/pudendal artery or in the obturator region (“vulnerable field”). The cancer-related 5-year survival rate among the patients with LNI was 42%; the therapeutic index for lateral dissection was calculated as 7.0 patients, which was much higher than that of lymphadenectomy of the SRA area (1.6 patients) and the IMA area (0.4 patients), and almost comparable to that of lymphadenectomy of the upward mesorectal area (6.9 patients). Although it was possible to select groups at high and low risk for LNI based on several parameters related to tumor aggressiveness, such as tumor differentiation in biopsy specimens, the therapeutic value index was not significantly different between these groups. Unlike these parameters, the diameter of the largest lymph node in the “vulnerable field,” which was positively correlated with the rate of LNI but irrelevant to the prognosis, was able to successfully stratify patients by therapeutic index. Conclusions:Advanced lower rectal cancer patients having LNI in the lateral pelvic area are likely to receive prognostic benefit from lymphadenectomy. The most efficient means of determining the effectiveness of lateral dissection preoperatively is to estimate the nodal diameter in the “vulnerable” lateral regions by diagnostic imaging.

Clinical Significance of Osteoprotegerin Expression in Human Colorectal Cancer

Purpose: This study aimed to identify a novel biomarker or a target of treatment for colorectal cancer (CRC). Experimental Design: The expression profiles of cancer cells in 104 patients with CRC were examined using laser microdissection and oligonucleotide microarray analysis. Overexpression in CRC cells, especially in patients with distant metastases, was a prerequisite to select candidate genes. The mRNA expression of candidate genes was investigated by quantitative reverse transcriptase PCR (RT-PCR) in 77 patients as a validation study. We analyzed the protein expression and localization of the candidate gene by immunohistochemical study and investigated the relationship between protein expression and clinicopathologic features in 274 CRC patients. Results: Using microarray analysis, we identified 6 candidate genes related to distant metastases in CRC patients. Among these genes, osteoprotegerin (OPG) is known to be associated with aggressiveness in several cancers through inhibition of apoptosis via neutralization of the function of TNF-related apoptosis-inducing ligand. The mRNA expression of OPG in cancer tissues was significantly higher in patients with distant metastases than those without metastases. Overexpression of OPG protein was associated with significantly worse overall survival and relapse-free survival. Moreover, overexpression of the OPG protein was an independent risk factor for CRC recurrence. Conclusion: Overexpression of OPG may be a predictive biomarker of CRC recurrence and a target for treatment of this disease. Clin Cancer Res; 17(8); 2444–50. ©2011 AACR.

Methylation of BNIP3 and DAPK indicates lower response to chemotherapy and poor prognosis in gastric cancer

Aberrant promoter hypermethylation (methylation) is an epigenetic change that silences the expression of crucial genes, thus inactivating the apoptotic pathway in various cancers. Inactivation of the apoptotic pathway has been considered to be associated with chemoresistance. The objective of the present study was to clarify the effect of the methylation of the apoptosis-related genes, Bcl-2/adenovirus E1B 19 kDa-interacting protein 3 (BNIP3) and death-associated protein kinase (DAPK), on the response to chemotherapy in metastatic or recurrent gastric cancers. Tumor samples were obtained from 80 gastric cancer patients who were treated with fluoropyrimidine-based chemotherapy for distant metastatic or recurrent disease, after surgical resection of the primary tumor. The methylation status of the apoptosis-related genes, BNIP3 and DAPK, was investigated by methylation-specific PCR. Methylation in BNIP3 was detected in 31 tumors (39%) and in DAPK in 33 tumors (41%). There was no correlation between the methylation status of BNIP3 and that of DAPK. The response rate was significantly lower in patients with methylation of DAPK, than in those without (21 vs. 49% p=0.012). Progression-free survival time (PFS) was shorter in patients with methylation of DAPK than in those without (p=0.007). The overall survival time (OS) was shorter in patients with methylation of BNIP3 than in those without (p=0.031). The response rate was significantly lower in patients with methylation of either DAPK or BNIP3, or both, than in those without methylation (p=0.003). PFS and OS were significantly shorter in patients with methylation of either or both of these genes than in those without (p=0.002, p=0.001). The methylation of BNIP3 and DAPK can predict lower response to chemotherapy and poor prognosis in gastric cancer.

S-1 as adjuvant chemotherapy for stage III colon cancer: a randomized phase III study (ACTS-CC trial)

BACKGROUND S-1 is an oral fluoropyrimidine whose antitumor effects have been demonstrated in treating various gastrointestinal cancers, including metastatic colon cancer, when administered as monotherapy or in combination chemotherapy. We conducted a randomized phase III study investigating the efficacy of S-1 as adjuvant chemotherapy for colon cancer by evaluating its noninferiority to tegafur-uracil plus leucovorin (UFT/LV). PATIENTS AND METHODS Patients aged 20-80 years with curatively resected stage III colon cancer were randomly assigned to receive S-1 (80-120mg/day on days 1-28 every 42 days; four courses) or UFT/LV (UFT: 300-600mg/day and LV: 75mg/day on days 1-28 every 35 days; five courses). The primary end point was disease-free survival (DFS) at 3 years. RESULTS A total of 1518 patients (758 and 760 in the S-1 and UFT/LV group, respectively) were included in the full analysis set. The 3-year DFS rate was 75.5% and 72.5% in the S-1 and UFT/LV group, respectively. The stratified hazard ratio for DFS in the S-1 group compared with the UFT/LV group was 0.85 (95% confidence interval: 0.70-1.03), demonstrating the noninferiority of S-1 (noninferiority stratified log-rank test, P < 0.001). In the subgroup analysis, no significant interactions were identified between the major baseline characteristics and the treatment groups. CONCLUSION Adjuvant chemotherapy using S-1 for stage III colon cancer was confirmed to be noninferior in DFS compared with UFT/LV. S-1 could be a new treatment option as adjuvant chemotherapy for colon cancer. CLINICALTRIALS.GOV: NCT00660894.This phase III study, ACTS-CC, is the first study in which demonstrated the efficacy of S-1, an oral fluoropyrimidine, as adjuvant chemotherapy for stage III colon cancer by confirming its noninferiority to UFT/LV in terms of disease-free survival. S-1 could be a new treatment option as adjuvant chemotherapy for colon cancer.

Identification of NUCKS1 as a colorectal cancer prognostic marker through integrated expression and copy number analysis

We identified a novel prognostic biomarker for the distant metastasis of colorectal cancer (CRC) using comprehensive combined copy number and gene expression analyses. Expression of mRNA in CRC tissue was profiled in 115 patients using an Affymetrix Gene Chip, and copy number profiles were generated for 122 patients using an Affymetrix 250K Sty array. Genes showing both upregulated expression and copy number gains in cases involving distant CRC metastasis were extracted as candidate biomarkers. Expression of the candidate gene mRNA was validated in 86 patients using quantitative reverse transcription polymerase chain reaction assays. Expression of the protein encoded by the candidate gene was assessed using immunohistochemical staining of tissue from 269 patients. The relationship between protein expression and clinicopathologic features was also examined. Following combined copy number and gene expression analyses, three genes linked to distant metastasis of CRC were extracted as candidate biomarkers. The expression of NUCKS1, reportedly overexpressed in several cancers other than CRC, was significantly higher in CRC tissue than in normal tissue. Overexpression of the NUCKS1 protein in CRC cells was found to be associated with significantly worse overall survival and relapse‐free survival, indicating that NUCKS1 is an independent risk factor for CRC recurrence. The overexpression of NUCKS1 in cancer cells could be used as a CRC prognostic marker and might also be a target for treatment of this disease.

Effect of Combined Therapy With Low-Dose 5-Aza-2′-Deoxycytidine and Irinotecan on Colon Cancer Cell Line HCT-15

BackgroundAberrant promoter hypermethylation is an epigenetic change that silences the expression of crucial genes, resulting in inactivation of the apoptotic pathway in various cancers. This hypermethylation can be restored by the demethylating agent 5-aza-2′-deoxycytidine (DAC). DAC might increase the tumor sensitivity to chemotherapy through demethylation and restoration of gene expression. We investigated the effect of combined therapy with DAC and irinotecan (CPT-11) on the human colon cancer cell line HCT-15.MethodsHuman colon cancer cell line HCT-15 was treated with DAC and/or CPT-11 both in vitro and in vivo. The changes in mRNA expression of several apoptosis-related genes were investigated by reverse transcriptase–polymerase chain reaction (PCR). Promoter methylation was detected by methylation-specific PCR and combined bisulfite restriction analysis. Suppression of tumor growth was observed during the treatment with DAC and/or CPT-11 and apoptosis in the tumors was investigated by TUNEL (terminal deoxynucleotidyl transferase dUTP nick-end labeling) assay.ResultsPromoter methylation of p14ARF, p16INK4a, BNIP3, and XAF1 was confirmed, and DAC restored mRNA expression of these genes. Demethylation and restoration of gene expression was observed with low-dose DAC, and demethylation status was sustained for several weeks. Combined therapy with DAC and CPT-11 produced marked suppression in tumor growth compared with DAC or CPT-11 alone, both in vitro and in vivo.ConclusionsPretreatment with low-dose DAC may have the potential to be used as a “biosensitizer” of DNA-damaging agents such as CPT-11 when the apoptotic pathway is inactivated as a result of aberrant promoter methylation in the cancer.

Histological grading of colorectal cancer: a simple and objective method.

Objective:Tumor grade employed for colorectal cancer has long been based on the degree of differentiation, which is difficult to judge objectively. The aim of this study was to determine whether the extent of the poorly differentiated component (POR) could be a valuable criterion for a grading system. Patients and Methods:A total of 1075 patients with advanced colorectal cancer were pathologically reviewed. POR was newly defined as a region in which a cancer has no glandular formation, irrespective of a mucin-producing or invasive pattern, and we quantitatively classified the POR into 6 degrees using the microscopic field of an objective lens as a standard. Results:Survival analyses of the extent of POR demonstrated that a 3-category grading system provides the most efficient survival stratification. Grade III was applied to tumors (n = 339) for which the POR fully occupied the microscopic field of a 40× objective lens. For tumors having a smaller POR, cancer clusters without a gland structure composed of ≥5 cancer cells (“clusters”) were counted in the microscopic field of a 4× objective lens, where “clusters” were observed most intensively. Tumors with <10 “clusters” were classified as grade I (n = 161), and those with ≥10 “clusters” as grade II (n = 575). Patients classified as grade I demonstrated a very favorable prognosis, with a 99.3% cancer-related 5-year survival rate, whereas the survival was 86.0% for grade II and 68.9% for grade III (P < 0.0001 in each group). Multivariate analysis demonstrated that the grades of POR function as an independent prognosticator, as do T-stage and N-stage. Conclusions:The grading system utilizing POR is distinctive in terms of the simplicity of judgment based on its quantification and the ability to determine which patients will likely be cured by surgery alone. It will aid in selecting postoperative treatment strategies.

Validation and Clinical Use of the Japanese Classification of Colorectal Carcinomatosis: Benefit of Surgical Cytoreduction Even without Hyperthermic Intraperitoneal Chemotherapy

Background: This study aimed to validate an easy to use practical classification of peritoneal metastasis arising from colorectal cancer. Patients and Methods: Data from 2,134 consecutive patients who underwent resection for colorectal cancer at a single institution were reviewed. Peritoneal metastasis was classified depending on extent into three groups (P1–P3). The macroscopic radical resection rates and survival of patients with colorectal cancer complicated with peritoneal metastasis were analyzed. Results: Of the 2,134 patients, 116 (5.4%) had peritoneal metastasis. Among them, 20 (17.2%) underwent macroscopic radical resection. Tumor location on the right side was associated with more extensive peritoneal metastasis (p = 0.010). Male gender (p = 0.0027), liver metastasis (p = 0.0021), and P3 peritoneal metastasis were independent risk factors for noncurative resection. The Cox proportional hazards model showed that gender (p = 0.031), operation period (p = 0.031), and macroscopic radical resection for colorectal cancer and peritoneal metastasis (p = 0.031) were independent prognostic factors. Conclusions: Being female with left colon cancer complicated with P1 or P2 peritoneal metastasis is a good indicator for macroscopic radical resection if liver metastasis is absent. The present classification helped to determine surgical indication for patients with colorectal cancer complicated with synchronous peritoneal metastasis in routine clinical practice.

Clinical Significance of Lymph Node Ratio and Location of Nodal Involvement in Patients with Right Colon Cancer

Background/Aims: Increasing negative lymph node count has been reported to be associated with better outcomes in patients with colon cancer. The present study aimed to clarify the clinical significance of the lymph node ratio (LNR) and location of lymph node metastasis (LNM) in patients with stage III right colon cancer. Methods: We enrolled 820 patients who had undergone curative resection due to colon cancer at a single institution between 1991 and 2005. Among them, 197 underwent curative resection for T2–T4 right colon cancer. We evaluated the oncological outcomes according to LNR (quartiles) and distribution of LNM (n1 = LNM adjacent to the colon or along the vascular arcades of the marginal arteries; n2 = LNM along the major vessels; n3 = LNM near the roots of the major vessels). Results: The rates of LNM in T2, T3 and T4 right colon cancer were 11.1, 38.6 and 58.0%, respectively (p < 0.0001). Recurrence rates were 27.3, 37.5 and 57.1% in patients with n1, n2 and n3 LNM, respectively (p < 0.0001). LNR (p < 0.0001) and distribution of LNM (p = 0.046) were independent risk factors for recurrence in patients with stage III right colon cancer. Conclusions: Some patients with extensive LNM benefited from lymph node dissection with high ligation. Those with T3–T4 right colon cancer are suitable candidates for lymph node dissection with high ligation. Adding the concept of LNR and location of LNM to conventional TNM staging could improve the accuracy of evaluating nodal status.