Shigeki Yamaguchi

Randomised phase III trial of adjuvant chemotherapy with oral uracil and tegafur plus leucovorin versus intravenous fluorouracil and levofolinate in patients with stage III colorectal cancer who have undergone Japanese D2/D3 lymph node dissection: final results of JCOG0205.

BACKGROUND NSABP C-06 demonstrated the non-inferiority of oral adjuvant uracil and tegafur plus leucovorin (UFT/LV) to weekly fluorouracil and folinate (5-FU/LV) with respect to disease-free survival (DFS) for stage II/III colon cancer. This is the first report of JCOG0205, which compared UFT/LV to standard 5-FU/levofolinate (l-LV) for stage III colorectal cancer patients who have undergone Japanese D2/D3 lymph node dissection. METHODS Patients were randomised to three courses of 5-FU/l-LV (5-FU 500 mg/m(2), l-LV 250 mg/m(2) on days 1, 8, 15, 22, 29, 36 every 8 weeks) or five courses of UFT/LV (UFT 300 mg m(-2)day(-1), LV 75 mg/day on days 1-28 every 5 weeks). The primary end-point was DFS. The sample size was 1100 determined with one-sided alpha of 0.05, power of 0.78 and non-inferiority margin of hazard ratio of 1.27. This trial is registered with UMIN-CTR (C000000193). FINDINGS Between February 2003 and November 2006, 1,101 patients (1092 eligible patients) were randomised to 5-FU/l-LV (n=550) or UFT/LV (n=551). Median age: 61 years, colon/rectum: 67%/33%, number of positive nodes ⩽3/>3: 73%/27%, stage IIIa/IIIb: 75%/25%. The hazard ratio of DFS was 1.02 (91.3% confidence interval, 0.84-1.23), demonstrating the non-inferiority of UFT/LV (P=0.0236). Five-year overall survival (87.5%) was higher than that in NSABP C-06 (69.6%). Grade 3/4 toxicities were 8.4% neutropenia in 5-FU/l-LV and 8.7% alanine aminotransferase elevation in UFT/LV, respectively. The incidences of diarrhoea (9.6% versus 8.5%) and anorexia (4.0% versus 3.7%) were similar between the two arms. No treatment-related deaths were reported. INTERPRETATION Adjuvant UFT/LV is non-inferior to standard 5-FU/l-LV with respect to DFS. UFT/LV should be an oral treatment option for patients with stage III colon cancer who have undergone Japanese D2/D3 lymph node dissection.

Laparoscopic surgery for stage 0/I rectal carcinoma: short-term outcomes of a single-arm phase II trial.

Background and Objectives: To examine the technical and oncological feasibility of laparoscopic surgery for rectal carcinoma, we conducted a single-arm phase II trial to evaluate laparoscopic surgery for stage 0/I rectal carcinoma, and short-term surgical outcomes were evaluated. Methods: Accredited surgeons from 43 institutions in Japan participated in the study. Eligibility criteria included histologically proven rectal carcinoma; clinical stage 0/I; tumor size 8 cm or smaller; patient age 20 to 75 years; no bowel obstruction; and written informed consent. Patients were registered preoperatively. The planned sample size was 490. Surgical outcomes were evaluated. Results: A total of 495 patients were registered between February 2008 and August 2010. Five patients were ineligible after registration. Conversion to open surgery was needed for 8 (1.6%) patients. Sphincter-preserving procedures were performed in 477 (97%) patients. Median operative time was 270 minutes, and median blood loss was 28 mL. Postoperative median intervals until liquid and solid intake were 1 and 3 days, respectively, and the median postoperative hospital stay was 12 days. The positive resection margin rate was 0.4% (2/490), and 68.6% (336/490) of the patients were graded stage 0/I. There were no perioperative mortalities. Twenty-four intraoperative and 160 postoperative complications occurred, and the morbidity rate was 23.9% (117/490). The anastomotic leakage rate in patients who underwent anterior resection was 8.3% (33/400), and that in patients who underwent intersphincteric resection was 9.1% (7/77). Nineteen (3.9%) patients underwent reoperation. Conclusions: Technically, laparoscopic surgery can be used for safe and radical resection of clinical stage 0/I rectal carcinoma. (ClinicalTrials.gov No. NCT00635466.)

Development and validation of a modified fecal incontinence quality of life scale for Japanese patients after intersphincteric resection for very low rectal cancer

PurposeFecal incontinence is a frequently observed symptom after lower rectal surgery with sphincter manipulation. The aim of this study was to evaluate a proposed modification to the fecal incontinence quality of life (FIQL) scale for the assessment of the quality of life among patients with very low rectal cancer who have undergone intersphincteric resection.MethodsA single 14-item composite scale was prepared that was derived from items in the “Lifestyle” and “Coping” subscales of the original FIQL. The scale was tested with a convenience sample of 152 postoperative patients. In addition to classic psychometric evaluation, newer statistical techniques, such as a multiple correspondence analysis and partial credit model, were performed to evaluate the item response patterns.ResultsThe proposed scale exhibited an item-rest correlation of 0.66–0.84 and a Cronbach’s alpha of 0.96, and was correlated with concurrently measured Social Functioning subscale of the Medical Outcomes Study Short Form 36 (−0.70), physical role limitation (−0.61), and Wexner continence grading scale (−0.61). Multiple correspondence analysis supported a uni-dimensional construct, and the partial credit model showed a varying yet overlapping range of item response thresholds across items. Several items, such as “Locating bathroom whenever going out”, reflected more a serious condition than items such as “Avoiding eating-out.” Weighted item scores based on estimated thresholds provided results comparable with those based on non-weighted scores.ConclusionsThe proposed modification to the FIQL scale exhibited high internal consistency and satisfactory concurrent and convergence validity. The modified scale is practical to administer and is sensitive to a range of functional problems associated with fecal incontinence among patients who have undergone intersphincteric resection.

Magnitude of serosal changes predicts peritoneal recurrence of gastric cancer

BACKGROUND Peritoneal dissemination is the most frequent mode of recurrence in patients with gastric cancer. We tried to identify factors that predict peritoneal recurrence with high sensitivity. STUDY DESIGN Clinical and pathologic data from 587 consecutive patients with gastric cancer were reviewed retrospectively. The stepwise Cox proportional hazards regression model was used to assess the prognostic significance of the magnitude of serosal changes. Multiple stepwise logistic regression analysis was used to determine factors associated with peritoneal recurrence in 375 patients who underwent curative resection. RESULTS The 5-year survival rate of patients with S2 disease (greatest dimension of macroscopic serosal changes >/= 2.5 cm) was 18%, which was worse than S0 (no serosal changes) and S1 disease (macroscopic serosal changes < 2.5 cm)(p < 0.001). Patients with S0 tumors who underwent curative resection had the best 5-year survival rate. Multivariate analyses indicated that the magnitude of serosal changes was an independent prognostic factor for survival both overall and after curative resection. Logistic regression analysis showed that peritoneal recurrence was more than four times as likely with S2 than with S0 or S1 tumors. The sensitivity for predicting peritoneal recurrence was 79%; the sensitivity of cytologic examination was 38%. CONCLUSIONS Magnitude of serosal changes is easy to measure intraoperatively and predicts peritoneal recurrence of gastric cancer with greater sensitivity than conventional peritoneal lavage cytology.

Analysis of HLA‐A24‐restricted peptides of carcinoembryonic antigen using a novel structure‐based peptide‐HLA docking algorithm

Carcinoembryonic antigen (CEA) is a very common tumor marker because many types of solid cancer usually produce a variety of CEA and a highly sensitive measuring kit has been developed. However, immunological responses associated with CEA have not been fully characterized, and specifically a weak immunogenicity of CEA protein as a tumor antigen is reported in human leukocyte antigen (HLA)‐A24‐restricted CEA peptide‐based cancer immunotherapy. These observations demonstrated that immunogenic and potent HLA‐A24‐restricted CTL epitope peptides derived from CEA protein are seemingly difficult to predict using a conventional bioinformatics approach based on primary amino acid sequence. In the present study, we developed an in silico docking simulation assay system of binding affinity between HLA‐A24 protein and A24‐restricted peptides using two software packages, AutoDock and MODELLER, and a crystal structure of HLA‐A24 protein obtained from the Protein Data Bank. We compared the current assay system with HLA–peptide binding predictions of the bioinformatics and molecular analysis section (BIMAS) in terms of the prediction capability using MHC stabilization and peptide‐stimulated CTL induction assays for CEA and other HLA‐A24 peptides. The MHC stabilization score was inversely correlated with the affinity calculated in the docking simulation alone (r = −0.589, P = 0.015), not with BIMAS score or the IFN‐γ production index. On the other hand, BIMAS was not significantly correlated with any other parameters. These results suggested that our in silico assay system has potential advantages in efficiency of epitope prediction over BIMAS and ease of use for bioinformaticians. (Cancer Sci 2011; 102: 690–696)

Genome-wide association study identifies candidate loci associated with postoperative fentanyl requirements after laparoscopic-assisted colectomy

AIMS Opioids are widely used as effective analgesics, but opioid sensitivity is well known to vary widely among individuals and the underlying genetic factors are not fully understood, thus hampering efficient pain treatment. We explored the genetic factors that contribute to individual differences in opioid sensitivity by performing a genome-wide association study. METHODS We conducted a multistage genome-wide association study in subjects who underwent laparoscopic-assisted colectomy (LAC). RESULTS A nonsynonymous SNP in the LAMB3 gene region, rs2076222, was strongly associated with postoperative opioid requirements. The C allele of this best-candidate SNP was associated with lower opioid sensitivity and/or higher pain sensitivity in the patient subjects. CONCLUSION Our findings provide valuable information for personalized pain treatment after LAC, in which the C allele of the rs2076222 SNP is associated with lower opioid sensitivity and requires more opioid analgesic after LAC.

Does transumbilical incision increase incisional hernia at the extraction site of laparoscopic anterior resection

BACKGROUND It is unclear whether transumbilical incision for laparoscopic colectomy has a risk of incisional hernia at the extraction site similar to left lower incision. METHODS Consecutive patients who underwent laparoscopic sigmoid plus high and low anterior resection between August 2008 and February 2011 were included in the study. Incision for specimen extraction was changed from left lower to transumbilical incision in February 2010. The main outcome was the incidence of incisional hernia diagnosed by computed tomography. RESULTS One hundred and eighty-six patients underwent laparoscopic anterior resection (94 transumbilical incisions and 92 left lower transverse incisions). Three percent of patients had an incisional hernia at the extraction site, and the incidence of this phenomenon was not significantly different between the 2 groups. Surgical wound infection was lower in the transumbilical incision group than in the left lower incision group. CONCLUSIONS Extraction site for transumbilical incision may not affect the risk of incisional hernia.

Current therapeutic strategies for anal squamous cell carcinoma in Japan

BackgroundIn Western countries, chemoradiotherapy (CRT) is well established as the standard therapy for stages II/III anal squamous cell carcinoma (ASCC). In Japan, the therapeutic modalities for and outcomes of this disease have not been clarified because ASCC is quite rare. The Colorectal Cancer Study Group of the Japan Clinical Oncology Group (JCOG-CCSG) conducted a survey to determine the current therapeutic strategies for ASCC in Japan.MethodsIn July 2006, a questionnaire was sent to 49 institutions affiliated with the JCOG-CCSG to gather information on numbers of cases, therapeutic modalities, and outcomes. The target subjects were patients with stages II/III ASCC, diagnosed from January 2000 to December 2004, who were 20–80 years of age with normal major organ function and no severe complications.ResultsReplies were received from 40 institutions. A total of 59 patients satisfied the subject criteria. Detailed information was obtained for 55 subjects; 25 (45%) had stage II ASCC and 30 (55%) had stage III ASCC. CRT was performed in 25 patients (45%); surgery in 17 (31%); surgery combined with radiotherapy (RT), chemotherapy, or CRT in 8 (15%); and RT in 5 (9%). Complete response rate in CRT was 80% (20/25). The 3-year progression-free survival rates for all subjects and for CRT-only subjects were 67% and 77%, respectively.ConclusionFrom 2000 to 2004, only 59 patients with ASCC were identified in the JCOG-CCSG survey and about half of them underwent CRT.

Inferior oncological prognosis of surgery without oral chemotherapy for stage III colon cancer in clinical settings

BackgroundCancer patients not admissible for adjuvant chemotherapy are generally at high risk of considerably inferior prognosis. The aim of this retrospective study was to evaluate poorer survival without administration of oral adjuvant chemotherapy of stage III colon cancer patients in clinical settings.MethodsBetween April 2007 and September 2011, 259 patients with stage III colon cancer who underwent curative surgery were retrospectively assigned to the adjuvant chemotherapy group of 171 patients (66%) and the surgery alone group of 88 patients. Oral fluorouracil (5-FU) derivatives used in adjuvant chemotherapy, such as oral uracil and tegafur plus leucovorin (UFT/LV) or capecitabine, were the most commonly used.ResultsThe 3-year relapse-free survival (RFS) rates were 74.9% for all cases, 58.3% for the surgery alone group, and 83.4% for the adjuvant chemotherapy group (P = 0.0001). The chemotherapy group was associated with a dramatic improvement in survival for stage IIIB (surgery alone 57.7% versus adjuvant chemotherapy 83.9%; P = 0.0001) and stage IIIC (surgery alone 18.2% versus adjuvant chemotherapy 57.3%; P = 0.006) patients. There was a significant difference in the overall recurrence rate between groups (surgery alone 35.2% versus adjuvant chemotherapy 18.1%; P = 0.002). Multivariate analysis identified adjuvant therapy as an independent predictive factor of reduced recurrence (hazard ratio (HR): 3.231; P = 0.004) and improved RFS (HR: 2.653; P = 0.001).ConclusionIn clinical settings, adjuvant therapy was the only significant prognostic factor of survival. Since many patients prefer not to receive chemotherapy, it is critical to inform stage III colon cancer patients that chemotherapy raises their chances of survival by three-fold compared with curative surgery alone.

A Randomized Controlled Trial Comparing Laparoscopic Surgery with Open Surgery in Palliative Resection of Primary Tumor in Incurable Stage IV Colorectal Cancer: Japan Clinical Oncology Group Study JCOG 1107 (ENCORE Trial)

A randomized controlled trial was started in Japan to evaluate the non-inferiority of overall survival of laparoscopic surgery to open surgery for palliative resection of primary tumor in incurable Stage IV colorectal cancer. Symptomatic, Stage IV colorectal cancer patients with non-curable metastasis are pre-operatively randomized to either open or laparoscopic colorectal resection. Surgeons in 56 specialized institutions will recruit 450 patients. The primary endpoint is overall survival. Secondary endpoints are progression-free survival, the proportion of conversion from laparoscopic surgery to open surgery, the proportion of patients who fulfill the criteria of starting chemotherapy by 6 weeks after operation, intraoperative and post-operative complications, adverse events during chemotherapy and serious adverse events.