Prospective observational study of the efficacy of oral uracil and tegafur plus leucovorin for stage II colon cancer with risk factors for recurrence using propensity score matching (JFMC46-1201).

BACKGROUND: The efficacy of adjuvant chemotherapy for high-risk stage II colon cancer (CC) has not been well established. We compared the effects of surgery with and without oral uracil and tegafur plus leucovorin (UFT/LV) in patients with high-risk stage II CC, adjusting for potential risk factors. METHODS: We enrolled patients with histologically confirmed stage II colon adenocarcinoma with at least one of the following conditions: T4 disease, perforation/penetration, poorly differentiated adenocarcinoma/mucinous carcinoma, or < 12 dissected lymph nodes. Patients chose to be non-randomized or randomized to undergo surgery alone (NR-Group S or R-Group S) or surgery followed by 6 months of UFT/LV (NR-Group U or R-Group U). The primary endpoint was disease-free survival (DFS) after adjusting for previously reported risk factors using propensity score matching (1:2) and inverse probability of treatment weighting (IPTW) in the non-randomized arm. RESULTS: Overall, 1,902 (98%) and 36 (2%) patients were enrolled in the non-randomized and randomized arms, respectively. There were too few patients in the randomized arm and these were therefore excluded from the analysis. Of the 1,902 patients, 402 in NR-Group S and 804 in NR-Group U were propensity score-matched. The 3-year DFS rate (95% confidence interval) was significantly higher in NR-Group U (80.9% [77.9%-83.4%]) than in NR-Group S (74.0% [69.3%-78.0%]) (hazard ratio, 0.64 [0.50-0.83]; P = 0.0006). The 3-year overall survival rate was not significantly different between NR-Group S and NR-Group U. Significantly higher 3-year DFS (P = 0.0013) and overall survival (P = 0.0315) rates were observed in NR-Group U compared with NR-Group S using IPTW. CONCLUSIONS: Adjuvant chemotherapy with UFT/LV showed a significant survival benefit over surgery alone in patients with high-risk stage II CC characterized by at least one of the following conditions: T4 disease, perforation/penetration, poorly differentiated adenocarcinoma/mucinous carcinoma, or < 12 dissected lymph nodes. TRIAL REGISTRATION: Japan Registry of Clinical Trials: jRCTs031180155 (date of registration: 25/02/2019) (UMIN Clinical Trials Registry: UMIN000007783 , date of registration: 18/04/2012).

S-1 and Oxaliplatin Versus Tegafur-uracil and Leucovorin as Postoperative Adjuvant Chemotherapy in Patients With High-risk Stage III Colon Cancer (ACTS-CC 02): A Randomized, Open-label, Multicenter, Phase III Superiority Trial.

BACKGROUND: The efficacy of S-1 plus oxaliplatin (SOX) as postoperative adjuvant chemotherapy for colon cancer has not been established. This randomized phase III study was designed to verify the superiority of SOX over tegafur-uracil and leucovorin (UFT/LV) in patients with high-risk stage III colon cancer (any T, N2, or positive nodes around the origin of the feeding arteries). PATIENTS AND METHODS: Patients who underwent curative resection for pathologically confirmed high-risk stage III colon cancer were randomly assigned to receive either UFT/LV (300 mg/m2 of UFT and 75 mg/day of LV on days 1-28, every 35 days, 5 cycles) or SOX (100 mg/m2 of oxaliplatin on day 1 and 80 mg/m2 of S-1 on days 1-14, every 21 days, 8 cycles). The primary endpoint was disease-free survival (DFS). RESULTS: A total of 478 patients in the UFT/LV group and 477 patients in the SOX group were included in the primary analysis. The 3-year DFS was 60.6% (95% confidence interval [CI], 56.0%-64.9%) in the UFT/LV group and 62.7% (95% CI, 58.1%-66.9%) in the SOX group. The stratified hazard ratio for DFS was 0.90 (95% CI, 0.74-1.09; stratified log-rank test, P = .2780). In the N2b subgroup, the 3-year DFS was 46.0% (95% CI, 37.5%-54.0%) in the UFT/LV group and 54.7% (95% CI, 45.7%-62.7%) in the SOX group (hazard ratio, 0.76; 95% CI, 0.55-1.05). CONCLUSION: As postoperative adjuvant chemotherapy, SOX was not superior to UFT/LV in terms of DFS in patients with high-risk stage III colon cancer.

Factors affecting R0 resection of colorectal cancer with synchronous peritoneal metastases: a multicenter prospective observational study by the Japanese Society for Cancer of the Colon and Rectum.

BACKGROUND: In Japan, R0 resection has been recommended for colorectal cancer patients with peritoneal metastases confined to the adjacent peritoneum and those with a few metastases to the distant peritoneum. R0 resection for M1c disease has drawn attention in Western countries and is currently considered an acceptable therapeutic option in the US National Comprehensive Cancer Network guidelines. However, clinical factors that affect the choice of R0 resection are unknown. METHODS: This multicenter, prospective, observational study was conducted by the Japanese Society for Cancer of the Colon and Rectum. Colorectal cancer patients with synchronous peritoneal metastases were enrolled at 28 institutions in Japan from October 2012 to December 2016. To determine factors affecting R0 resection and R1 resection with intended R0 resection, stepwise logistic regression analyses were performed on clinical factors including age, sex, performance status (PS), body mass index, peritoneal cancer index (PCI) score, presence of ascites, presence of distant metastases, and primary tumor site. RESULTS: R0/R1 resection was performed in 36 (31/5; 25%) of 146 patients. No distant metastases [odds ratio (OR) 52.9; 95% confidence interval (CI) 13.3-210.1; p < 0.0001], low PCI score (1-6) (OR 20.0; 95% CI 4.8-83.4; p < 0.0001), and high PS (0) (OR 2.40; 95% CI 0.66-8.68; p = 0.18) were independent factors affecting R0/R1 resection. PCI score and PS were also independent factors affecting R0/R1 resection in M1c patients without non-peritoneal distant metastases (n = 59). CONCLUSION: Distant metastases, PCI score, and PS are three factors which affect R0 resection for M1c disease.

Planned Safety Analysis of the ACTS-CC 02 Trial: A Randomized Phase III Trial of S-1 With Oxaliplatin Versus Tegafur and Uracil With Leucovorin as Adjuvant Chemotherapy for High-Risk Stage III Colon Cancer.

BACKGROUND: This trial was designed to verify the superiority of 6 months of postoperative adjuvant chemotherapy with SOX (S-1 with oxaliplatin) with UFT (tegafur and uracil) with LV (leucovorin) in terms of disease-free survival in patients with high-risk stage III colon cancer. We report the results of a planned safety analysis. PATIENTS AND METHODS: Patients who underwent curative resection for high-risk stage III colon cancer (any T, N2, or positive nodes around the origin of the feeding arteries) were randomly assigned to receive either UFT/LV (300-600 mg/d UFT with 75 mg/d LV on days 1-28, every 35 days, for 5 cycles) or SOX (100 mg/m2 of oxaliplatin on day 1 with 80-120 mg/d S-1 on days 1-14, every 21 days, for 8 cycles). Treatment status and safety were evaluated. RESULTS: A total of 966 patients were enrolled, and 932 patients were included in safety analyses. The planned 6-month protocol treatment was received by 76.9% of the patients in the UFT/LV group and 65.8% of those in the SOX group. The overall incidence of any Grade adverse events (AEs) were 91.3% in the UFT/LV group and 98.7% in the SOX group, and those of Grade ≥ 3 AEs were 16.1% and 36.1%, respectively. As for Grade ≥ 3 AEs, leukopenia, neutropenia, thrombocytopenia, and sensory neuropathy were more common in the SOX group. The incidence of Grade ≥ 3 sensory peripheral neuropathy was 4.6% in the SOX group. CONCLUSION: The completion rate of adjuvant SOX and its incidence of AEs were acceptable in patients with colon cancer.

Efficacy and safety of neoadjuvant chemotherapy with oxaliplatin, 5-fluorouracil, and levofolinate for T3 or T4 stage II/III rectal cancer: the FACT trial.

PURPOSE: A multicenter phase II clinical study was performed in patients with T3 or T4 stage II/III rectal cancer to evaluate the efficacy and safety of neoadjuvant chemotherapy with 5-fluorouracil, levofolinate, and oxaliplatin (mFOLFOX6). METHODS: Patients received four 2-week cycles of mFOLFOX6 therapy (oxaliplatin at 85 mg/m2 + leucovorin at 200 mg/m2 + fluorouracil as a 400 mg/m2 bolus followed by infusion of 2400 mg/m2 over 46 h, all on Day 1). They were evaluated by computed tomography after completion of the fourth cycle. If there was no disease progression, two additional cycles were administered and then surgery was performed. Adjuvant chemotherapy was generally administered for 6 months using appropriate regimens at the discretion of the physician. RESULTS: mFOLFOX6 therapy was given to 52 patients with locally advanced rectal cancer. The preoperative response rate was 48.8% and the operation rate was 80.8%. Serious adverse events of Grade 3-4 were neutropenia (n = 5), leukopenia (n = 1), thrombocytopenia (n = 1), febrile neutropenia (n = 1), nausea (n = 1), vomiting (n = 1), and peripheral neuropathy (n = 2). The R0 resection rate, pathologic complete response rate, and sphincter preservation rate were 91.0, 11.9, and 73.8%, respectively. Postoperative complications were tolerable. CONCLUSIONS: The present results suggested that neoadjuvant therapy with mFOLFOX6 is safe and effective, representing a reasonable treatment option for locally advanced rectal cancer.

A case of gastrojejunocolic fistula with steatohepatitis.

A man in his 30s, who had undergone retrocolic Billroth II reconstruction for perforated duodenal ulcer, presented with watery diarrhea for 2 years and suspected fatty liver. He was referred to our hospital for management of chronic diarrhea, weight loss, hepatopathy and hypoalbuminemia. Initial upper and lower gastrointestinal endoscopies were negative. Since a small bowel lesion was suspected, peroral single-balloon enteroscopy was performed, which identified feces-like residue near the Billroth II anastomotic site and a connection to the colon separate from the afferent and efferent loops. Transanal single-balloon enteroscopy identified a fistula between the gastrojejunal anastomosis and transverse colon, with the scope reaching the stomach transanally. Barium enema confirmed flow of contrast medium from the transverse colon through the fistula to the anastomotic site, allowing the diagnosis of gastrojejunocolic fistula. Liver biopsy showed relatively severe steatohepatitis (Brunt's classification: stage 2-3, grade 3). Resection of the anastomotic site and partial transverse colectomy were performed to remove the fistula, followed by Roux-en-Y reconstruction. Postoperatively, watery diarrhea resolved and the stools became normal. Hepatopathy and hypoproteinemia improved. One year later, liver biopsy showed marked improvement of steatosis. This case demonstrated marked improvement of both diarrhea/nutritional status and steatohepatitis after treatment of gastrojejunocolic fistula, suggesting that the fistula caused non-alcoholic steatohepatitis.

Treatment Rationale and Study Design for Clinical Trial on the Efficacy of UFT/LV for Stage II Colorectal Cancer With Risk Factors for Recurrence (JFMC46-1201).

BACKGROUND: The usefulness of adjuvant chemotherapy for stage II colon cancer has not been established. Meanwhile, the presence of stage II colon cancer with high-risk factors for recurrence has been reported. To our knowledge, no prospective study of adjuvant chemotherapy for stage II colon cancer with high-risk factors has been implemented to date. PATIENTS AND METHODS: This study is a prospective nonrandomized controlled study based on patients' selection of treatment option, including randomized therapeutic decision-making, to evaluate the usefulness of adjuvant chemotherapy with tegafur-uracil (UFT) with leucovorin (LV) for stage II colon cancer with high-risk factors for recurrence, compared with surgery alone. Five courses of UFT/LV therapy will be given as follows: UFT (300 mg/m(2)/d) with LV (75 mg/d) will be orally administered in 3 doses per day. Treatment will be received daily for 28 days, followed by a 7-day rest or will be received daily for 5 days, followed by a 2-day rest. For both regimens, 1 course will last 5 weeks, and 5 courses will be given. The primary end point is disease-free survival. A propensity score matching will be conducted based on 7 variables that represent risk factors to minimize selection bias in a comparison between the nonrandomized arms. For this nonrandomized comparison, a target sample size is set at 1200 (400 and 800 patients for the surgery alone and UFT/LV groups, respectively) and 1720 patients will be enrolled. In this study we aim to evaluate the therapeutic usefulness of adjuvant chemotherapy with UFT/LV for stage II colorectal cancer with risk factors for recurrence.

Case of peritoneal dissemination of colon cancer in which PET/CT was useful in determining the indicated surgical procedure.

The right half of the colon was resected in a 70-year-old woman in August 2002 for ascending colon cancer. The peritoneum was also resected because of metastasis (Stage IV). Since tumor markers gradually increased, positron emission tomography (PET)/ computed tomography (CT) revealed peritoneal dissemination. Abdominal pain appeared 40 months after surgery. Barium enema findings revealed an ileal constriction approximately 25 cm from the anastomosed site toward the anus. Repeat PET/CT revealed peritoneal dissemination coinciding with ileal constriction. CT did not reveal well-defined tumor shadows. The patient was diagnosed with constriction associated with peritoneal metastasis and underwent surgery. Surgical findings revealed a roughly 2-cm peritoneal metastatic focus and ileal constriction. The site was resected and anastomosed. Postoperative progress was favorable; the patient was discharged and enjoys a favorable quality of life through outpatient adjuvant chemotherapy. PET/CT is suggested to be useful in observing the progress of peritoneal dissemination and may be of assistance in determining the course of treatment.