The Conventional Technique Versus the No-touch Isolation Technique for Primary Tumor Resection in Patients With Colon Cancer (JCOG1006): A Multicenter, Open-label, Randomized, Phase III Trial.

OBJECTIVE: This phase III trial evaluated whether the no touch was superior to the conventional in patients with cT3/T4 colon cancer. BACKGROUND: No touch involves ligating blood vessels that feed the primary tumor to limit cancer cell spreading. However, previous studies did not confirm the efficacy of the no touch. METHODS: This open-label, randomized, phase III trial was conducted at 30 Japanese centers. The eligibility criteria were histologically proven colon cancer; clinical classification of T3-4, N0-2, andM0; and patients aged 20 to 80years. Patients were randomized (1:1) to undergo open surgery with conventional or the no touch. Patients with pathological stage III disease received adjuvant capecitabine chemotherapy. The primary endpoint was disease-free survival (DFS) according to the intention-to-treat principle. RESULTS: Between January 2011 and November 2015, 853 patients were randomized to the conventional group (427 patients) or the no touch group (426 patients). The 3-year DFS were 77.3% [95% confidence interval (CI) 73.1%-81.0%] and 76.2% (95% CI 71.9%-80.0%) in the conventional and no touch groups, respectively. The superiority of no touch was not confirmed: hazard ratio for DFS = 1.029 (95% CI 0.800- 1.324; 1-sided P = 0.59). Operative morbidity was observed in 31 of 427 conventional patients (7%) and 26 of 426 no touch patients (6%). All grade adverse events were similar between the conventional and no touch groups. No in-hospital mortality occurred in either group. CONCLUSION: The present study failed to confirm the superiority of the no touch.

Cost-effectiveness of 12 months of capecitabine as adjuvant chemotherapy for stage III colon cancer: preplanned cost-effectiveness analysis of the JFMC37-0801 study.

OBJECTIVES: We evaluated the cost-effectiveness of a 12-month regimen of oral capecitabine versus a standard 6-month regimen as postoperative adjuvant chemotherapy for stage III colon cancer. METHODS: We utilized patient-level data from a multi-institutional randomized controlled trial (JFMC37-0801) that investigated prolonged oral fluoropyrimidine monotherapy. The analysis considered three health states: stable disease, post-metastasis, and death. A parametric statistical model with a cure model was used to estimate the survival curve. The analysis was conducted from the Japanese public healthcare payer's perspective, considering only direct medical costs. A lifetime horizon was used, with a discount rate of 2% for both cost and health outcomes. Health outcomes were evaluated in terms of quality-adjusted life-years (QALYs). RESULTS: The estimated cure rates for colon cancer were 0.726 [95% confidence interval (CI) 0.676-0.776] and 0.694 (95% CI 0.655-0.733) with the 12- and 6-month regimens, respectively; and the estimated 5-year relapse-free survival rates were 74.4% and 69.8%, respectively. The estimated lifetime cost for 12 months of capecitabine was JPY 3.365 million (USD 31,159), compared with JPY 3.376 million (USD 31,262) for 6 months. The estimated QALY were 12.48 and 11.77 for the 12- and 6-month regimens, respectively. Thus, the 12-month capecitabine regimen was dominant. Using a willingness-to-pay threshold of JPY 5 million per QALY, we determined a 97.4% probability that the 12-month capecitabine regimen is more cost-effective than the 6-month regimen. CONCLUSIONS: Twelve months of capecitabine is the favorable option for postoperative adjuvant chemotherapy for stage III colon cancer from the perspective of cost-effectiveness.

Evaluation of FOLFOX or CAPOX reintroduction with or without bevacizumab in relapsed colorectal cancer patients treated with oxaliplatin as adjuvant chemotherapy (REACT study).

BACKGROUND: Chemotherapy in relapsed colorectal cancer patients treated with oxaliplatin as adjuvant chemotherapy is under debate. REACT study aimed to investigate the efficacy of reintroducing modified FOLFOX6 (mFOLFOX6) or CAPOX with or without bevacizumab in recurrent colorectal cancer patients after oxaliplatin adjuvant chemotherapy. METHODS: Patients that participated in this trial had a medical history of adjuvant chemotherapy, including oxaliplatin with a cumulative dose greater than 400 mg/m2, and recurrence that was diagnosed more six months post adjuvant chemotherapy. Primary endpoints were response rate (RR) and disease control rate (DCR), while key secondary endpoints were time to treatment failure (TTF), progression-free survival (PFS), overall survival (OS), and safety. RESULTS: A total of 31 patients were enrolled between October 2012 and October 2016. Of the 29 eligible patients, 7 received mFOLFOX6 and 22 received CAPOX. The RR was 62.1% (95% confidence interval 42.3-79.3) and the DCR was 82.8% (95% confidence interval 64.2-94.2). The RR for oxaliplatin-free interval was 100.0% in months 6-12 and 56.0% after 12 months. Median TTF, PFS, and OS were 6.3, 10.8, and 28.7 months, respectively. Grade 3 or worse peripheral sensory neuropathy developed in 6.5%. Allergic reactions occurred in 12.9% of the patients, with one (3.2%) grade 3 episode. There were no other severe treatment-related adverse events. CONCLUSION: Reintroduction of oxaliplatin was feasible and achieved high RR or DCR in patients after more than 6 months post oxaliplatin adjuvant chemotherapy.

A patient-derived xenograft and a cell line derived from it form a useful preclinical model for small bowel adenocarcinoma.

Basic and clinical studies on small bowel adenocarcinoma (SBA) are limited due to the rare nature of this cancer. We established a patient-derived xenograft (PDX) model from the tumor tissue of an advanced SBA patient with liver and peritoneal metastasis, and a cell line from the PDX. In the PDX model, compared to the control group, 5-fluorouracil (5-FU) treatment resulted in statistically significant tumor growth inhibition (TGI), while oxaliplatin (OHP) and irinotecan had no significant inhibitory effects. In combination with 5-FU, OHP showed the highest rate of TGI. The IC50 for OHP was significantly lower than those for paclitaxel, gemcitabine, and trifluorothymidine in the PDX-derived cell line when compared to in HT29, a colon cancer cell line. Genetic analysis of the patient tumor, PDX tumor, and the cell line demonstrated consistency in the microsatellite status and mutations in TP53, APC, HRAS, CSF1R, FGFR3, FLT3, PDGFRA, and RET genes. However, the PDX tumor alone had additional mutations, indicating that the PDX-derived cell line may support the unstable genetic status of the PDX. Our findings confirmed the effectiveness of the combination of OHP and 5-FU, which is a common treatment for advanced SBA and advanced colorectal cancer, in a preclinical model. This preclinical model of SBA can help in further understanding the biology of SBA.

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.

[Diagnosis of duplication of the sigmoid colon prior to surgery:a case study].

A 16-year-old woman identified with colonic distention using chest X-rays visited our hospital. Although abdominal computed tomography (CT), colonoscopy, and barium enema study indicated suspected duplication of the sigmoid colon, the exact portion of communication between the normal colon and the duplicated colon could not be determined. The patient was released, but followed up due to the lack of symptoms. After 7 months, she was urgently re-hospitalized due to the complaint of abdominal pain. Her abdominal CT revealed the wall thickness and distention of the duplication as well as voluminous stool containing barium. After the improvement of her symptoms and on the basis of the inflammatory findings, laparoscopic surgery was performed on the patient. Finally, the lesion was diagnosed as tubular- and continuous-type colonic duplication. Duplication of the colon is a relatively rare occurrence in adulthood. Herein, we report a case of duplication of the sigmoid colon diagnosed prior to surgery in an adult.

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.

Functional Outcomes of Patients Treated with Intensive Medications for Bowel and Pain Control for Low-Lying Rectal Cancer Who Received Preoperative Chemoradiotherapy.

PURPOSE: The aim of this study was to assess the functional outcomes of patients treated with intensive medications for bowel and pain control for low-lying rectal cancer who received preoperative chemoradiotherapy (CRT). METHODS: The inclusion criterion was sphincter-preserving surgery following CRT for T3 middle and low rectal cancer. Postoperative defecation control was conducted using calcium polycarbophil and loperamide, and anal pain control was conducted using oxycodone hydrochloride hydrate. The functional outcomes were determined by an annual questionnaire after stoma closure. RESULTS: Of 64 patients evaluated, 33 were reconstructed using the double stapling technique (DST) and 31 were reconstructed using the intersphincteric resection (ISR) technique. The median Visual Analogue Scale at ISR was improved from 7 to 1.5 at 1 year after surgery. The median Wexner scores were 6.0, 6.0, 5.0 and 5.0 for DST and 14.5, 12.0, 10.0 and 8.0 for ISR for the first 4 years, respectively. The only independent predictor of a poor bowel function (Wexner score >10) according to a multivariate analyses was pelvic infection (OR 3.994, 95% CI 1.235-13.52, p = 0.021), while ISR was not a predictor. CONCLUSIONS: Anal pain following ISR can be controlled with oxycodone hydrochloride hydrate therapy. ISR is feasible following CRT for low-lying rectal cancer.

Preventive effect of Goshajinkigan on peripheral neurotoxicity of FOLFOX therapy (GENIUS trial): a placebo-controlled, double-blind, randomized phase III study.

BACKGROUND: Peripheral sensory neurotoxicity is a frequent adverse effect of oxaliplatin therapy. Calcium and magnesium (Ca/Mg) infusions are frequently used as preventatives, but a recent phase III trial failed to show that they prevent neurotoxicity. We therefore conducted a multicenter randomized phase III trial to compare fluorouracil, leucovorin, and oxaliplatin (mFOLFOX6) with and without Goshajinkigan (GJG), a traditional Japanese herbal medicine (Kampo), to determine GJG's potential for reducing peripheral neuropathy in patients with colorectal cancer. METHODS: Patients with colon cancer who were undergoing adjuvant therapy with infusional mFOLFOX6 were randomly assigned to GJG (7.5 mg three times daily) or placebo in a double-blind manner. The primary endpoint was the time to grade 2 or greater neuropathy, which was determined at any point during or after oxaliplatin-based therapy using version 3 of the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE). FINDINGS: An interim analysis was performed when 142 of the planned 310 patients had been enrolled and the safety assessment committee recommended that the study be discontinued. One hundred eighty-two patients were evaluable for response. They included 89 patients in the GJG group and 93 patients in the placebo group. The incidence of grade 2 or greater neurotoxicity was 50.6 % in the GJG group and 31.2 % in the placebo group. A Cox proportional hazards analysis indicated that the use of GJG was significantly associated with the incidence of neuropathy (hazard ratio, 1.908; p = 0.007). CONCLUSION: Goshajinkigan did not prevent oxaliplatin-associated peripheral neuropathy in this clinical trial. The clinical study was therefore terminated.

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.

Development of an integrated support system for hereditary cancer and its impact on gynecologic services.

OBJECTIVE: Patients with hereditary cancer need an integrated support system. A recently launched project was evaluated in terms of its efficacy in screening patients with hereditary cancer at the gynecologic service. METHODS: The project team comprised gynecologists, surgeons, medical geneticists, and certified genetic counselors (CGCs) in our hospital. At the gynecologic service, a newly developed self-administered family history questionnaire (SAFHQ) was given to patients with ovarian, endometrial, or breast cancer as well as a history of multiple cancers. After an interview, a CGC constructed a pedigree and evaluated the risk for hereditary cancer. Patients at risk were recommended by a gynecologist to receive further genetic counseling at the Department of Genetics according to the modified Bethesda criteria, Amsterdam II criteria, and National Comprehensive Cancer Network (NCCN) guidelines 2012 for breast-ovarian cancer syndrome (HBOC). The numbers of newly screened patients were compared before and after the project launch. RESULTS: The SAFHQ was administered to 131 patients and 106 (81 %) pedigrees were constructed between August 2012 and July 2013. The number of newly screened patients according to the Bethesda criteria was 4 and 8 at 10 years before and 1 year after the project launch, respectively. Two and 31 patients met the NCCN criteria for HBOC excluding ovarian cancer alone, respectively, at these 2 time points. Of 54 patients who were recommended to undergo further counseling, 10 (19 %) visited the Department of Genetics. CONCLUSION: After the launch of an integrated support system, the number of patients with hereditary cancers who were screened increased. The gynecologic service played a pivotal role in patient and family care.

Topical tacrolimus therapy for antibiotic-refractory pouchitis.

BACKGROUND: Pouchitis is the most common complication after restorative proctocolectomy for ulcerative colitis, and it leads to pouch failure. The administration of oral antibiotics is the main treatment for pouchitis; however, in some cases, antibiotic-refractory pouchitis may develop, which requires further medical therapy. OBJECTIVE: We investigated the applicability of topical tacrolimus for refractory pouchitis. DESIGN: We performed a prospective pilot study. The study protocols were registered with the University Hospital Medical Information Network Clinical Trials Registry, 000006658. SETTING: This study was conducted in the Surgical Department of Hyogo College of Medicine. PATIENTS: Patients with antibiotic-refractory pouchitis were treated for 8 weeks with a tacrolimus enema. MAIN OUTCOME MEASURES: The efficacy was assessed by comparing Pouchitis Disease Activity Index scores. Safety was assessed by measuring whole blood tacrolimus trough levels. RESULTS: Ten patients with refractory pouchitis were enrolled. No severe adverse events occurred. The mean scores decreased from 15.9 ± 0.8 to 7.8 ± 0.8 during 8 weeks of treatment (p < 0.01). Specifically, the clinical symptom, endoscopic finding, and histological finding subscores decreased to 0.8 ± 0.6, 3.9 ± 0.2, and 2.9 ± 0.4. Nine patients recovered from their clinical symptoms, and 3 patients recovered from pouchitis. LIMITATIONS: This small study was neither blinded nor randomized. CONCLUSIONS: This study demonstrates that the use of topical tacrolimus for the treatment of refractory pouchitis is safe and effective in the short term for clinical symptoms. Although complete endoscopic healing was not achieved, this treatment may have early rescue efficacy in the treatment of antibiotic-refractory pouchitis.

Does 1 year adjuvant chemotherapy with oral 5-FUs in colon cancer reduce the peak of recurrence in 1 year and provide long-term OS benefit?

The objective of our study was to clarify the characteristics of survival and hazard function in patients who received adjuvant chemotherapy after surgery for colon cancer. The data of 2848 patients with curatively resected colon cancer were analyzed; we used the patient data provided by the Japanese Foundation for Multidisciplinary Treatment for Cancer in three trials, namely, JFMC7-1 (n = 869), JFMC7-2 (n = 978) and JFMC15 (n = 1001). The total number of events were 605 (overall survival) and 724 (disease-free survival). The disease-free survival events consisted of 117 cases of death and 607 cases of disease recurrences. Logrank test showed a borderline significant difference in both overall survival (P = 0.0452) and disease-free survival (P = 0.0462). The 5 year overall survival proportion was 0.769 (control) and 0.802 (treated), and the absolute drug effect was 3.3%. The difference between the 5 year disease-free survival proportion (0.728 [control] and 0.760 [drug]) was 3.2%, which is almost similar to the result of overall survival. The disease-free survival curve of the treated group differed from that of the control group after 1 year, whereas the overall survival curve of the treated group became distinct from that of the control group after 2 years. The hazard rate plots indicated the possibility that 1 year adjuvant chemotherapy with oral 5-fluorouracils may translate the short-term reduction in the risk of recurrence in patients with resected colon cancer into a delayed advantage in overall survival.

[Analysis of microsatellite instability and p53 LOH in advanced colorectal cancers--first report of the No. 3 protocol].

In order to establish the most appropriate protocol of adjuvant chemotherapy for colorectal cancers, several cooperative studies have been undertaken by the Kinki Cooperative Study Group of Chemotherapy for Colorectal Carcinoma (KCSGCCC). In the No. 3 protocol of KCSGCCC, several cancer-associated molecular markers were analyzed to investigate a possible correlation with chemosensitivity and/or patient's prognosis. Here, we report the preliminary results of the analysis of microsatellite instability (MSI) and p53 LOH in 559 cases of Stage II, III colorectal cancer. The MSI was detected in 51 cases (9%) and was shown to have a significant correlation with right-sided localization and histology (poorly differentiated, mucinous). p53 LOH was positive in 225 cases (40%) and was shown to have a significant correlation with left-sided localization and histology (well to moderately differentiated). These results might support the concept of 2 distinct pathways of colorectal carcinogenesis, e.g., RER pathway and LOH pathway.