Yasumasa Takii

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.

Safety of UFT/LV and S-1 as adjuvant therapy for stage III colon cancer in phase III trial: ACTS-CC trial

Background:The Adjuvant Chemotherapy Trial of TS-1 for Colon Cancer (ACTS-CC) is a phase III trial designed to validate the non-inferiority of S-1 to UFT/leucovorin (LV) as postoperative adjuvant chemotherapy for stage III colon cancer. We report the results of a planned safety analysis.Methods:Patients aged 20–80 years with curatively resected stage III colon cancer were randomly assigned to receive UFT/LV (UFT, 300 mg m−2 per day as tegafur; LV, 75 mg per day on days 1–28, every 35 days, 5 courses) or S-1 (80, 100, or 120 mg per day on days 1–28, every 42 days, 4 courses). Treatment status and safety were evaluated.Results:Of 1535 enrolled patients, a total of 1504 (756 allocated to S-1 and 748 to UFT/LV) were analysed. The completion rate of protocol treatment was 77% in the S-1 group and 73% in the UFT/LV group. The overall incidence of adverse events (AEs) were 80% in S-1 and 74% in UFT/LV. Stomatitis, anorexia, hyperpigmentation, and haematological toxicities were common in S-1, whereas increased alanine aminotransferase and aspartate aminotransferase were common in UFT/LV. The incidences of ⩾grade 3 AEs were 16% and 14%, respectively.Conclusion:Although AE profiles differed between the groups, feasibility of the protocol treatment was good. Both S-1 and UFT/LV could be safely used as adjuvant chemotherapy.

Clinical Significance of the Mesorectal Extension of Rectal Cancer: A Japanese Multi-institutional Study

Objective:The aim of this study was to emphasize the importance of a subclassification in the TNM staging system of rectal cancer. Background:The clinical significance of the mesorectal extension of rectal cancer is unclear. Patients and Methods:Data from 463 consecutive patients with stage IIa disease (T3N0) undergoing curative surgery at 28 institutes were analyzed. The measurement of the distance of the mesorectal extension (DME) was histologically evaluated. Risk factors for recurrence, for the optimal cutoff point of the DME, independent prognostic factors, and for survivals were studied using receiver operating characteristic curve and logistic and Cox regression analyses. Survivals were calculated using the Kaplan-Meier method. Results:A value of 4 mm was determined as the optimal cutoff point. The patients were subdivided into 2 groups: DME ⩽ 4 mm and DME > 4 mm at the optimal cutoff point. DME > 4 mm had the greatest impact on recurrence-free survival [P = 0.00023, hazard ratio (HR): 2.26, 95% confidence interval (95% CI): 1.465-3.492, L/U ratio: 0.420] and was an independent adverse prognostic factor (P = 0.00323, HR: 1.97, 95% CI: 1.254-3.091). The distant metastasis rate in DME > 4 mm was higher 16.7% than that in DME ⩽ 4 mm (P = 0.00177, OR: 2.61, 95% CI: 1.430-4.761). The incidence of local recurrence was not influenced by DME. The recurrence-free 5-year survival rate in DME ⩽ 4 mm was significantly better than that in DME > 4 mm (86.6% vs 71.3%, P = 0.00015, HR: 0.44, 95% CI: 0.286-0.683). The cancer-specific survival rate in DME ⩽ 4 mm was also significantly better than that in DME > 4 mm (91.3% vs 82.2%, P = 0.000664, HR: 0.52, 95% CI: 0.325-0.843). Conclusions:A subclassification according to mesorectal extension based on a 4-mm cutoff point is needed for the TNM staging system. However, further prospective study is necessary to prove reproducibility and validity of the cutoff point.

A Randomized Controlled Trial of the Conventional Technique Versus the No-touch Isolation Technique for Primary Tumor Resection in Patients with Colorectal Cancer: Japan Clinical Oncology Group Study JCOG1006

A randomized controlled trial is currently being conducted in Japan to demonstrate the superiority of the no-touch isolation technique over the conventional technique for patients with potentially curative colon and rectosigmoid cancer. The conventional technique procedure gives first priority to mobilization of the tumor-bearing segment of the colon, which is followed by central vascular ligation and ligation of other vasculature. Conversely, the no-touch isolation technique gives first priority to central vascular ligation, which is followed by mobilization of the tumor-bearing segment of the colon. A total of 850 patients will be enrolled in this trial. The primary endpoint is disease-free survival. Secondary endpoints are overall survival, relapse-free survival, liver metastasis-free survival, mode of recurrence, surgical morbidity, adverse events due to postoperative chemotherapy, serious adverse events and short-term clinical outcomes.

Predicting oncologic outcomes by stratifying mesorectal extension in patients with pT3 rectal cancer: a Japanese multi-institutional study

The goal of this study was to clarify the clinical significance of mesorectal extension in pT3 rectal cancer. This currently remains unclear. Data from 975 consecutive patients with pT3 rectal cancer that underwent curative surgery at 28 institutes were reviewed. The distance of the mesorectal extension (DME) was measured histologically. The optimal prognostic cut‐off point of the DME for oncologic outcomes was determined using the receiver operating characteristic curve and Cox regression analysis. When patients were subdivided into two groups according to the optimal cut‐off point, DME ≤ 4 mm and DME > 4 mm, DME was found to be a powerful independent risk factor for postoperative recurrence. A DME > 4 mm was significantly correlated with distant and local recurrences at Stage IIA and IIIB diseases. The recurrence‐free 5‐year‐survival rate was significantly higher in patients with a DME ≤ 4 mm [86.6% at Stage IIA (p = 0.00015), and 68.7% at Stage IIIB (p < 0.0001)] than in patients with a DME > 4 mm (71.3% at Stage IIA and 49.1% at Stage IIIB). No significant difference was noted in the oncologic outcomes between the two groups at Stage IIIC. A value of 4 mm provides the best prognostic cut‐off point for patient stratification and for the prediction of oncologic outcomes. A subclassification based on a 4‐mm cut‐off point may improve the utility of the TNM 7th staging system except for Stage IIIC. These findings warrant further prospective studies to determine the reliability and validity of this cut‐off point.

Benefit of the measurement of mesorectal extension in patients with pT3N1-2 rectal cancer without pre-operative chemoradiotherapy: Post-operative treatment strategy

A treatment strategy based on the distance of mesorectal extension (DME) for pT3N1-2 rectal cancer patients without pre-operative chemoradiotherapy has not yet been defined. The present study aimed to describe the benefit of the measurement of mesorectal extension in stratifying treatment for pT3N1-2 rectal cancer patients. Data from 512 patients with pT3N1-2 rectal cancer undergoing curative surgery at 28 institutes were analyzed in this study. DME was measured histologically, and the optimal prognostic cut-off point of the DME was determined using Cox regression analyses. Survival was calculated using the Kaplan-Meier method. The patients were subdivided into two groups based on the optimal prognostic cut-off point: DME ≤4 mm and DME >4 mm. The DME was found to be a powerful independent risk factor for predicting distant and local recurrences. The recurrence-free 5-year survival rates of patients with DME >4 mm were significantly poorer for Stages IIIB (53.3%; p=0.0015; HR, 1.76; 95% CI, 1.233–2.501) and IIIC (32.9%; p=0.0095; HR, 1.64; 95% CI, 1.119–2.407) than for patients with DME ≤4 mm (69.7 and 50.4%, respectively). The cancer-specific survival rates of patients with DME >4 mm were also significantly worse than those with DME ≤4 mm. A value of 4 mm provides the best cut-off point for subdividing the mesorectal extension to predict oncologic outcomes. Measurement of mesorectal extension appears to be of benefit in stratifying patients for post-operative adjuvant treatments.