Phase II study of capecitabine plus oxaliplatin (CapOX) as adjuvant chemotherapy for locally advanced rectal cancer (CORONA II).

OBJECTIVE: This multicenter, single-arm phase II study (UMIN000008429) aimed to evaluate the efficacy and safety of capecitabine plus oxaliplatin (CapOX) as postoperative adjuvant chemotherapy for patients with locally advanced rectal cancer. METHODS: Patients with resectable clinical Stage II or III rectal cancer were enrolled to receive eight cycles of CapOX therapy (130 mg/m2 oxaliplatin on day 1 and 2000 mg/m2 oral capecitabine on days 1-14, every 3 weeks) after curative surgical resection. The primary endpoint was 3-year relapse-free survival (RFS) rate, and secondary endpoints were 3-year overall survival (OS) rate, treatment compliance, and safety. RESULTS: A total of 40 patients (Stage II, 21; Stage III, 19) were enrolled between September 2012 and November 2015 from seven institutions. Thirty-nine patients (97%) received R0 resection, and 32 patients (84%) received postoperative CapOX therapy. The completion rate of all eight cycles of CapOX therapy was 66%. Relative dose intensities were 87% for oxaliplatin and 84% for capecitabine. At a median follow-up period of 46 months, disease recurrence was observed in nine patients, including three with local recurrence. Three-year RFS and OS rates were 75% (95% CI 57-86%) and 96% (95% CI 80-99%), respectively. Frequencies of Grade ≥ 3 hematological and non-hematologic adverse events were 19% and 38%, respectively. CONCLUSION: CapOX therapy is feasible as adjuvant chemotherapy for locally advanced rectal cancer.

Rupture of the common bile duct due to blunt trauma, presenting difficulty in diagnosis.

Rupture of the common bile duct because of blunt trauma is extremely rare. Preoperative diagnosis is very difficult because bile causes little peritoneal irritation. We present a case of a 19-year-old young woman with rupture of the common bile duct due to blunt trauma. She arrived at our hospital 1 hour after a car accident. She was diagnosed as pancreatic head injury, and conservative therapy was administered. It was effective, but after starting oral intake 6 days after the injury, she presented with abdominal fullness because of increased ascites. The ascites contained large amounts of bile. Rupture of the common bile duct became apparent, thus, she underwent emergency surgery 13 days after the injury. The common bile duct was ruptured completely at the lower bile duct. We repaired it by choledochojejunostomy. Her postoperative course was uneventful, and she discharged on the 12 days after the surgery. Preoperative drip-infusion-cholangiography-CT was useful for its diagnosis.

Phase II multicenter study of adjuvant S-1 for colorectal liver metastasis: survival analysis of N-SOG 01 trial.

PURPOSE: We previously showed that S-1 after curative resection of colorectal liver metastasis had acceptable toxicity and a high rate of completion of therapy in a prospective phase II trial. We here reported the primary endpoint of disease-free survival (DFS). METHODS: Between October 2008 and August 2010, 60 patients were eligible for this study and received S-1 for 28 days followed by a 2-week rest period. Treatment was started within 8 weeks after surgery and repeated for eight cycles. RESULTS: Median follow-up was 41 months. Among 60 patients, 45 had solitary metastasis, and the median maximum tumor diameter was 2.6 cm. The 3-year DFS and overall survival were 47.4 and 80.0 %, respectively. Recurrences developed in 31 patients, with the remnant liver the most common site (19 patients). Multivariate analysis showed that positive lymph node metastasis around the primary site (p = 0.013) and early liver metastasis (synchronous disease or metachronous disease within 12 months) (p = 0.041) were independent poor prognostic factors for DFS. Patients having both risk factors had a significantly worse DFS than those without these risk factors (p < 0.001). Early liver metastasis was an independent indicator of early recurrence within 1 year. CONCLUSIONS: S-1 after curative liver resection yielded promising survival in patients with a low tumor burden. Outcome in patients having both positive lymph node metastasis around the primary site and early liver metastasis was much worse than in patients without these conditions; therefore, they might warrant more aggressive therapy.

Neoadjuvant oxaliplatin and capecitabine and bevacizumab without radiotherapy for poor-risk rectal cancer: N-SOG 03 Phase II trial.

OBJECTIVE: This Phase II trial was designed to evaluate the safety and efficacy of neoadjuvant oxaliplatin and capecitabine and bevacizumab without radiotherapy in patients with poor-risk rectal cancer. METHODS: Patients with magnetic resonance imaging-defined poor-risk rectal cancer received neoadjuvant oxaliplatin and capecitabine and bevacizumab followed by total mesorectal excision or more extensive surgery. RESULTS: Between February 2010 and December 2011, 32 patients were enrolled in this study. The completion rate of the scheduled chemotherapy was 91%. Reasons for withdrawal were refusal to continue therapy in two patients and disease progression in one, with two of these three patients not undergoing surgery. Among the 29 patients who completed the scheduled chemotherapy, one refused surgery within 8 weeks after the completion of chemotherapy, which was the period stipulated by the protocol, and another had rectal perforation, requiring urgent laparotomy. As a result, the completion rate of this experimental treatment was 84%. Of the 30 patients who underwent surgery, the R0 resection rate was 90% and a postoperative complication occurred in 43%. A pathological complete response was observed in 13% and good tumor regression was exhibited in 37%. CONCLUSIONS: Neoadjuvant oxaliplatin and capecitabine plus bevacizumab for poor-risk rectal cancer caused a high rate of anastomotic leakage and experienced a case with perforation during chemotherapy, both of which were bevacizumab-related toxicity. Although the short-term results with the completion rate of 84.4% and the pathological complete response rate of 13.3% were satisfactory, we have to reconsider the necessity of bevacizumab in neoadjuvant chemotherapy (UMIN number, 000003507).

Optimal schedule of adjuvant chemotherapy with S-1 for stage III colon cancer: study protocol for a randomized controlled trial.

BACKGROUND: Although, in Western countries, oxaliplatin-based regimens have been established as a gold standard treatment for patients with stage III or high risk stage II colon cancer after curative resection, in Japan fluorouracil-based regimens have been widely accepted and recommended in the guidelines for adjuvant settings in patients with stage III colon cancer. S-1, an oral preparation evolved from uracil and tegafur, has equivalent efficacy to uracil and tegafur/leucovorin for treating patients with advanced colorectal cancer and might be a suitable regimen in an adjuvant setting. However, the completion rate of the standard six-week cycle of the S-1 regimen is poor and the establishment of an optimal treatment schedule is critical. Therefore, we will conduct a multicenter randomized phase II trial to compare six-week and three-week cycles to establish the optimal schedule of S-1 adjuvant therapy for patients with stage III colon cancer after curative resection. METHODS/DESIGN: The study is an open-label, multicenter randomized phase II trial. The primary endpoint of this study is three-year disease-free survival rate. Secondary endpoints are the completion rate of the treatment, relative dose intensity, overall survival, disease-free survival, and incidence of adverse events. The sample size was 200, determined with a significance level of 0.20, power of 0.80, and non-inferiority margin of a 10% absolute difference in the primary endpoint. DISCUSSION: Although S-1 has not been approved yet as a standard treatment of colon cancer in an adjuvant setting, it is a promising option. Moreover, in Japan S-1 is a standard treatment for patients with stage II/III gastric cancer after curative resection and a promising option for patients with colorectal liver metastases in an adjuvant setting. However, a six-week cycle of treatment is not considered to be the best schedule, and some clinicians use a modified schedule, such as a three-week cycle to keep a sufficient dose intensity with few adverse events. Therefore, it will be useful to determine whether a three-week cycle has an equal or greater efficacy and tolerance to side-effects compared with the standard six-week cycle schedule, and thus may be the most suitable treatment schedule for S-1 treatment. TRIAL REGISTRATION: The University Hospital Medical Information Network (UMIN) Clinical Trials Registry UMIN000006750.

Multicenter phase II study of modified FOLFOX6 as neoadjuvant chemotherapy for patients with unresectable liver-only metastases from colorectal cancer in Japan: ROOF study.

BACKGROUND: Neoadjuvant chemotherapy for unresectable colorectal liver metastases can reduce tumor size, which sometimes leads to curative resection. The aim of the present study was to identify and describe patients with initially unresectable liver-only metastases from colorectal cancer who obtained sufficient chemotherapeutic benefit that eventually lead to the removal of the metastatic diseases in the liver. METHODS: A phase II multicenter cooperative study was conducted in 38 medical institutions using modified FOLFOX6 (mFOLFOX6) as neoadjuvant chemotherapy from January 2008 to June 2009. Patients with liver-only metastases from colorectal cancer that was deemed not optimally resectable by liver surgeons received mFOLFOX6 as preoperative neoadjuvant chemotherapy for 6-8 cycles. Patients were reassessed for resectability after 6 cycles of mFOLFOX6. Surgery was carried out 3-6 weeks after chemotherapy. The primary endpoint was the rate of macroscopic curative surgery including liver resection. RESULTS: 36 patients (23 male/13 female, ECOG performance status 0-1) were enrolled. The median age of the patients was 62.5 years; 78% (28 patients) had 5 or more metastatic tumors, and 50% (18 patients) had metastatic tumors over 5 cm diameter. The mFOLFOX6 regimen was safety administered resulting in 18 partial responses (50%), 12 stable disease, and 4 progressive disease. There was no grade 3/4 neurotoxicity. Fourteen patients (38.9%) underwent surgery (R0: 13; R1: 1). Of these, thirteen patients (36.1%) underwent R0 surgery. CONCLUSIONS: Our data suggest that mFOLFOX6 has a high response rate in patients with liver-only metastases from colorectal cancer, allowing for R0 resection of liver metastases in a proportion of patients initially not judged to be optimally resectable.

Phase II trial of adjuvant chemotherapy with S-1 for colorectal liver metastasis.

BACKGROUND: This phase II trial was designed to evaluate the safety and efficacy of adjuvant chemotherapy with S-1 in patients with curatively resected liver metastasis from colorectal cancer. Results of an interim analysis of safety and short-term outcomes are reported. METHODS: Patients who underwent curative resection of liver metastasis from colorectal cancer received S-1 monotherapy (on days 1-28, followed by 14 days' rest, 8 cycles) as adjuvant chemotherapy. RESULTS: Among 62 patients enrolled between October 2008 and August 2010, a total of 60 patients were eligible for analysis. The most frequent grade 3 or higher hematologic toxicity involved neutropenia in three patients (5.0 %). Nonhematologic toxicities of grade 3 or higher were fatigue in 6.7 % of patients. Grade 4 enteritis occurred in one patient, but resolved promptly after withdrawal of S-1 therapy. The completion rate of the eight scheduled cycles of chemotherapy was 58.3 %. The most common reasons for withdrawal of treatment was the detection of early relapse in 16 patients (64 %). When the 16 patients who had recurrence during adjuvant treatment were excluded from analysis, 79.5 % of the remaining 44 patients completed the scheduled treatment. Early recurrence within 1 year after curative liver resection occurred in 21 patients (35 %). The most common site was the remnant liver in 14 patients. CONCLUSIONS: Orally administered S-1 after curative liver resection has an acceptable toxicity profile and a high rate of completion of the therapy. S-1 can be safely used and might be a viable treatment option in an adjuvant setting.

Phase II trial of neoadjuvant chemotherapy with XELOX plus bevacizumab for locally advanced rectal cancer.

In Western countries, the standard treatment for locally advanced rectal cancer is preoperative chemoradiotherapy followed by total mesorectal excision. On the other hand, in Japan, treatment results without radiotherapy are by no means inferior; therefore, extrapolation of results of preoperative treatment in Western countries to Japan is controversial. We consider that survival may be improved by preoperative treatment with new anticancer agents as they are expected not only to decrease the local recurrence rate but also to prevent distant metastases. We are conducting a multicentre Phase II study to evaluate the safety and efficacy of neoadjuvant chemotherapy using XELOX plus bevacizumab without radiotherapy in patients with locally advanced rectal cancer. The primary endpoint of the study is treatment compliance. Secondary endpoints are overall survival, disease-free survival, local recurrence-free survival, objective response rate, R0 resection rate and adverse events. Thirty patients are required for this study.

Immunohistochemically demonstrated lymph node micrometastasis and prognosis in patients with otherwise node-negative hilar cholangiocarcinoma.

OBJECTIVE: To investigate whether immunohistochemically demonstrated lymph node micrometastasis has prognostic significance in patients with histologically node-negative (pN0) hilar cholangiocarcinoma. SUMMARY BACKGROUND DATA: The clinical significance of immunohistochemically detected lymph node micrometastasis recently has been evaluated in various tumors. However, no reports have addressed this issue with regard to hilar cholangiocarcinoma. METHODS: A total of 954 lymph nodes from surgical specimens of 45 patients with histologically node-negative hilar cholangiocarcinoma who underwent macroscopically curative resection were immunostained with monoclonal antibody against cytokeratins 8 and 18. The results were examined for relationships with clinical and pathologic features and with patient survival. RESULTS: Lymph node micrometastases were detected immunohistochemically in 11 (24.4%) of the 45 patients, being found in 13 (1.4%) of 954 lymph nodes examined. Of the 13 nodal micrometastases, 11 (84.6%) were found in the N2 regional lymph node group rather than N1. Clinicopathologic features showed no associations with lymph node micrometastases. Survival curves were essentially similar between patients with and without micrometastasis. In addition, the grade of micrometastasis showed no effect on survival. The Cox proportional hazard model identified microscopic venous invasion, microscopic resection margin status, and histologic differentiation as significant prognostic factors in patients with pN0 disease. CONCLUSIONS: Lymph node micrometastasis has no survival impact in patients with otherwise node-negative hilar cholangiocarcinoma. The authors do not recommend extensive lymph node sectioning with keratin immunostaining for prognostic evaluation.