[Regorafenib versus S-1 plus Bevacizumab for Metastatic Colorectal Cancer as Salvage Line-A Phase â ¡ Study (OGSG1301)].

BACKGROUND: Regorafenib(Rego)is the salvage line standard treatment for metastatic colorectal cancer(mCRC), which often causes severe toxicities, such as hand-foot syndrome. Previously, we reported that in phase Ⅱ study, S-1 plus bevacizumab( Bev)(SB)showed favorable anticancer activity and feasibility as a salvage line. The aim of this study was to evaluate 2 treatments for mCRC as salvage line. PATIENTS AND METHODS: In this multicenter phase Ⅱ study, the patients were randomly assigned(1:1)to the Rego or SB group. In the Rego group, Rego 160 mg/kg body weight was orally administered every 28 days for 21 days. In the SB group, S-1 was orally administered every 42 days for 28 days, according to body surface area, and Bev 5 mg/kg was administered by intravenous infusion on days 1, 15, and 29. Administration of S-1 every 21 days for 14 days and Bev 7.5 mg/kg on day 1 was also permitted. The primary endpoint was overall survival(OS), and the planned sample size was 86. RESULTS: This study was ended prematurely due to poor accrual. Overall, 8 patients were enrolled from 6 institutions between Oct 2013 and May 2015. Although 4 patients were assigned to each group, one patient in the Rego group was excluded after enrollment. The median OS in the Rego and SB groups was 30.2 months and 6.6 months, respectively(hazard ratio: 0.205, p=0.123). The median progression-free survival in the Rego and SB groups was 3.7 months and 1.6 months, respectively. The disease control rate in the Rego and SB groups was 100% and 75%, respectively. The Grade 3 or 4 adverse events were increased, including AST/ALT(n=1, 25%), hyponatremia(n=1, 25%), hand-foot syndrome(n=1, 25%), hypertension(n=1, 25%), and proteinuria(n=1, 25%)in the Rego group and colitis( n=1, 25%)in the SB group; the treatment was discontinued. CONCLUSION: Despite the fact that data could only be collected from a small number of patients, SB is not recommended as salvage line for mCRC.

Phase II study of S-1-based sequential combination chemotherapy including oxaliplatin plus bevacizumab and irinotecan with or without cetuximab for metastatic colorectal cancer: the SOBIC trial.

BACKGROUND: Fluorouracil and leucovorin combined with oxaliplatin or irinotecan plus bevacizumab (Bmab) or cetuximab (Cmab) are now widely accepted treatment options as first-line or second-line chemotherapy for metastatic colorectal cancer (mCRC). Sequential chemotherapy with oral 5-FU backbone for mCRC without using central venous ports is beneficial for both patients and physicians. We designed the SOBIC trial to validate the effectiveness of the first- and second-line oral combination chemotherapy for mCRC. PATIENTS AND METHODS: From May 2010 through March 2013, 52 patients were enrolled from 47 institutions in the Hyogo Colorectal Cancer Surgery Group. First-line chemotherapy was S-1 + oxaliplatin (SOX) plus Bmab, and second-line chemotherapy after first-line failure was irinotecan + S-1 (IRIS) + Cmab, IRIS + Bmab, or IRIS based on the KRAS status. RESULTS: The 50 finally included patients received first-line chemotherapy. Second-line therapy was administered to 20 patients (40%): 12 patients received IRIS + Cmab and 8 patients received IRIS + Bmab. The median follow-up period was 48.6 months (range 35-67 months). The median second progression-free survival was 24.2 months (95% confidence interval [CI] 17.7-35.2). The response rate after first- and second-line chemotherapy was 46.7% and 15%, respectively. The median overall survival was 35.2 months (95% CI: 27.8 to not reached). The main grade 3-4 adverse events were sensory neuropathy (18%) and fatigue (10%). There were no treatment-related deaths. CONCLUSION: Sequential S-1-based combination regimens including oxaliplatin, irinotecan, Bmab, and Cmab were beneficial for patients with mCRC.

Phase II study of 5-fluorouracil-leucovorin plus bevacizumab for chemotherapy-naïve older or frail patients with metastatic colorectal cancer (OGSG 0802).

BACKGROUND: Older or frail patients are often underrepresented in clinical trials for metastatic colorectal cancer (mCRC). We here assessed the efficacy and safety of 5-fluorouracil (5-FU)-leucovorin plus bevacizumab in such patients. METHODS: The study (OGSG 0802) was designed as a single-arm, open-label, multicenter phase II trial. Eligible patients had mCRC and at least one of the following: an age of ≥ 65 years, an Eastern Cooperative Oncology Group performance status of 1 or 2, a serum albumin level of ≤ 3.5 g/dL, incompatibility with oxaliplatin or irinotecan, and a history of abdominal or pelvic radiotherapy. Patients received 5-FU (600 mg/m2) and l-leucovorin (200 mg/m2) on days 1, 8, and 15 together with bevacizumab (5 mg/kg) on days 1 and 15 every 4 weeks. The primary end point was objective response rate (ORR), and secondary end points were progression-free survival (PFS), overall survival (OS), and safety. RESULTS: Forty-one patients were enrolled and eligible. Median age was 76 years (range 56-90 years), and 51% of patients had a performance status of 0. The ORR was 36.6% [95% confidence interval (CI) 22.1-53.1%], median PFS was 9.4 months (95% CI 7.4-17.7 months), and median OS was 24.0 months (95% CI 19.9 months-not reached). The most common treatment-related adverse events of grade ≥ 3 were neutropenia (24%), anorexia (10%), leukopenia (7%), and mucositis/stomatitis (7%). There were no treatment-related deaths. CONCLUSION: Weekly 5-FU-leucovorin with biweekly bevacizumab may be a tolerable and effective treatment option for older or frail patients with mCRC.

Multicenter randomized phase II clinical trial of oxaliplatin reintroduction as a third- or later-line therapy for metastatic colorectal cancer-biweekly versus standard triweekly XELOX (The ORION Study).

BACKGROUND: The aim of this multicenter, open-label, randomized phase II trial was to evaluate the efficacy of a dose-dense capecitabine and oxaliplatin (XELOX) regimen in patients with metastatic colorectal cancer (mCRC) for whom reintroduction of oxaliplatin had been planned as a third- or later-line regimen. METHODS: The patients with mCRC who had received prior chemotherapy including oxaliplatin and were scheduled for reintroduction of oxaliplatin were randomized to capecitabine (1,000 mg/m(2)) twice daily on days 1-14 and oxaliplatin (130 mg/m(2)) on day 1 every 21 days (Q3W group) or capecitabine (2,000 mg/m(2)) twice daily on days 1-7 and oxaliplatin (85 mg/m(2)) on day 1 every 14 days (Q2W group). The primary endpoint was the time-to-treatment failure (TTF). Other endpoints included overall survival (OS), progression-free survival (PFS) and other adverse events (AEs). RESULTS: A total of 46 patients were enrolled in the trial-22 patients were randomly assigned to the Q3W group and 23 to the Q2W group. The median TTF was 3.4 months in both groups (hazard ratio [HR] 1.053; p = 0.880). The median PFS and OS were 3.3 and 9.2 months in the Q2W group and 4.3 and 12.1 months in the Q3W group, respectively (HR 1.15; p = 0.153 and 0.672; p = 0.836). The most common grade 3-4 AEs in the Q3W and Q2W groups were fatigue (27.3 vs 21.7), neuropathy (9.1 vs 0 %) and diarrhea (9.1 vs 0 %), respectively. CONCLUSION: There was no significant inter-group difference in any of the efficacy and safety endpoints, including TTF, OS, RFS and AEs. The results of this clinical trial were convincingly negative.

Clinical utility of sclerotherapy with a new agent for treatment of rectal prolapse in patients with risks.

BACKGROUND: Perineal approaches are widely applied for the treatment of rectal prolapse. Recently, less-invasive treatments such as sclerotherapy using aluminum potassium sulfate/tannic acid (ALTA) have been introduced for internal hemorrhoids. Herein, we report the results of ALTA injection for the treatment of rectal prolapse in high-risk patients. METHODS: Between January 2009 and March 2011, we performed ALTA injection sclerosing therapy in 12 female patients with high risk for preoperative complications. Using the perineal approach, 0.5 to 1 mL of ALTA was injected into the submucosa at 30 to 60 different sites. RESULTS: All patients were successfully treated without any operative or postoperative morbidity. Average operation time took 35±7 (mean±SD) minutes, and average volume of ALTA injected was 39±6 mL per patient. Neither complaints of bleeding nor findings of anal stenosis were noted. A slight degree of recurrence of prolapse developed in a patient after 8 months. The patient required an additional injection to be cured. CONCLUSIONS: ALTA injection could be administered for the treatment of rectal prolapse without any pain or complication and would be useful even for patients with risks due to preoperative complications and/or medical history.

A phase I study of triplet combination chemotherapy of paclitaxel, cisplatin and S-1 in patients with advanced gastric cancer.

OBJECTIVE: S-1 and cisplatin combination therapy is a standard regimen for patients with advanced gastric cancer in Japan. The primary objective of this study was to determine the maximum tolerated dose and dose-limiting toxicities of a triplet regimen adding paclitaxel to S-1 and cisplatin combination therapy. METHODS: Patients with previously untreated metastatic or recurrent gastric cancer were enrolled. Patients received S-1 (40 mg/m(2) p.o., twice daily, on days 1-21 every 35 days), cisplatin (30 mg/m(2) divided, on days 1 and 15) and paclitaxel (divided on days 1 and 15). The starting dose of paclitaxel was 50 mg/m(2) (level 1); the dose was escalated to 60 (level 2), 70 (level 3) and 80 mg/m(2) (level 4) in a stepwise fashion. Dose-limiting toxicity was determined during the first treatment cycle. RESULTS: Eighteen patients enrolled. During the first cycle, no dose-limiting toxicity was observed at dose levels 1 and 2. At dose level 3, one of the six patients had dose-limiting toxicity (one patient had grade 4 neutropenia) and at dose level 4, one of the six patients had dose-limiting toxicity (one patient had febrile neutropenia, hypoalbuminemia and fatigue of grade 3). The maximum tolerated dose was not reached at level 4; however, grade 3 hyponatremia and hypokalemia in two of the six patients occurred during the second treatment course at level 4. From the point of view of safety in the outpatient setting, the recommended dose of paclitaxel was determined at 70 mg/m(2). The overall response rate was 50%. CONCLUSIONS: The recommended dose of paclitaxel added to S-1 (80 mg/m(2) days 1-21) plus cisplatin (30 mg/m(2) days 1 and 15) was 70 mg/m(2) on days 1 and 15 of a 5-week cycle.

Clinical role of a modified seton technique for the treatment of trans-sphincteric and supra-sphincteric anal fistulas.

PURPOSES: We have devised a modified seton technique that resects the external fistula tract while preserving the anal sphincter muscle. This study assessed the technique when used for the management of complex anal fistulas. METHODS: Between January 2006 and December 2007, 239 patients (208 males and 31 females, median age: 41 years) underwent surgery for complex anal fistulas using the technique. Of the 239 patients, 198 patients had trans-sphincteric fistula and 41 patients had supra-sphincteric fistula. RESULTS: The durations of the surgeries were 17 min (47, 13) [median (range, interquartile range)] for trans-sphincteric fistulas and 38 (44, 16) for supra-sphincteric fistulas. The durations of the surgeries were significantly (P < 0.05) longer for supra-sphincteric fistula than trans-sphincteric fistula. The hospital stays were 4 (13, 2) days and 5 (14, 3) days, respectively, for trans- and supra-sphincteric fistulas. The durations of seton placement until the spontaneous dropping of the seton were 42 (121, 48) and 141 (171, 55) days respectively. The recurrence rate was 0 % in patients with trans-sphincteric fistulas and 4.9 % (2 of 41) in patients with supra-sphincteric fistulas (P < 0.01). Serious incontinence was not observed. CONCLUSIONS: The technique provided favorable results for the treatment of complex anal fistulas and could be safely applied while preserving the sphincter function and conserving fecal continence.

Combination chemotherapy with S-1 plus cisplatin for gastric cancer that recurs after adjuvant chemotherapy with S-1: multi-institutional retrospective analysis.

BACKGROUND: It is unclear whether S-1 plus cisplatin is effective for patients with recurrent gastric cancer after adjuvant S-1 chemotherapy. METHODS: We retrospectively evaluated the efficacy of S-1 plus cisplatin in patients whose gastric cancer recurred after adjuvant S-1 chemotherapy. RESULTS: In the 52 patients evaluated, the median duration of adjuvant S-1 chemotherapy was 8.1 months, and the median recurrence-free interval (RFI) since the last administration of adjuvant S-1 was 6.4 months. Among the 36 patients with measurable lesions, 7 achieved a complete or partial response, and 13 were evaluated as having stable disease, for an overall response rate of 19.4% and a disease control rate of 55.6%. For all patients, the median progression-free survival (PFS) was 4.8 months, and the median overall survival (OS) was 12.2 months. Compared with patients with an RFI of <6 months (n = 25), patients with an RFI of ≥6 months (n = 27) had a significantly higher response rate (5.0 vs. 37.5%, respectively), longer PFS (2.3 vs. 6.2 months, respectively), and longer overall survival (7.3 vs. 16.6 months, respectively). According to a multivariate Cox model including performance status (PS) and reason for discontinuation of adjuvant S-1, an RFI of 6 months was still significantly associated with PFS and OS. CONCLUSIONS: S-1 plus cisplatin is effective for patients with gastric cancer that recurs after adjuvant S-1 chemotherapy, especially for those with an RFI of ≥6 months.

[Investigation of chemotherapy based on enzyme expression and drug sensitivity test in colorectal cancer].

UNLABELLED: In colorectal cancer (CRC), 5-fluorouracil (5-FU) has been a basic chemotherapeutic agent. Orotate phosphoribosyltransferase (OPRT) and thymidine phosphorylase (TP) are essential enzymes for activation of 5-FU. Dihydropyrimidine dehydrogenase (DPD) is an enzyme for degradation. The feasibility of individualized chemotherapy was studied using the enzyme expression and drug sensitivity test. METHODS: The study included 160 surgical patients (stage II to IV). OPRT, TP, and DPD expressions, assessed with immunohistochemistry, were evaluated in relation to clinicopathological features and patient survival. We assessed 5-FU sensitivity using the collagen gel droplet. Embedded culture-drug sensitivity test(CDDST). The area under the concentration curve (AUC) and growth inhibition curve (IR) were combined in the AUC-IR curve, according to which the individual AUC(IR50) was calculated. Durations to achieve AUC(IR50) were calculated using AUC(24hr) values in UFT and S-1. RESULTS: TP and DPD expression were positively associated with CRC progression and related with poor prognosis, although OPRT expression was negatively associated with CRC progression and related with better prognosis. Patient survival was best in patients with OPRT (+) DPD (-), and worst in those with OPRT (-) DPD (+). Individual AUC(IR50) ranged from less than 100 mg·hr/mL to more than 10,000 mg·hr/mL. In the chemotherapy with UFT, 55% of patients achieved AUC(IR50) within 6 months, 13% of patients achieved it 6 to 12 months, another 13% of patients in 12 to 24 months, and the other 19% after 24 months of chemotherapy. In the chemotherapy with S-1, 31% of patients achieved AUC(IR50) within 1 course, 15% in 1 to 2 courses, another 23% in 2 to 6 courses and the other 31% of patients achieved AUC(IR50) after 6 courses. CONCLUSIONS: The present results suggest that patients' prognosis may be improved with selection of an anti-cancer drug based on the 5-FU metabolizing enzyme expressions and prognostic factors. CD-DST may predict the duration of chemotherapy.

[Assessment of quality of life by questionnaires between S-1/CPT-11 and mFOLFOX6 in patients with advanced colorectal cancer].

UNLABELLED: Injectable combination chemotherapy with 5-fluorouracil (5-FU)/Leucovorin (LV), oxaliplatin (OHP), and irinotecan (CPT-11) has been a standard treatment for advanced colorectal cancer (CRC). An oral fluoropyrimidine, S-1 (tegafur, gimeracil, and oteracil), has been developed recently, and a combination of S-1/CPT-11 demonstrated effects comparable to FOLFIRI for the treatment of advanced CRC. Being without continuous infusion lasting for days, combination chemotherapy with oral fluoropyrimidine may limit inconvenience and improve the quality of life (QOL) of patients. There have been few studies evaluating chemotherapy with oral fluoropyrimidine in terms of patient QOL and convenience. PATIENTS AND METHODS: We assessed the patients' QOL by questionnaire, comparing experiences of those treated with S-1/CPT-11 to those treated with mFOLFOX6 in patients with advanced CRC. The questionnaire, selected from EORTC QLQ, FACT-G, and FACT/GOG-Ntx, consisted of six categories: moving activity, willingness, pain and numbness, gastrointestinal symptoms, daily life, and convenience. The questionnaire had 5 questions in each category and a total of 30 questions. RESULTS: Patients' background and characteristics were similar. No significant difference was observed in response rates and time to progression between the groups. As for adverse effects, there was a case of fatigue (grade 2), five cases of neurotoxicites (grade 1 and 2) in mFOL-FOX6, and a case of diarrhea (grade 3) in S-1/CPT-11. No difference between the two groups was observed in responses to the questionnaire asking about moving activity, willingness, gastrointestinal symptoms, and daily life. As for neurotoxicity and convenience, however, S-1/CPT-11 showed significantly better results than mFOLFOX6. CONCLUSION: The present results suggest that questionnaires are useful for assessing patients' QOL with advanced CRC treated chemotherapy. Combination chemotherapy with oral fluoropyrimidine S-1 could provide similar response rates, limit inconvenience, and improve QOL.