[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 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.

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.

A phase II study of bevacizumab and irinotecan plus alternate-day S-1 as a second-line therapy in patients with metastatic colorectal cancer: the AIRS study.

BACKGROUND: The aim of this single-arm phase II clinical trial was to evaluate whether the alternate-day administration of S-1 plus irinotecan would reduce the incidence of severe diarrhea in comparison to consecutive-day S-1 administration (standard IRIS regimen) in second-line treatment for patients with metastatic colorectal cancer. METHODS: Patients with metastatic colorectal cancer after failure with first-line treatment of oxaliplatin and fluoropyrimidine were enrolled. Irinotecan (150 mg/m2) and bevacizumab (5 mg/kg) were given intravenously on day 1. Oral S-1 was administered on alternate days at a dose of 40-60 mg twice a day. Cycles were repeated every 2 weeks. The primary endpoint was the incidence of grade ≥ 3 diarrhea. Our hypothesis set 21% as a threshold incidence and 10% as an expected incidence from previous studies with one-sided alpha 0.05. The secondary endpoints included the relative dose intensity, progression-free survival, overall survival and other adverse events. RESULTS: A total of 51 patients were enrolled. The incidence of grade ≥ 3 diarrhea was 15.7% (8/51). Other common grade ≥ 3 adverse events were neutropenia, anemia, thrombocytopenia and fatigue were 13.7% (7/51), 5.9% (3/51), 2.0% (1/51) and 5.9% (3/51), respectively. The relative dose intensities of irinotecan, bevacizumab, and S-1 were 80.0, 86.8, and 77.7%, respectively. The median progression-free survival and overall survival were 8.4 months (5.8-9.8) and 17.1 months (11.8-22.3). CONCLUSIONS: The alternate-day S-1 administration does not have significant effectiveness to reduce diarrhea in patients who received second-line treatment for metastatic colorectal cancer.

A phase II trial to evaluate the efficacy of panitumumab combined with fluorouracil-based chemotherapy for metastatic colorectal cancer: the PF trial.

PURPOSE: Fluorouracil monotherapy, instead of the FOLFOX or FOLFIRI regimen, is administered to patients intolerant to oxaliplatin or irinotecan because of their adverse effects. A prospective clinical trial was designed to evaluate the efficacy and safety of fluorouracil monotherapy combined with panitumumab administered to patients with KRAS wild-type (WT) metastatic colorectal cancer (mCRC) intolerant to oxaliplatin and irinotecan. Screening for potential serum biomarkers to predict early therapeutic responses was conducted. METHODS: This single-arm, open-label multicenter phase II trial recruited patients with KRAS WT mCRC from 16 institutes between January 2012 and October 2014. Panitumumab (6 mg/kg) was intravenously administered every 2 weeks, combined with fluorouracil monotherapy, in 2-week cycles. The primary objective was overall response rate, and secondary endpoints included disease-control rate, progression-free survival, overall survival, toxicity, and blood-test data. RESULTS: Forty patients (male, 65.0%; median age, 74 years; colon cancer, 72.5%) met eligibility criteria and received 7 cycles (median) of fluorouracil chemotherapy combined with panitumumab. There were no treatment-related deaths. Median time to treatment failure was 3.2 months. 23 (57.5%) patients experienced at least one adverse effect ≥ grade 3. The response rate was 10.0% (95% confidence interval 2.8-23.7%). Median progression-free survival and overall survival were 4.3 and 11.3 months, respectively. Total lactase dehydrogenase (LDH) levels and those of LDH-4 and LDH-5, quickly changed with disease reduction or progression. CONCLUSIONS: Fluorouracil monotherapy combined with panitumumab was safely administered to patients with KRAS WT mCRC intolerant to oxaliplatin and irinotecan. Serum LDH levels may predict early responses.

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.

Effect of pH adjustment by mixing steroid for venous pain in colorectal cancer patients receiving oxaliplatin through peripheral vein: a multicenter randomized phase II study (APOLLO).

PURPOSE: The aim of this phase II clinical trial was to evaluate the preventive effect of dexamethasone mixing injection for venous pain in patients with colorectal cancer during chemotherapy. MATERIALS AND METHODS: Patients were randomized to receive a 2-h intravenous infusion of oxaliplatin 130 mg/m(2) on day 1 followed by capecitabine 1000 mg/m(2) (or S-1 40-60 mg/m(2)) twice daily on days 1 through 14 of every 3 weeks with or without dexamethasone 1.65 mg at the infusion on day 1. RESULTS: A total of 53 patients were enrolled. The analysis population consisted of 49 patients (arm A, with dexamethasone N = 24; arm B, without dexamethasone N = 25). The incidence of venous pain ≥grade 2 based on the CTCAE version 4.0 was 33.3 % in arm A and 56.0 % in arm B (relative risk 0.60; 95 % CI 0.31-1.16). The incidences based on the verbal rating scale for arms A and B were 50.0 and 64.0 %, respectively (relative risk 0.78; 95 % CI 0.48-1.28). CONCLUSION: The primary endpoint was not met in this preliminary study.

Clinical Role of Modified Seton Procedure and Coring Out for Treatment of Complex Anal Fistulas Associated With Hidradenitis Suppurativa.

A variety of techniques have been described to treat complex anal fistulas. When complex anal fistulas are associated with hidradenitis suppurativa, the treatment has to be appropriately tailored for the severity and distribution of the disease so as to remove the external fistula tract to prevent recurrence while ensuring fecal continence. Between 2007 and 2011, a total of 10 males (ranging in age from 32 to 54 years) complained of recurrent purulent discharge in the buttocks and thigh regions. The discharge had started about 12 to 18 months prior, and had increased progressively resulting in complex anal fistulas and hidradenitis suppurativa in the buttocks. They underwent surgical operation according to a modified seton procedure for complex anal fistulas and coring out for hidradenitis suppurativa. They were discharged from the hospital in 4 to 5 days, while the seton dropped spontaneously about 6 to 8 months after surgery. They have been well without any morbidities or recurrence. The present paper demonstrates that cases of complex anal fistulas associated with hidradenitis suppurativa can be successfully treated with a modified seton procedure and coring out of hidradenitis suppurativa.

Impact of 5-fluorouracil metabolizing enzymes on chemotherapy in patients with resectable colorectal cancer.

Although 5-fluorouracil (5-FU) is an important drug for colorectal cancer (CRC) treatment, no useful biomarker is currently available to predict treatment response. Since 5-FU is converted into active or inactive forms by orotate phosphoribosyltransferase (OPRT) or dihydropyrimidine dehydrogenase (DPD), a correlation between these enzymes and response to 5-FU has been suggested. However, such a correlation has not been investigated prospectively. Therefore, in the present study, we aimed to prospectively evaluate whether OPRT and DPD were predictive factors of the response to 5-FU treatment in patients with resectable CRC. The present investigation was designed as a multicenter prospective cohort study. OPRT and DPD activities were assessed in biopsy samples, obtained surgically from patients with resectable CRC. The OPRT/DPD ratio was calculated and the cut-off values for this ratio were determined for 5-year disease-free survival (DFS) and overall survival (OS). Patients were treated with 5-FU/leucovorin (LV) regimens and oral 5-FU. The endpoint of this study was the correlation between the OPRT/DPD ratio and 5-year DFS and OS. The cut-off value for the OPRT/DPD ratio was determined by using the maximum χ2 statistic method against 5-year DFS and OS. Sixty-eight patients were enrolled from July 2003 to May 2005. The median follow-up period was 1925 days. The OPRT/DPD ratio cut-off values for 5-year DFS and OS were 0.015 and 0.013, respectively. During the 5-year DFS and OS periods, patients with higher cut-off values had a better prognosis than those with lower ratios (P=0.03 and 0.02, respectively). In conclusion, our results suggest that the OPRT/DPD ratio could be a predictive factor for response to 5-FU/LV adjuvant chemotherapy.

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.

Impact of less invasive treatments including sclerotherapy with a new agent and hemorrhoidopexy for prolapsing internal hemorrhoids.

Conventional hemorrhoidectomy is applied for the treatment of prolapsing internal hemorrhoids. Recently, less-invasive treatments such as sclerotherapy using aluminum potassium sulphate/tannic acid (ALTA) and a procedure for prolapse and hemorrhoids (PPH) have been introduced. We compared the results of sclerotherapy with ALTA and an improved type of PPH03 with those of hemorrhoidectomy. Between January 2006 and March 2009, we performed hemorrhoidectomy in 464 patients, ALTA in 940 patients, and PPH in 148 patients with second- and third-degree internal hemorrhoids according to the Goligher's classification. The volume of ALTA injected into a hemorrhoid was 7.3 ± 2.2 (mean ± SD) mL. The duration of the operation was significantly shorter in ALTA (13 ± 2 minutes) than in hemorrhoidectomy (43 ± 5 minutes) or PPH (32 ± 12 minutes). Postoperative pain, requiring intravenous pain medications, occurred in 65 cases (14%) in hemorrhoidectomy, in 16 cases (1.7%) in ALTA, and in 1 case (0.7%) in PPH. The disappearance rates of prolapse were 100% in hemorrhoidectomy, 96% in ALTA, and 98.6% in PPH. ALTA can be performed on an outpatient basis without any severe pain or complication, and PPH is a useful alternative treatment with less pain. Less-invasive treatments are beneficial when performed with care to avoid complications.

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.

Phase II study of bi-weekly irinotecan for patients with previously treated HER2-negative metastatic breast cancer: KMBOG0610B.

BACKGROUND: A trial was conducted to evaluate the feasibility, efficacy, and safety of biweekly administration of irinotecan, a novel topoisomerase I inhibitor, for patients with metastatic breast cancer (MBC) previously treated with either anthracycline-based or taxane-based chemotherapy. METHODS: Eligible patients were HER2-negative, had a performance status of 0 to 2, and had been treated previously with either anthracyclines or taxanes for MBC. Patients received irinotecan intravenously at 150 mg/m(2) on days 1 and 15 every 4 weeks. The primary end-point was feasibility, and the treatment was considered feasible if a patient was able to receive three administrations of irinotecan within the first 8 weeks, as pre-specified in the protocol. RESULTS: Eighteen patients (median age 60 years) were enrolled. Fifteen patients received irinotecan more than 3 times within the first 8 weeks, with resulting feasibility of 83.3%. The median number of treatment cycles was 2 (range 1-16) during this period, and the relative dose intensity was 91.2%. Partial response was observed for one patient, so overall response rate was 5.6%. Nine patients (50.0%) had stable disease, and overall disease control was 50.0%. Median progression-free survival and overall survival periods were 3.2 and 9.6 months, respectively. The only grade 3/4 hematological toxicity was neutropenia (22.2%). Grade 3/4 non-hematological toxicities were anorexia (11.2%), diarrhea (11.2%), and fatigue (5.6%). No treatment-related death occurred. CONCLUSIONS: This study demonstrated that biweekly administration of 150 mg/m(2) irinotecan was feasible for patients with MBC treated previously with anthracyclines or taxanes.

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.

Feasibility of 5-days-on/2-days-off UFT/leucovorin in post-operative long-term adjuvant chemotherapy for colorectal cancer.

Previous clinical studies have shown that the oral uracil/tegafur (UFT)/leucovorin (LV) regimen, in which the drugs are taken for 28 consecutive days every 35 days, is equivalent to an infusional 5-fluorouracil (5-FU)/LV regimen for the treatment of colorectal cancer. A 5-days-on/2-days-off schedule for UFT/LV has been proposed as the same schedule for UFT has been reported to be safe and have good compliance. However, few studies have been performed with regards to the feasibility of the UFT/LV regimen. The results of the 5-days-on/2-days-off schedule were compared with those of the consecutive schedule in adjuvant chemotherapy. Twenty-eight patients were treated with the 5-days-on/ 2-days-off schedule of UFT (300 mg/m(2)/day)/LV (75 mg/body/day), and another 12 patients were treated with the consecutive schedule. In the 5-days-on/2-days-off schedule, 24 of 28 patients (86%) received all the scheduled doses. In the consecutive schedule, 10 of 12 patients (83%) received all the scheduled doses. The mean relative dose intensities for the 5-days-on/2-days-off and consecutive schedules were 0.92 and 0.87, respectively. The toxicities were milder in the 5-days-on/2-days-off schedule compared with the consecutive schedule. The disease-free survival in patients with the 5-days-on/2-days-off schedule tended (P=0.13) to be longer compared with the consecutive schedule. The results of the present study indicate that the 5-days-on/2-days-off schedule of UFT/LV may be feasible and cause no severe toxicities in long-term adjuvant chemotherapy.

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.

[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.

[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.

Evaluation of sclerotherapy with a new sclerosing agent and stapled hemorrhoidopexy for prolapsing internal hemorrhoids: retrospective comparison with hemorrhoidectomy.

BACKGROUND: We retrospectively compared the results of sclerotherapy with a new sclerosing agent (aluminum potassium sulphate/tannic acid) and hemorrhoidopexy using an improved type of circular stapler with hemorrhoidectomy. METHODS: Between January 2006 and September 2008, we performed hemorrhoidectomy in 416 patients, sclerotherapy in 784 patients and hemorrhoidopexy in 118 patients with prolapsing internal hemorrhoids. RESULTS: The median volume of the agent injected into a hemorrhoid was 7 ml (interquartile range = 4). The operation duration was significantly shorter (p < 0.01) in sclerotherapy, 13 min (interquartile range = 7), than in hemorrhoidectomy, 43 min (interquartile range = 15), and hemorrhoidopexy, 31 min (interquartile range = 16). Postoperative pain, needing pain killer injection, occurred in 59 patients (14%) in hemorrhoidectomy, 14 patients (1.8%) in sclerotherapy and 1 patient (0.8%) in hemorrhoidopexy (p < 0.01). The disappearance rates of prolapse were 100% (416/416 patients) in hemorrhoidectomy, 96% (753/784 patients) in sclerotherapy and 98.3% (116/118 patients) in hemorrhoidopexy. CONCLUSIONS: Hemorrhoidectomy, widely applied for hemorrhoids, needs hospitalization, being accompanied by pain. Sclerotherapy could be performed on outpatient bases without any severe pain or complication. Hemorrhoidopexy is a useful alternative treatment with less pain. Less invasive treatments would be useful when performed paying attention to avoid complications.

[Successful management with S-1 of recurrent gastric cancer after adjuvant chemotherapy with paclitaxel/UFT].

We report here two cases of recurrent gastric cancer after post operative adjuvant chemotherapy, in which S-1 has been effective to control the recurrence and provided long-term survival. Case 1: A 75-year-old male presented with malaise. Endoscopy showed an advanced gastric cancer. He underwent total gastrectomy with lymph adenectomy and received adjuvant chemotherapy with 3 courses of weekly paclitaxel and 6 months of UFT. An abdominal tumor developed with elevation of tumor markers 1 year and 2 months after surgery. After 5 courses of S-1(100mg/day), the tumor resolved and a complete response(CR)was obtained with decline of the markers for 2 years. Case 2: A 62-year-old male presented with abdominal pain. Endoscopy showed an advanced gastric cancer. He underwent distal gastrectomy with lymph adenectomy. Peritonitis carcinomatosa developed with ascites though adjuvant chemotherapy with UFT had been continued for 6 months after paclitaxel. After 10 courses of S-1(100 mg/day), ascites disappeared with decline of the markers. He has been well without any sign of recurrence or elevation of tumor markers for 2 years. Differences in the 5-fluorouracil concentration of UFT and that of S-1 may explain the effectiveness of S-1 for recurrence of gastric cancer after adjuvant chemotherapy with UFT.