[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.

aCGH Analysis of Predictive Biomarkers for Response to Bevacizumab plus Oxaliplatin- or Irinotecan-Based Chemotherapy in Patients with Metastatic Colorectal Cancer.

BACKGROUND: The randomized phase III study (WJOG4407G) showed equivalent efficacy between FOLFOX and FOLFIRI in combination with bevacizumab as the first-line treatment for metastatic colorectal cancer (mCRC). We studied whole genome copy number profiles using array-based comparative genomic hybridization (aCGH) analysis of tumor tissue samples obtained in this study. The aim of this study was to identify gene copy number alterations that could aid in selecting either FOLFOX or FOLFIRI in combination with bevacizumab for patients with mCRC. MATERIALS AND METHODS: DNA was purified from 154 pretreatment formalin-fixed paraffin-embedded tissue samples (75 from the FOLFOX arm and 79 from the FOLFIRI arm) of 395 patients enrolled in the WJOG4407G trial and analyzed by aCGH. Genomic regions greater than 1.2-fold were regarded as copy number gain (CNG). RESULTS: Patient characteristics between the treatment arms were well balanced except for tumor laterality (left side; 64% in FOLFOX arm and 80% in FOLFIRI arm, p = .07). FOLFIRI showed a trend toward better response rate (RR), progression-free survival (PFS) and overall survival (OS) than FOLFOX in the patients with CNG of chromosome 8q24.1 (Fisher's exact test, p = .134 for RR; interaction test, p = .102 for PFS and p = .003 for OS) and 8q24.2 (Fisher's exact test, p = .179 for RR; interaction test, p = .144 for PFS and p = .002 for OS). CONCLUSION: Chromosome 8q24.1-q24.2 may contain genes that could potentially serve as predictive markers for selecting either FOLFOX or FOLFIRI in combination with bevacizumab for treatment of patients with mCRC. IMPLICATIONS FOR PRACTICE: Bevacizumab has been used as a standard first-line treatment for patients with metastatic colorectal cancer (mCRC) in combination with either oxaliplatin-based or irinotecan-based chemotherapy. Until now, there has been no predictive marker to choose between the two combination chemotherapies. This array-based comparative genomic hybridization analysis revealed that the difference in therapeutic effect between the two combination chemotherapies is prominent in patients with mCRC with gene copy number gain in chromosome 8p24.1-p24.2. Such patients showed more favorable response and survival when treated with irinotecan-based combination chemotherapy. Overlapping genes commonly found in this region may be predictive biomarkers of the efficacy of the combination chemotherapy with bevacizumab.

A Phase II Study of Third-Line Combination Chemotherapy with Bevacizumab Plus S-1 for Metastatic Colorectal Cancer with Mutated KRAS (SAVIOR Study).

OBJECTIVE: No salvage treatment had been established for metastatic colorectal cancer (mCRC) with mutated KRAS before the emergence of the new drugs regorafenib and TAS-102. We performed a phase II study of third-line chemotherapy with combined bevacizumab and S-1 for mCRC. METHODS: Subjects were mCRC patients with mutated KRAS who showed disease aggravation even after two regimens with oxaliplatin and irinotecan. Bevacizumab was given intravenously every 2 weeks, and S-1 was administered orally on days 1-28 of a 42-day cycle. The primary endpoint was disease control rate (DCR). RESULTS: In total, 31 subjects were enrolled between August 2009 and June 2011. Three subjects in whom antitumor effects could not be evaluated were excluded. The median follow-up period was 8.6 months. The DCR was 67.9%, the response rate 0%, median progression-free survival 3.7 months, and overall survival 8.6 months. In 30 subjects evaluated for safety, there was no treatment-related death. The most common adverse events were anorexia (grade ≥3, 20%), diarrhea (grade 3, 10%), and decreased hemoglobin (grade ≥3, 17%). CONCLUSIONS: The results suggest that third-line chemotherapy with combined bevacizumab and S-1 is safe and may delay the progression of mCRC resistant to oxaliplatin and irinotecan with mutated KRAS.

Leucovorin, fluorouracil, and oxaliplatin plus bevacizumab versus S-1 and oxaliplatin plus bevacizumab in patients with metastatic colorectal cancer (SOFT): an open-label, non-inferiority, randomised phase 3 trial.

BACKGROUND: Studies done in Asia have shown that a regimen of S-1 plus oxaliplatin (SOX) has promising efficacy and safety in patients with metastatic colorectal cancer. We aimed to establish whether SOX plus bevacizumab is non-inferior to mFOLFOX6 (modified regimen of leucovorin, fluorouracil, and oxaliplatin) plus bevacizumab as first-line chemotherapy for metastatic colorectal cancer. METHODS: We undertook an open-label, non-inferiority, randomised phase 3 trial in 82 sites in Japan. We enrolled individuals aged 20-80 years who had metastatic colorectal cancer, had an Eastern Cooperative Oncology Group performance status of 0 or 1, had assessable lesions, had received no previous chemotherapy or radiotherapy, could take drugs orally, and had adequate organ function. Eligible patients were randomly assigned (1:1) to receive either mFOLFOX6 plus bevacizumab (on day 1 of each 2-week cycle, 5 mg/kg intravenous infusion of bevacizumab and a simultaneous intravenous infusion of 85 mg/m(2) oxaliplatin, 200 mg/m(2)l-leucovorin, 400 mg/m(2) bolus fluorouracil, and 2400 mg/m(2) infusional fluorouracil) or SOX plus bevacizumab (on day 1 of each 3-week cycle, 7·5 mg/kg intravenous infusion of bevacizumab and 130 mg/m(2) intravenous infusion of oxaliplatin; assigned dose of S-1 twice a day from after dinner on day 1 to after breakfast on day 15, followed by 7-day break). Randomisation was done centrally with the minimisation method, with stratification by institution and whether postoperative adjuvant chemotherapy had been given. Participants, investigators, and data analysts were not masked to treatment assignment. The primary endpoint was progression-free survival (PFS), which was defined as the interval between enrolment and progressive disease (≥20% increase in sum of longest dimensions of target lesions from baseline, or appearance of new lesions) or death, whichever came first. The primary analysis was done by modified intention to treat. This trial is registered with the Japan Pharmaceutical Information Center, number JapicCTI-090699. FINDINGS: Between Feb 1, 2009, and March 31, 2011, 512 patients underwent randomisation. 256 patients assigned to receive SOX plus bevacizumab and 255 assigned to receive mFOLFOX6 plus bevacizumab were included in the primary analysis. Median PFS was 11·5 months (95% CI 10·7-13·2) in the group assigned to mFOLFOX6 plus bevacizumab and 11·7 months (10·7-12·9) in the group assigned to SOX plus bevacizumab (HR 1·04, 95% CI 0·86-1·27; less than non-inferiority margin of 1·33, pnon-inferiority=0·014). The most common haematological adverse events of grade 3 or higher were leucopenia (21 [8%] of 249 patients given mFOLFOX6 plus bevacizumab included in safety analysis vs six [2%] of 250 given SOX plus bevacizumab; p=0·0029) and neutropenia (84 [34%] vs 22 [9%]; p<0·0001). Grade 3 or higher anorexia (13 [5%] vs three [1%]; p=0·019) and diarrhoea (23 [9%] vs seven [3%]; p=0·0040) were significantly more common in patients given SOX plus bevacizumab than in those given mFOLFOX6 plus bevacizumab. We recorded seven treatment-related deaths (three in the group given mFOLFOX6 plus bevacizumab; four in that given SOX plus bevacizumab). INTERPRETATION: SOX plus bevacizumab is non-inferior to mFOLFOX6 plus bevacizumab with respect to PFS as first-line treatment for metastatic colorectal cancer, and could become standard treatment in Asian populations. FUNDING: Taiho.

Retrospective study as first-line chemotherapy combined anti-VEGF antibody with fluoropyrimidine for frail patients with unresectable or metastatic colorectal cancer.

BACKGROUND/AIM: Combination chemotherapies of oxaliplatin or irinotecan with fluoropyrimidine and molecular target drug were reported to be active in several clinical studies and so regarded as a first-line standard therapy for unresectable or metastatic colorectal cancer. However, the incidence of adverse events is not so low. We investigated the efficacy and safety of chemotherapy combined bevacizumab with fluoropyrimidine as a first-line treatment for frail patients. METHODS: Twenty-six patients with unresectable or metastatic colorectal cancer who were treated with first-line chemotherapy combined bevacizumab with S-1 or 5FU/LV (modified Roswell Park Memorial Institute regimen) at our hospital between October 2007 and December 2010 were retrospectively investigated. RESULTS: The median age was 72 years (range 66-84). Performance status was 0, 1 and 2 in 8, 17 and 1 patient, respectively. The primary lesion was located in the colon in 14 patients and in the rectum in 12. Twenty patients were with resection of the primary lesion and 6 were without, 8 were with postoperative adjuvant chemotherapy and 18 were without. The number of metastasized organs was 1, 2 and 3 in 17, 9 and 0 patients, respectively. The liver, lung, lymph node and peritoneum were metastasized in 9, 9, 11 and 5 patients, respectively. The KRAS gene was wild in 11, mutated in 7 and unknown in 8 patients. Bevacizumab with S-1 was used in 17 patients and bevacizumab with 5FU/LV was used in 9. Response and disease control rates were 50 and 100%, respectively. The median duration of progression-free survival was 9.1 months and the median time to treatment failure was 9.0 months. The incidences of all grades of neutropenia and hypertension were 31%, those of grade 3 or severer were 12%, and those of other adverse events were low. Grade 3 cerebral hemorrhage, grade 4 pulmonary embolism and grade 5 febrile neutropenia each occurred in 1 patient. CONCLUSION: The first-line chemotherapy combined bevacizumab with fluoropyrimidine for frail patients with unresectable or metastatic colorectal cancer in Japan was comparable to the safety and efficacy of combination therapy reported previously in Western countries.

First-line sunitinib plus FOLFIRI in Japanese patients with unresectable/metastatic colorectal cancer: a phase II study.

This phase II, open-label, single-arm study investigated sunitinib + FOLFIRI in Japanese patients with treatment-naïve unresectable/metastatic colorectal cancer. Patients received i.v. FOLFIRI (levo-leucovorin 200 mg/m(2) + irinotecan 180 mg/m(2), followed by 5-fluorouracil 400 mg/m(2) bolus then 2400 mg/m(2) 46-h infusion) every 2 weeks, and oral sunitinib 37.5 mg/day on Schedule 4/2 (4 weeks on, 2 weeks off), until disease progression or treatment withdrawal. Progression-free survival (PFS) was the primary endpoint, with a target median of 10.8 months (35% improvement over FOLFIRI alone). Seventy-one patients started a median of 3 (range 1-11) sunitinib cycles (median relative dose intensity, <60%). The median PFS was 6.7 months (95% confidence interval, 4.7-9.2) by independent review, 7.2 months (95% confidence interval, 5.4-9.5) by investigator assessment. Objective response rate (complete responses + partial responses) was 36.6% (independent review) and 42.3% (investigator assessment). Clinical benefit rate (complete responses + partial responses + stable disease) was 83.1% (independent review) and 88.7% (investigator assessment). Common all-causality, any-grade, adverse events were: neutropenia and leukopenia (both 97.2%); thrombocytopenia (84.5%); diarrhea and nausea (both 78.9%); decreased appetite (74.6%); and fatigue (66.2%). Neutropenia (96%) was the most frequent grade 3/4 adverse event. This study was closed early due to findings from a concurrent phase III study of sunitinib + FOLFIRI in non-Japanese patients with metastatic colorectal cancer. In conclusion, the median PFS for sunitinib + FOLFIRI in Japanese patients was shorter than the 10.8 month target, indicating that sunitinib did not add to the antitumor activity of FOLFIRI. This study was registered with www.ClinicalTrials.gov (NCT00668863).

Phase II study of combination chemotherapy with biweekly cetuximab and irinotecan for wild-type KRAS metastatic colorectal cancer refractory to irinotecan, oxaliplatin, and fluoropyrimidines.

The aim of this study is to prospectively evaluate the efficacy of combination chemotherapy with every second week cetuximab and irinotecan in patients with pretreated metastatic colorectal cancer harboring wild-type KRAS. Patients with wild-type KRAS metastatic colorectal cancer that had progressed after chemotherapy with irinotecan, oxaliplatin, and fluoropyrimidine were included. Cetuximab was administered at 500 mg/m(2) biweekly with irinotecan. The primary endpoint was response rate. The pharmacokinetics of cetuximab was also evaluated in 5 patients. From May 2009 to February 2010, a total of 31 patients were enrolled from five institutions. One patient was not eligible. Among the 30 patients who were treated with biweekly cetuximab plus irinotecan, partial response was observed in 9 patients. The objective response rate was 30.0% (95% confidence interval [CI], 14.7%-49.4%) and the disease control rate (complete response, partial response, or stable disease) was 76.7% (95% CI, 57.7%-90.0%). The median progression-free survival was 5.3 months and median overall survival was 10.8 months. Grade 3 skin toxicity was observed in 3 patients (10.0%) and one treatment related death due to pneumonia was observed. Combination chemotherapy with biweekly cetuximab and irinotecan was effective for pretreated metastatic colorectal cancer with wild-type KRAS.

[Comparison of chemotherapy side effects between elderly and young subjects].

UNLABELLED: With the aging of society, the number of elderly patients receiving chemotherapy has increased. Since organ function, particularly the liver and kidney function, is known to decrease with age, there is concern that severe side effects may develop in the elderly because of chemotherapy. It is a considerable challenge to establish safe, effective chemotherapy that enables elderly patients to maintain a favorable QOL. Therefore, we conducted a survey of the current status of chemotherapy side effects. METHODS: The subjects were patients enrolled in physician-led clinical trials between April 2006 and December 2010. A survey of the chemotherapy regimens used, PS, and, side effects(CTC-AE v3.0)was conducted to examine differences in the incidence and Grade of side effects between elderly and younger subjects(aged 65 years or older, and younger than 65 years, respectively). The subjects consisted of9 3 elderly and younger people, with mean ages of 70 and 59. 5 years, respectively. Myelosuppression of Grade 3, or more severe side effects in the elderly and younger subjects, was 22. 5% and 16. 3%, respectively. The incidence of side effects was slightly higher in the elderly than in the younger subjects. In general clinical practice, side effects are controlled by selecting regimens and adjusting doses for the elderly. However, in clinical trials in which the dosage is predetermined regardless of age, the elderly are more prone to develop side effects than young people. We compare and present the current status regarding the side effects, effectiveness, and contents of chemotherapy regimens.

Sequential Treatment Strategy Using Fluoropyrimidine plus Bevacizumab Followed by Oxaliplatin for Metastatic Colorectal Cancer: A Phase II Study (OGSG 1107).

Introduction: Previous prospective studies suggest that the sequential use of cytotoxic agents, such as oxaliplatin, in patients with metastatic colorectal cancer (mCRC) has the potential to improve prognosis and maintain quality of life than combination chemotherapy. The purpose of this study was to investigate the feasibility and effectiveness of a sequential treatment strategy consisting of an initial therapy (capecitabine, S-1, or 5-fluorouracil with leucovorin [LV/5-FU] plus bevacizumab) and subsequent therapy (i.e., initial therapy plus oxaliplatin) for mCRC. Methods: The primary endpoint was second progression-free survival (2nd PFS) between the start of initial therapy and tumor progression after sequential therapy; secondary endpoints were PFS after initial treatment, overall survival (OS), objective response rate (ORR), and safety. Results: Sixty-six patients were planned to be recruited. However, owing to a slow accrual rate, recruitment was terminated when only 19 patients were enrolled between 2011 and 2015; 4, 10, and 5 patients were administered capecitabine plus bevacizumab, S-1 plus bevacizumab, and LV/5-FU plus bevacizumab, respectively. The proportions of those with a KRAS status (wild-type/mutant/unknown) were 26%, 21%, and 53%, respectively. The median 2nd PFS and OS were 19.1 months and not reached, respectively. The ORR was 45.5% in the initial therapy and 16.7% in the subsequent therapy. Grade 3/4 toxicities included neutropenia (5%), proteinuria (5%), and hypertension (47%). Conclusion: Although our data are limited and preliminary, the sequential treatment strategy may provide a survival benefit in patients with mCRC. Further investigation of this treatment approach is warranted.

A phase II study of biweekly mitomycin C and irinotecan combination therapy in patients with fluoropyrimidine-resistant advanced gastric cancer: a report from the Gastrointestinal Oncology Group of the Japan Clinical Oncology Group (JCOG0109-DI Trial).

BACKGROUND: Preclinical studies have shown that mitomycin C (MMC) acts synergistically with irinotecan (CPT-11). In this phase II study, we evaluated the efficacy and toxicity of MMC/CPT-11 therapy as second-line chemotherapy for patients with fluoropyrimidine-resistant advanced gastric cancer. METHODS: Eligible patients had evidence of tumor progression despite prior treatment with fluoropyrimidine-based regimens or had relapsed within 6 months after completion of therapy with adjuvant fluoropyrimidines. Treatment consisted of MMC (5 mg/m(2)) and CPT-11 (150 mg/m(2)) administered i.v. every 2 weeks. The primary endpoint was the response rate (RR). Our hypothesis was that this combination therapy was efficacious when the lower boundary of the 95% confidence interval (CI) of the RR exceeded 20% of the threshold RR. RESULTS: Between April 2002 and July 2003, 45 eligible patients were registered and analyzed. Among the 45 patients, 40 (89%) had previously received chemotherapy for metastasis and 24 (53%) had a performance status (PS) of 0. Thirteen partial responses were obtained among the 45 patients, resulting in an overall RR of 29% (95% CI, 16-42%). The median time to progression was 4.1 months, and the median survival time was 10 months, with a 1-year survival rate of 36%. Grade 4 neutropenia was observed in 29% of the patients, whereas febrile neutropenia occurred in 9%. The incidence rates of grade 3 nausea and diarrhea were 13 and 2%, respectively. CONCLUSIONS: Although this study did not achieve the per-protocol definition of activity, the progression-free survival and overall survival appeared to be promising, with acceptable tolerability. Thus, MMC/CPT-11 therapy as second-line chemotherapy for fluoropyrimidine-resistant advanced gastric cancer presents a potential treatment option in patients with a good PS.

[Chemotherapy for gastrointestinal cancer in elderly patients].

Since elderly people have decreased renal function along with increased risks for complications of cardiac disorders such as hypertension and decreased physical strength, compared to in younger people, drug therapy for them is associated more with concern about drug-related toxicity. Therefore, dose reduction or discontinuation of drug administration is sometimes considered during earlier stages of therapy. On the other hand, there are some reports suggesting that as long as proper organ function is maintained, the elderly can be treated in the same way as younger people. However, given limited information and depending on the therapeutic goal of each patient, it should be carefully considered whether the same medicinal strategy used for younger patients is appropriate for treating elderly patients or not.

Inhibitory effects of carbocisteine on type A seasonal influenza virus infection in human airway epithelial cells.

Type A human seasonal influenza (FluA) virus infection causes exacerbations of bronchial asthma and chronic obstructive pulmonary disease (COPD). l-carbocisteine, a mucolytic agent, reduces the frequency of common colds and exacerbations in COPD. However, the inhibitory effects of l-carbocisteine on FluA virus infection are uncertain. We studied the effects of l-carbocisteine on FluA virus infection in airway epithelial cells. Human tracheal epithelial cells were pretreated with l-carbocisteine and infected with FluA virus (H(3)N(2)). Viral titers in supernatant fluids, RNA of FluA virus in the cells, and concentrations of proinflammatory cytokines in supernatant fluids, including IL-6, increased with time after infection. l-carbocisteine reduced viral titers in supernatant fluids, RNA of FluA virus in the cells, the susceptibility to FluA virus infection, and concentrations of cytokines induced by virus infection. The epithelial cells expressed sialic acid with an alpha2,6-linkage (SAalpha2,6Gal), a receptor for human influenza virus on the cells, and l-carbocisteine reduced the expression of SAalpha2,6Gal. l-carbocisteine reduced the number of acidic endosomes from which FluA viral RNA enters into the cytoplasm and reduced the fluorescence intensity from acidic endosomes. Furthermore, l-carbocisteine reduced NF-kappaB proteins including p50 and p65 in the nuclear extracts of the cells. These findings suggest that l-carbocisteine may inhibit FluA virus infection, partly through the reduced expression of the receptor for human influenza virus in the human airway epithelial cells via the inhibition of NF-kappaB and through increasing pH in endosomes. l-carbocisteine may reduce airway inflammation in influenza virus infection.

Phase II study of combination chemotherapy with biweekly cetuximab and irinotecan for pre-treated metastatic colorectal cancer harboring wild-type KRAS.

Standard weekly cetuximab and irinotecan is an effective regimen in heavily pre-treated patients with metastatic colorectal cancer. The aim of this study is to prospectively evaluate the efficacy of combination chemotherapy with biweekly cetuximab and irinotecan in patients with pre-treated metastatic colorectal cancer harboring wild-type KRAS. A total of 30 patients will be enrolled at four medical institutions. The primary endpoint is response rate. The secondary endpoints include adverse events, progression-free survival and overall survival. The pharmacokinetics of cetuximab will also be evaluated in five patients.

[A resected case of effective treatment with S-1+CPT-11 combination chemotherapy for advanced gastric cancer].

We report a resected case of effective treatment with S-1+CPT-11 combination chemotherapy for advanced gastric cancer. The patient was a 65-year-old man who had a type 3 gastric cancer from the middle body of the stomach to the angle. An abdominal CT scan demonstrated bulky lymph node metastasis (cType 3, T3, N2, M0, cStage IIIb), which was then treated with S-1+CPT-11 (S-1 80 mg/m2 day 1-21, CPT-11 80 mg/m2 day 1, 15/5 weeksx2 courses)as neoadjuvant chemotherapy. After 2 courses of chemotherapy, the primary lesion and regional metastatic lymph nodes were reduced by CT (cType 3, T2, N2, M0, cStage IIIa). Total gastrectomy with D3 nodal dissection was performed. The histological diagnosis was pT2 (ss), pN0, sH0, pCY0, sP0, sM0, tub2, INF beta, ly0, v1, n0, stage I b, Cur A, and the histological effect of the main tumor was judged to be Grade 1b. He was treated by S-1 after surgery. The patient has been in good health without a recurrence for 3 years after surgery. This case suggests that neoadjuvant chemotherapy with S-1+CPT-11 is a potential regimen for advanced gastric cancer.

Carbocisteine inhibits oxidant-induced apoptosis in cultured human airway epithelial cells.

BACKGROUND AND OBJECTIVE: Increased oxidant levels have been associated with exacerbations of COPD, and L-carbocisteine, a mucolytic agent, reduces the frequency of exacerbations. The mechanisms underlying the inhibitory effects of L-carbocisteine on oxidant-induced COPD exacerbations were examined in an in vitro study of human airway epithelial cells. METHODS: In order to examine the antioxidant effects of L-carbocisteine, human tracheal epithelial cells were treated with L-carbocisteine and exposed to hydrogen peroxide (H(2)O(2)). Cell apoptosis was assessed using a cell death detection ELISA, and the pathways leading to cell apoptosis were examined by measurement of caspase-3 and caspase-9 by western blot analysis with fluorescent detection. RESULTS: The proportion of apoptotic cells in human tracheal epithelium was increased in a concentration- and time-dependent manner, following exposure to H(2)O(2). Treatment with L-carbocisteine reduced the proportion of apoptotic cells. In contrast, H(2)O(2) did not increase the concentration of LDH in supernatants of epithelial cells. Exposure to H(2)O(2) activated caspase-3 and caspase-9, and L-carbocisteine inhibited the H(2)O(2)-induced activation of these caspases. L-carbocisteine activated Akt phosphorylation, which modulates caspase activation, and the inhibitors of Akt, LY294002 and wortmannin, significantly reversed the inhibitory effects of L-carbocisteine on H(2)O(2)-induced cell apoptosis. CONCLUSIONS: These findings suggest that in human airway epithelium, L-carbocisteine may inhibit cell damage induced by H(2)O(2) through the activation of Akt phosphorylation. L-carbocisteine may have antioxidant effects, as well as mucolytic activity, in inflamed airways.

[Combination of irinotecan and Mitomycin C as second-line chemotherapy for patients with unresectable advanced or recurrent gastric cancer in clinical practice].

BACKGROUND: Recently, combination S-1 and CDDP chemotherapy is considered as a standard regimen for unresectable or recurrent gastric cancer. Second-line chemotherapy is reportedly important to improve survival, and combination of Irinotecan and Mitomycin C as second-line chemotherapy has proven effective in phase II study of JCOG 0109-DI. PURPOSE: We assessed the efficacy of combination of Irinotecan and Mitomycin C as second-line chemotherapy for unresectable and recurrent gastric cancer. PATIENTS AND METHODS: We treated 12 patients receiving combination of Irinotecan and Mitomycin C as second-line chemotherapy between Nov. 2002 and Apr. 2006. RESULTS: The response rate was 42% including 2 complete response. Progression-free survival was 6.1 months, and time to progression was 5.4 months. Median survival time after the start of second-line chemotherapy was 11.2 months, and after first-line treatment 20.5 months. One-year survival rate was 50%, and 2-year survival rate was 33%. CONCLUSION: In our hospital, combination of Irinotecan and Mitomycin C as second-line chemotherapy prolonged median survival time, and seemed to be an effective regimen.

Updated 5-year survival and exploratory T x N subset analyses of ACTS-CC trial: a randomised controlled trial of S-1 versus tegafur-uracil/leucovorin as adjuvant chemotherapy for stage III colon cancer.

OBJECTIVE: Adjuvant Chemotherapy Trial of TS-1 for Colon Cancer (ACTS-CC), a randomised phase III trial, demonstrated that adjuvant therapy with S-1 for stage III colon cancer was non-inferior in 3-year disease-free survival (DFS) to that of tegafur-uracil plus leucovorin (UFT/LV). We updated DFS and overall survival (OS) and performed T x N subset analysis. METHODS: A total of 1518 patients with curatively resected stage III colon cancer were randomly assigned to receive S-1 (80-120 mg/day on days 1-28 every 42 days, four courses) or UFT/LV (UFT: 300-600 mg/day and LV: 75 mg/day on days 1-28 every 35 days, five courses). RESULTS: The 5-year DFS rates of the S-1 and UFT/LV group were 70.2 % and 66.9 %, respectively (HR 0.88; 95% CI 0.74 to 1.06; p=0.177), and non-inferiority of DFS was reconfirmed with a median of 63.5-month follow-up. The similarity of OS was also confirmed (HR 0.92; 95% CI 0.72 to 1.17; p=0.488); 5-year OS rates of the S-1 and UFT/LV group were 86.0 % and 84.4 %, respectively. No significant interactions were identified between the major baseline characteristics and DFS of the S-1 and UFT/LV groups, except for histological type; S-1 was more favourable in patients with poorly differentiated adenocarcinoma. Patient outcomes were well separated by TNM-substages (IIIA/IIIB/IIIC). With the patients divided into 20 subsets by T and N factors, the DFS and OS rates of T3 and N1 subset, which accounted for 62 % of stage IIIB patients and 44 % of all studied subjects, were significantly better than those of the other subsets in stage IIIB and similar to those of stage IIIA. CONCLUSIONS: Adjuvant therapy of S-1 for stage III colon cancer was reconfirmed to be non-inferior in DFS to those of UFT/LV after long follow-up. No difference in OS was also demonstrated. T3N1 patients might be considered separately from other patients included in stage IIIB because of its favourable outcome. TRIAL REGISTRATION NUMBER: NCT00660894.

Nitroglycerin treatment may enhance chemosensitivity to docetaxel and carboplatin in patients with lung adenocarcinoma.

PURPOSE: Nitroglycerin may improve the response to chemotherapy in advanced non-small cell lung cancer. The effects and mechanisms of nitroglycerin on the enhancement of chemosensitivity to docetaxel and carboplatin regimen (DCb) in patients with lung adenocarcinoma have not been reported. EXPERIMENTAL DESIGN: Seventeen patients with operable lung adenocarcinoma and stable angina pectoris were selected to investigate the effects of nitroglycerin on immunoreactivity for hypoxia-inducible factor 1alpha (HIF-1alpha), vascular endothelial growth factor (VEGF), P-glycoprotein (P-gp), the production of which is regulated by HIF-1, and p53 proteins in their resected tumor by semiquantitative immunohistochemical analyses. Eight of 17 patients were treated with nitroglycerin patches before operation, but 9 of 17 patients were not. Furthermore, to study the relationship between changes in plasma VEGF levels by nitroglycerin treatment and response to DCb, 29 patients with advanced lung adenocarcinoma were treated with nitroglycerin for 3 days before chemotherapy using DCb. RESULTS: The rates of immunoreactive cells for HIF-1alpha, VEGF, and P-gp in tumor tissues treated with nitroglycerin were lower than those without nitroglycerin, but those for p53 were not different between those treated with and without nitroglycerin. Furthermore, the rates of immunoreactive cells for VEGF and P-gp proteins were significantly associated with those for HIF-1alpha in tumor tissue. The magnitude of decrease in plasma VEGF levels after treatment with nitroglycerin was significantly associated with response to DCb in patients with advanced lung adenocarcinoma. CONCLUSIONS: Nitroglycerin treatment may improve response to DCb in patients with lung adenocarcinoma, partly through decreasing VEGF and P-gp production via reduction of HIF-1alpha.

[Treatment and prevention of COPD exacerbation].

Airway inflammation, mucosal edema, epithelial hyperpermeability, mucus secretion and airway smooth muscle contraction induced by airway bacterial, virus infection and exposure to air pollution may be associated with COPD exacerbation. Severity of COPD exacerbation is estimated by blood gas analysis, serum CRP values and the chest radiograph. Patients with COPD exacerbations are recommended to be treated with additional inhalations of beta-2 agonists and anti -cholinergic agents, systemic administered glucocorticosteroids, oxygen inhalation, and, in cases with purulent sputum, antibiotics. Glucocorticosteroids, beta-2 agonists and anti-cholinergic agents reduce the frequency of COPD exacerbation. We reported the inhibitory effects of glucocorticosteroids on rhinovirus infection, the major cause of common colds, and the inhibitory effects of L-carbocisteine and erythromycin on COPD exacerbations and rhinovirus infection.

S-1 and oxaliplatin (SOX) plus bevacizumab versus mFOLFOX6 plus bevacizumab as first-line treatment for patients with metastatic colorectal cancer: updated overall survival analyses of the open-label, non-inferiority, randomised phase III: SOFT study.

OBJECTIVE: The SOFT study previously demonstrated that S-1 and oxaliplatin (SOX) plus bevacizumab was non-inferior to l-leucovorin, fluorouracil and oxaliplatin (mFOLFOX6) plus bevacizumab in terms of the primary end point of progression-free survival (PFS) as first-line chemotherapy for metastatic colorectal cancer (mCRC). The overall survival (OS) data were immature at the time of the primary analysis. METHODS: A total of 512 patients were enrolled and randomly assigned to receive either mFOLFOX6 plus bevacizumab (5 mg/kg of bevacizumab, followed by 200 mg/m2 of l-leucovorin given simultaneously with 85 mg/m2 of oxaliplatin, followed by a 400 mg/m2 bolus of 5-FU on day 1 and then 2400 mg/m2 of 5-FU as an intravenous infusion over the course of 46 hours, every 2 weeks) or SOX plus bevacizumab (7.5 mg/kg of bevacizumab, 130 mg/m2 of oxaliplatin on day 1 and 40-60 mg of S-1 two times per day for 2 weeks, followed by a 1-week rest). The primary end point was PFS. After the primary analysis, the follow-up survey was cut-off on 30 September 2013, and the final OS data were analysed. RESULTS: With a median follow-up of 37.7 months, the median survival time (MST) was 29.7 months with mFOLFOX6 plus bevacizumab and 29.6 months with SOX plus bevacizumab (HR, 1.018; 95% CI 0.823 to 1.258). Median PFS was 11.7 months in the mFOLFOX6 plus bevacizumab group and 12.2 months in the SOX plus bevacizumab group (HR, 1.051; 95% CI 0.876 to 1.262; pnon-inferiority=0.0115). CONCLUSION: Our results reconfirmed that SOX plus bevacizumab is non-inferior to mFOLFOX6 plus bevacizumab in terms of PFS. MST did not differ between the groups. SOX plus bevacizumab is considered an effective regimen for first-line chemotherapy in patients with mCRC and can be used instead of mFOLFOX6 plus bevacizumab. TRIAL REGISTRATION NUMBER: JapicCTI-090699.