Kensei Yamaguchi

Fluorouracil versus combination of irinotecan plus cisplatin versus S-1 in metastatic gastric cancer: a randomised phase 3 study

BACKGROUND The best chemotherapy regimen for metastatic gastric cancer is uncertain, but promising findings have been reported with irinotecan plus cisplatin and S-1 (tegafur, 5-chloro-2,4-dihydropyrimidine, and potassium oxonate). We aimed to investigate the superiority of irinotecan plus cisplatin and non-inferiority of S-1 compared with fluorouracil, with respect to overall survival, in patients with metastatic gastric cancer. METHODS We undertook a phase 3 open label randomised trial in 34 institutions in Japan. We enrolled patients aged 20-75 years or younger, who had histologically proven gastric adenocarcinoma, and randomly assigned them by minimisation to receive either: a continuous infusion of fluorouracil (800 mg/m(2) per day, on days 1-5) every 4 weeks (n=234); intravenous irinotecan (70 mg/m(2), on days 1 and 15) and cisplatin (80 mg/m(2), on day 1) every 4 weeks (n=236); or oral S-1 (40 mg/m(2), twice a day, on days 1-28) every 6 weeks (n=234). The primary endpoint was overall survival. Analyses were done by intention to treat. This study is registered with Clinicaltrials.gov, number NCT00142350, and with UMIN-CTR, number C000000062. FINDINGS All randomised patients were included in the primary analysis. Median overall survival was 10.8 months (IQR 5.7-17.8) for individuals assigned fluorouracil, 12.3 months (8.1-19.5) for those allocated irinotecan plus cisplatin (hazard ratio 0.85 [95% CI 0.70-1.04]; p=0.0552), and 11.4 months (6.4-21.3) for those assigned S-1 (0.83 [0.68-1.01]; p=0.0005 for non-inferiority). Three treatment-related deaths occurred in the irinotecan plus cisplatin group and one was recorded in the S-1 group. INTERPRETATION S-1 is non-inferior to fluorouracil and, in view of the convenience of an oral administration, could replace intravenous fluorouracil for treatment of unresectable or recurrent gastric cancer, at least in Asia. Irinotecan plus cisplatin is not superior to fluorouracil in this setting.

Irinotecan plus S-1 (IRIS) versus fluorouracil and folinic acid plus irinotecan (FOLFIRI) as second-line chemotherapy for metastatic colorectal cancer: a randomised phase 2/3 non-inferiority study (FIRIS study)

BACKGROUND Fluorouracil and folinic acid with either oxaliplatin (FOLFOX) or irinotecan (FOLFIRI) are widely used as first-line or second-line chemotherapy for metastatic colorectal cancer. However, infusional fluorouracil-based regimens, requiring continuous infusion and implantation of an intravenous port system, are inconvenient. We therefore planned an open-label randomised controlled trial to verify the non-inferiority of irinotecan plus oral S-1 (a combination of tegafur, 5-chloro-2,4-dihydroxypyridine, and potassium oxonate; IRIS) to FOLFIRI as second-line chemotherapy for metastatic colorectal cancer. METHODS Between Jan 30, 2006, and Jan 29, 2008, 426 patients with metastatic colorectal cancer needing second-line chemotherapy from 40 institutions in Japan were randomly assigned by a computer-based minimisation method to receive either FOLFIRI (n=213) or IRIS (n=213). In the FOLFIRI group, patients received folinic acid (200 mg/m(2)) and irinotecan (150 mg/m(2)) and then a bolus injection of fluorouracil (400 mg/m(2)) on day 1 and a continuous infusion of fluorouracil (2400 mg/m(2)) over 46 h, repeated every 2 weeks. In the IRIS group, patients received irinotecan (125 mg/m(2)) on days 1 and 15 and S-1 (40-60 mg according to body surface area) twice daily for 2 weeks, repeated every 4 weeks. The primary endpoint was progression-free survival, with a non-inferiority margin of 1.333. Statistical analysis was on the basis of initially randomised participants. This study is registered with ClinicalTrials.gov, number NCT00284258. FINDINGS All randomised patients were included in the primary analysis. After a median follow-up of 12.9 months (IQR 11.5-18.2), median progression-free survival was 5.1 months in the FOLFIRI group and 5.8 months in the IRIS group (hazard ratio 1.077, 95% CI 0.879-1.319, non-inferiority test p=0.039). The most common grade three or four adverse drug reactions were neutropenia (110 [52.1%] of 211 patients in the FOLFIRI group and 76 [36.2%] of 210 patients in the IRIS group; p=0.0012), leucopenia (33 [15.6%] in the FOLFIRI group and 38 [18.1%] in the IRIS group; p=0.5178), and diarrhoea (ten [4.7%] in the FOLFIRI group and 43 [20.5%] in the IRIS group; p<0.0001). One treatment-related death from hypotension due to shock was reported in the FOLFIRI group within 28 days after the end of treatment; no treatment-related deaths were reported in the IRIS group. INTERPRETATION Progression-free survival with IRIS is not inferior to that with FOLFIRI in patients receiving second-line chemotherapy for metastatic colorectal cancer. Treatment with IRIS could be an additional therapeutic option for second-line chemotherapy in metastatic colorectal cancer. FUNDING Taiho Pharmaceutical Co Ltd and Daiichi Sankyo Co Ltd.

Phase III study comparing oxaliplatin plus S-1 with cisplatin plus S-1 in chemotherapy-naïve patients with advanced gastric cancer

BACKGROUND We evaluated the efficacy and safety of S-1 plus oxaliplatin (SOX) as an alternative to cisplatin plus S-1 (CS) in first-line chemotherapy for advanced gastric cancer (AGC). PATIENTS AND METHODS In this randomized, open-label, multicenter phase III study, patients were randomly assigned to receive SOX (80-120mg/day S-1 for 2 weeks with 100mg/m2 oxaliplatin on day 1, every 3 weeks) or CS (S-1 for 3 weeks with 60mg/m2 cisplatin on day 8, every 5 weeks). The primary end points were noninferiority in progression-free survival (PFS) and relative efficacy in overall survival (OS) for SOX using adjusted hazard ratios (HRs) with stratification factors; performance status and unresectable or recurrent (+adjuvant chemotherapy) disease. RESULTS Overall, 685 patients were randomized from January 2010 to October 2011. In per-protocol population, SOX (n = 318) was noninferior to CS (n = 324) in PFS [median, 5.5 versus 5.4 months; HR 1.004, 95% confidence interval (CI) 0.840-1.199; predefined noninferiority margin 1.30]. The median OS for SOX and CS were 14.1 and 13.1 months, respectively (HR 0.958 with 95% CI 0.803-1.142). In the intention-to-treat population (SOX, n = 339; CS, n = 337), the HRs in PFS and OS were 0.979 (95% CI 0.821-1.167) and 0.934 (95% CI 0.786-1.108), respectively. The most common ≥grade 3 adverse events (SOX versus CS) were neutropenia (19.5% versus 41.8%), anemia (15.1% versus 32.5%), hyponatremia (4.4% versus 13.4%), febrile neutropenia (0.9% versus 6.9%), and sensory neuropathy (4.7% versus 0%). CONCLUSION SOX is as effective as CS for AGC with favorable safety profile, therefore SOX can replace CS. CLINICAL TRIAL NUMBER JapicCTI-101021.BACKGROUND We evaluated the efficacy and safety of S-1 plus oxaliplatin (SOX) as an alternative to cisplatin plus S-1 (CS) in first-line chemotherapy for advanced gastric cancer (AGC). PATIENTS AND METHODS In this randomized, open-label, multicenter phase III study, patients were randomly assigned to receive SOX (80-120 mg/day S-1 for 2 weeks with 100 mg/m(2) oxaliplatin on day 1, every 3 weeks) or CS (S-1 for 3 weeks with 60 mg/m(2) cisplatin on day 8, every 5 weeks). The primary end points were noninferiority in progression-free survival (PFS) and relative efficacy in overall survival (OS) for SOX using adjusted hazard ratios (HRs) with stratification factors; performance status and unresectable or recurrent (+adjuvant chemotherapy) disease. RESULTS Overall, 685 patients were randomized from January 2010 to October 2011. In per-protocol population, SOX (n = 318) was noninferior to CS (n = 324) in PFS [median, 5.5 versus 5.4 months; HR 1.004, 95% confidence interval (CI) 0.840-1.199; predefined noninferiority margin 1.30]. The median OS for SOX and CS were 14.1 and 13.1 months, respectively (HR 0.958 with 95% CI 0.803-1.142). In the intention-to-treat population (SOX, n = 339; CS, n = 337), the HRs in PFS and OS were 0.979 (95% CI 0.821-1.167) and 0.934 (95% CI 0.786-1.108), respectively. The most common ≥grade 3 adverse events (SOX versus CS) were neutropenia (19.5% versus 41.8%), anemia (15.1% versus 32.5%), hyponatremia (4.4% versus 13.4%), febrile neutropenia (0.9% versus 6.9%), and sensory neuropathy (4.7% versus 0%). CONCLUSION SOX is as effective as CS for AGC with favorable safety profile, therefore SOX can replace CS. CLINICAL TRIAL NUMBER JapicCTI-101021.

Phase II study of paclitaxel with 3-h infusion in patients with advanced gastric cancer

Abstract.Abstract.Background: To increase the options for agents for gastric cancer chemotherapy, we performed a phase II clinical trial on the use of a 3-h infusion of paclitaxel to confirm its efficacy and the feasibility of its use in patients with advanced gastric cancer.Methods: Thirty-two (32) patients with measurable metastatic gastric cancer were enrolled in this study. Seventeen patients (53%) had received prior chemotherapy for metastatic disease, 4 patients (13%) had adjuvant chemotherapy alone, and 11 patients (34%) were chemotherapy-naive.Paclitaxel was intravenously infused for 3 h, at a dose of 210 mg/m2, once every 3 weeks. To prevent hypersensitivity reactions, standard premedication was administered to all patients.Results: Nine (28%; 9/32 ) objective partial responses (PRs) were observed (95% confidence interval [CI], 14%–47%), and the remaining 23 patients showed stable (12 patients; 37.5%) and progressive disease (11 patients; 34.4%). The median time to response was 20 days (range, 14–38 days). The median response duration was 87 days (range, 50–103 days). The median survival of all patients was 234 days (range, 13–646+ days). The major adverse reactions were myelosuppression (grade 3/4 leukopenia and neutropenia were observed in 59% and 88% of the patients, respectively), alopecia, and peripheral neuropathy. Peripheral neuropathy was observed in 19 patients, however, most of the patients recovered after the completion of treatment.Conclusion: A 3-h infusion of paclitaxel is an effective therapy for advanced gastric cancer and is clinically well tolerated by the patients.

Phase I/II study of docetaxel and S-1 in patients with advanced gastric cancer

The aims of this phase I/II study of docetaxel and S-1 were to determine the dose-limiting toxicity (DLT), maximum-tolerated dose (MTD), and recommended dose (RD) in the phase I part and to explore the tumour response, survival and safety in the phase II part. Patients with histologically- or cytologically confirmed unresectable or recurrent gastric cancer were eligible. Treatment consisted of intravenous docetaxel on day 1 (starting dose 50 mg m−2) and oral S-1 at a fixed dose of 40 mg m−2 twice daily on days 1–14, every 4 weeks up to six cycles. Nine patients took part in the phase I portion of the study. The MTD of docetaxel was determined to be 50 mg m−2, with the DLTs of grade 3 infection associated with grade 3 neutropenia and grade 4 neutropenia during S-1 administration. The RD of docetaxel was 40 mg m−2 in combination with S-1 40 mg m−2 b.i.d. The efficacy and safety of this regimen was therefore assessed in 46 patients with at least one measurable lesion. The overall response rate and estimated median overall survival were 46% (95% CI, 31–61%) and 14.0 months (8.3–17.3 months), respectively. The most common grade 3/4 toxicity was neutropenia (67% of patients), which was predictable and manageable. This regimen showed promising activity with moderate toxicities in advanced gastric cancer.

TNF-α-inducing protein, a carcinogenic factor secreted from H. pylori, enters gastric cancer cells

TNF‐α inducing protein (Tipα) is secreted from Helicobacter pylori (H. pylori): it is a potent inducer of TNF‐α and chemokine genes, mediated through NF‐κB activation, and it also induces tumor‐promoting activity in Bhas 42 cells. To investigate the carcinogenic mechanisms of H. pylori with Tipα, we first examined how Tipα acts on gastric epithelial cells. We found that fluorescent‐Tipα specifically bound to, and then entered, the cells in a dose‐ and temperature‐dependent manner, whereas deletion mutant of Tipα (del‐Tipα), an inactive form, neither bound to nor entered the cells, suggesting the presence of a specific binding molecule. Mutagenesis analysis of Tipα revealed that a dimer formation of Tipα with a disulfide bond is required for both specific binding and induction of TNF‐α gene expression. A confocal laser scanning microscope revealed some Tipα in the nuclei, but del‐Tipα was not present, which indicated that an active form of Tipα can penetrate the nucleus and may be involved in the induction of TNF‐α gene expression. Examination of Tipα production and secretion in 28 clinical isolates revealed that H. pylori obtained from gastric cancer patients secreted Tipα in significantly higher amounts than did H. pylori from patients with chronic gastritis, suggesting that Tipα is an essential factor in H. pylori inflammation and cancer microenvironment in the human stomach. Tipα is thus a new carcinogenic factor of H. pylori that can enter the nucleus through a specific binding molecule, and its mechanism of action is completely different from that of CagA.

Germline Mutation of Dihydropyrimidine Dehydrogenese Gene among a Japanese Population in Relation to Toxicity to 5‐Fluorouracil

5‐Fluorouracil (5FU) is most commonly used in chemotherapy for human malignancy. Over 80% of administered 5FU is metabolically degraded by dihydropyrimidine dehydrogenase (DPD), a primary and rate‐limiting enzyme in the 5FU metabolic pathway. A DPD‐deficient phenotype among cancer patients, which has posed a serious problem in 5FU‐based chemotherapy, was reported to be in part ascribed to germline mutations in dihydropyrimidine dehydrogenase (DPYD) gene. Therefore, we for the first tune examined the frequencies and types of germline mutations in the DPYD gene among a total of 107 Japanese cancer patients and healthy volunteers. Of 214 alleles examined among them, 181 alleles were of the same type, which was assigned as wild type; 21 alleles revealed a nucleotide substitution resulting in silent mutation; and the remaining 12 alleles showed five types of nucleotide deletion or substitutions resulting in one frameshift and four missense mutations. Three of them, A74G, 812delT and L572V, were novel mutations. None of the study subjects showed homozygous frameshift or missense mutated alleles. We also studied the association between toxic response to 5FU and heterozygous frame shift or missense mutation of the DPYD gene among eight cancer patients who had received 5FU‐based chemotherapy. These patients did not show any adverse effects higher than grade 3, suggesting that heterozygotes are not associated with increased toxicity to 5FU. Our results indicate that a very small percentage, about 0.2%, of the Japanese population seems to carry homozygous mutations in DPYD gene, mutations which possibly indicate genetically increased toxicity of 5FU‐based chemotherapy.

Nucleolin as cell surface receptor for tumor necrosis factor-α inducing protein: a carcinogenic factor of Helicobacter pylori

PurposeTumor necrosis factor-α inducing protein (Tipα) is a unique carcinogenic factor released from Helicobacter pylori (H. pylori). Tipα specifically binds to cells and is incorporated into cytosol and nucleus, where it strongly induces expression of TNF-α and chemokine genes mediated through NF-κB activation, resulting in tumor development. To elucidate mechanism of action of Tipα, we studied a binding protein of Tipα in gastric epithelial cells.MethodsTipα binding protein was found in cell lysates of mouse gastric cancer cell line MGT-40 by FLAG-pull down assay and identified to be cell surface nucleolin by flow cytometry using anti-nucleolin antibody. Incorporation of Tipα into the cells was determined by Western blotting and expression of TNF-α gene was quantified by RT-PCR.ResultsNucleolin was co-precipitated with Tipα-FLAG, but not with del-Tipα-FLAG (an inactive mutant). After treatment with Tipα-FLAG, incorporated Tipα was co-immunoprecipitated with endogenous nucleolin using anti-nucleolin antibody. The direct binding of Tipα to recombinant His-tagged nucleolin fragment (284–710) was also confirmed. Although nucleolin is an abundant non-ribosomal protein of the nucleolus, we found that nucleolin is present on the cell surface of MGT-40 cells. Pretreatment with anti-nucleolin antibody enhanced Tipα-incorporation into the cells through nucleolin internalization. In addition, pretreatment with tunicamycin, an inhibitor of N-glycosylation, decreased the amounts of cell surface nucleolin and inhibited both internalization of Tipα and expression of TNF-α gene.ConclusionsAll the results indicate that nucleolin acts as a receptor for Tipα and shuttles Tipα from cell surface to cytosol and nuclei. These findings provide a new mechanistic insight into gastric cancer development with Tipα.

Epithelial-mesenchymal transition in human gastric cancer cell lines induced by TNF-α-inducing protein of Helicobacter pylori.

Helicobacter pylori strains produce tumor necrosis factor‐α (TNF‐α)‐inducing protein, Tipα as a carcinogenic factor in the gastric epithelium. Tipα acts as a homodimer with 38‐kDa protein, whereas del‐Tipα is an inactive monomer. H. pylori isolated from gastric cancer patients secreted large amounts of Tipα, which are incorporated into gastric cancer cells by directly binding to nucleolin on the cell surface, which is a receptor of Tipα. The binding complex induces expression of TNF‐α and chemokine genes, and activates NF‐κB (nuclear factor kappa‐light‐chain‐enhancer of activated B cells). To understand the mechanisms of Tipα in tumor progression, we looked at numerous effects of Tipα on human gastric cancer cell lines. Induction of cell migration and elongation was found to be mediated through the binding to surface nucleolin, which was inhibited by the nucleolin‐targeted siRNAs. Tipα induced formation of filopodia in MKN‐1 cells, suggesting invasive morphological changes. Tipα enhanced the phosphorylation of 11 cancer‐related proteins in serine, threonine and tyrosine, indicating activation of MEK‐ERK signal cascade. Although the downregulation of E‐cadherin was not shown in MKN‐1 cells, Tipα induced the expression of vimentin, a significant marker of the epithelial–mesenchymal transition (EMT). It is of great importance to note that Tipα reduced the Youngs modulus of MKN‐1 cells determined by atomic force microscopy: This shows lower cell stiffness and increased cell motility. The morphological changes induced in human gastric cancer cells by Tipα are significant phenotypes of EMT. This is the first report that Tipα is a new inducer of EMT, probably associated with tumor progression in human gastric carcinogenesis.

Phase I/II study of capecitabine plus oxaliplatin (XELOX) plus bevacizumab as first-line therapy in Japanese patients with metastatic colorectal cancer.

Objective The addition of bevacizumab to fluoropyrimidine-based combination chemotherapy as first-line therapy for metastatic colorectal cancer results in clinically significant improvements in patient outcome. However, clinical trials have been conducted primarily in Caucasian patients with only a small proportion of Asian patients. This Phase I/II study was designed to evaluate the efficacy and safety of XELOX (capecitabine plus oxaliplatin) plus bevacizumab in Japanese patients with metastatic colorectal cancer. Methods Patients with previously untreated, measurable metastatic colorectal cancer received bevacizumab 7.5 mg/kg and oxaliplatin 130 mg/m2 on day 1, plus capecitabine 1000 mg/m2 twice daily on days 1–14, every 3 weeks. A three-step design evaluated in: step 1, initial safety of XELOX in six patients; step 2, initial safety of XELOX plus bevacizumab in six patients; and step 3, efficacy and safety in a further 48 patients. The primary study endpoints were safety and response rate. Results No dose-limiting toxicity occurred during Steps 1 and 2. Fifty-eight patients were enrolled in Steps 2 and 3 and received XELOX plus bevacizumab. In the 57 patients assessed for response, the overall response rate was 72% (95% confidence interval, 58.5–83.0). Median progression-free survival was 11.0 months (95% confidence interval, 9.6–12.5) and median overall survival was 27.4 months (95% confidence interval, 22.0–not calculated). Eight patients (14%) underwent surgery with curative intent. The most common grade 3/4 adverse events were neurosensory toxicity (17%) and neutropenia (16%). Conclusions XELOX plus bevacizumab is effective and has a manageable tolerability profile when given to Japanese patients with metastatic colorectal cancer.