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Purpose: Anticancer drugs for double cancers are selected based on their therapeutic effects on the target cancer, but there are insufficient data on the effects of anticancer drugs on comorbid cancer. We investigated the effect of chemotherapy on comorbid cancer in patients with simultaneous double cancers., Methods: The subjects of this retrospective study were 51 patients with simultaneous double cancers at the time of receiving systemic chemotherapy. We evaluated the types of anticancer drugs used for double cancers, the therapeutic effects on targeted and comorbid cancers, and prognoses., Results: Disease control was achieved for 90.9% of the target cancers and 90.7% of the comorbid cancers. The prognosis was significantly better when the disease was controlled, not only in the target cancer but also in the comorbid cancer., Conclusion: Physicians treating double cancers should develop treatment strategies focusing not only on the treatment for advanced cancer, but also on the course of comorbidities and the therapeutic effects of anticancer drugs. This study is important because it presents new possibilities to expand the indications for anticancer drugs, while allowing unnecessary clinical research to be avoided., (© 2022. The Author(s) under exclusive licence to Springer Nature Singapore Pte Ltd.)

Purpose: The relationship between activity of the small intestinal villi and the effectiveness of chemotherapy remains unclear. This study aimed to investigate how serum diamine oxidase (DAO) activity affects antitumor effects, adverse events, and amino acid absorption., Methods: We performed a single-center prospective cohort study that enrolled 50 patients with esophageal cancer (EC) receiving docetaxel, cisplatin, and 5-fluorouracil therapy. We determined the cut-off value of serum DAO activity contributing to a response to chemotherapy using a generalized additive model. Additionally, we compared adverse events, inflammatory markers, blood amino acid levels, and quality of life between the high and low DAO activity groups during chemotherapy., Results: The cut-off value of serum DAO activity at the first visit that contributed to a chemotherapy response was 6.5 units/L. Leukopenia and neutropenia of grade ≥ 3 were significantly higher in the DAO low (< 6.5 units/L) group (p = 0.044, 0.017, respectively). Interleukin-6 was significantly lower in the DAO high (≥ 6.5 units/L) group at the first visit and at 4 weeks after the end of chemotherapy (p = 0.039, 0.011, respectively). Glutamine was higher in the DAO high group at all measurement points during chemotherapy. Fatigue was significantly lower in the DAO high group (p = 0.001)., Conclusion: Serum DAO activity may be a predictor of the response to chemotherapy in patients with EC. The absorption capacity of amino acids was maintained in the group with high DAO activity, which may have contributed to the anti-inflammatory effect and provided a background for reducing adverse events., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Background/aim: We compared the efficacy and safety of second-line FOLFIRI with bevacizumab (Bmab) or aflibercept (AFL) in patients with unresectable metastatic colorectal cancer (mCRC) to clarify selection criteria for anti-angiogenic agents., Patients and Methods: The subjects were patients with mCRC who received second-line FOLFIRI in combination with Bmab or AFL. The primary endpoint was median overall survival (OS). Secondary endpoints were median time to treatment failure (TTF), overall response rate (ORR) and incidence of adverse events., Results: Data from 26 patients in the Bmab group and 19 in the AFL group were analyzed. Median OS was slightly longer in the AFL group compared to the Bmab group, whereas median TTF was similar. ORR tended to be higher in the AFL group. The incidence of ≥grade 2 diarrhea and proteinuria was significantly higher in the AFL group than the Bmab group., Conclusion: In patients given combination treatment with FOLFIRI for second-line treatment of mCRC, AFL can increase response rates compared to Bmab, which may contribute to longer survival., (Copyright© 2021, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Background: Outpatient cancer chemotherapy may lead to improved quality of life (QOL) by allowing treatment to continue without impairing the social lives of patients compared with hospitalization. However, the occurrence of serious adverse events may cause a decline in QOL. We investigated the relationship between outpatient chemotherapy-induced adverse events and QOL., Methods: A single-center retrospective descriptive study was conducted in patients who received outpatient chemotherapy at Gifu University Hospital (Gifu, Japan) between September 2017 and December 2018. The utility values of QOL, type and severity of adverse events, type of cancer, chemotherapy regimen, and other patient demographics were analyzed. Adverse events were graded according to the Common Terminology Criteria for Adverse Events, version 4.0. QOL was evaluated using the Japanese version of the EuroQol 5 Dimension 5 Level (EQ-5D-5L). Associations between the EQ-5D-5L utility value and serious adverse events were assessed using adjusted (age and sex) odds ratios obtained with a proportional odds logistic regression model., Results: Data from 1008 patients who received 4695 chemotherapy cycles were analyzed. According to proportional odds logistic regression, the adverse events that significantly correlated with a decreased EQ-5D-5L utility value were malaise, edema of the limbs, peripheral neuropathy, pruritus, and dry skin. Based on the proportional odds logistic analysis, neither cancer type nor anticancer drugs were significantly correlated with the EQ-5D-5L utility value in patients who received chemotherapy. Pharmaceutical care for peripheral neuropathy significantly improved patients' EQ-5D-5L utility value from 0.747 to 0.776 (P < 0.01)., Conclusions: Adverse events (i.e., peripheral neuropathy, malaise, and edema of the limbs) are significantly correlated with a decrease in QOL, regardless of the type of cancer or anticancer drugs used. Pharmaceutical care provided by pharmacists in collaboration with physicians may improve QOL.

Background/aim: Liver cancer has extremely poor prognosis. The cancerous tissues contain hypoxic regions, and the available drugs are poorly effective in hypoxic environments. NADPH oxidase 4 (NOX4), producing reactive oxygen species (ROS), may contribute to cancer malignancy under hypoxic conditions. However, its role in liver cancer has not been examined in detail. Our aim was to explore the effects of setanaxib, a recently developed selective NOX4 inhibitor, in liver cancer cells under hypoxic conditions., Materials and Methods: Liver cancer cell lines (HepG2, HLE and Alexander) were treated with hypoxia-mimetic agent cobalt chloride. Cytotoxicity assays, immunoblot analysis and ROS detection assay were performed to detect the effect of setanaxib under hypoxic conditions., Results: Setanaxib exhibited hypoxia-selective cytotoxicity and triggered apoptosis in cancer cells. Moreover, setanaxib caused mitochondrial ROS accumulation under hypoxic conditions. Treatment with antioxidants markedly attenuated setanaxib-induced cytotoxicity and apoptosis under hypoxic conditions., Conclusion: Setanaxib caused mitochondrial ROS accumulation in a hypoxia-selective manner and evoked cancer cell cytotoxicity by inducing apoptosis. Thus, setanaxib has a great potential as a novel anticancer compound under hypoxic conditions., (Copyright© 2020, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Background: Regorafenib is a multiple tyrosine kinase inhibitor, and the use of this drug is approved for the treatment of cancers that are resistant to chemotherapy, which include advanced colorectal cancer, gastrointestinal stromal tumor, and hepatocellular carcinoma. However, the drug causes adverse events, including skin toxicities that require dose modification in approximately 75% of cases. At present, the blood concentration of regorafenib is not assessed in clinical settings; thus, we recently developed a method that can assess the blood concentration of the drug using high-performance liquid chromatography., Methods: We measured the trough blood concentrations (C trough ) of regorafenib and its metabolites (M2 and M5) in 14 and 4 patients with advanced colorectal cancer and gastrointestinal stromal tumor, respectively, using high-performance liquid chromatography. Then, the correlation between the C trough and therapeutic outcomes of regorafenib was analyzed., Results: In patients who were receiving regorafenib 40-160 mg/day, the C trough values of regorafenib, M2, and M5 were 318-9467, 34-3594, and 38-3796 ng/mL, respectively. The difference in the values was significant. Although the specific factors influencing this difference were not elucidated, the C trough of regorafenib was extremely lower in some patients, even though the drug was administered at a standard dose, which may explain the lower response rate. Moreover, the C trough value of M5 was significantly correlated to the incidence of skin toxicities, which is the most frequent cause of dose modification., Conclusions: The use of regorafenib may not be suitable in patients with a low C trough value. To prevent skin toxicities, the C trough value of M5 should be monitored.

Rat sarcoma (RAS) is a well-known oncogene that plays important roles in cancer proliferation, cell survival and cell invasion. RAS exists as three major isoforms, Kirsten rat sarcoma (KRAS), Harvey rat sarcoma (HRAS) and neuroblastoma rat sarcoma (NRAS). Mutations of these genes account for approximately 30% of all cancers. Among them, KRAS mutations are the most common, responsible for 85%, followed by NRAS (12%) and HRAS (3%). Although the development of RAS inhibitors has been explored for over the past decade, so far, no effective inhibitor has been found. MicroRNA (miRNA) are a class of small non-coding RNA that control the gene expression of pleural target genes at the post-transcriptional level. MiRNA play critical roles in the physiological and pathological processes at work in cancers, such as cell proliferation, cell death, cell invasion and metastasis. MicroRNA-143 (MIR143) is known to function as a tumor suppressor in a variety of cancers. One of its known mechanisms is suppression of RAS expression and its effector signaling pathways, such as PI3K/AKT and MAPK/ERK. Within the last five years, we developed a potent chemically modified MIR143-3p that enabled us to elucidate the details of the KRAS signaling networks at play in colon and other cancer cells. In this review, we will discuss the role of MIR143-3p in those RAS signaling networks that are related to various biological processes of cancer cells. In addition, we will discuss the possibility of the use of MIR143 as a therapeutic drug for targeting RAS signaling networks., (© 2020 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.)

Importance: Ramucirumab, a human IgG 1 antibody against vascular endothelial growth factor receptor 2, has been shown to improve progression-free survival and overall survival in patients with advanced gastric cancer in the second-line setting., Objective: To compare progression-free survival for S-1 and oxaliplatin plus ramucirumab with that for S-1 and oxaliplatin plus placebo in patients with advanced gastric cancer., Design, Setting, and Participants: This phase 2, double-blind randomized clinical trial (RAINSTORM [First-line S-1 Plus Oxaliplatin With or Without Ramucirumab Followed by Paclitaxel Plus Ramucirumab in Patients With Advanced Gastric Cancer]) was conducted from October 12, 2015, to April 11, 2018, at 36 sites in Japan, South Korea, and Taiwan. Participants were chemotherapy-naive patients (n = 189) with metastatic gastric or gastroesophageal adenocarcinoma. Analyses of the full analysis set and safety population were conducted between November 27, 2017, and June 4, 2018., Interventions: Patients randomized to the ramucirumab plus S-1 and oxaliplatin arm received S-1, 80 to 120 mg/d twice daily, on days 1 to 14 and oxaliplatin, 100 mg/m2, on day 1 with ramucirumab, 8 mg/kg, on days 1 and 8 in part A (21-day cycle). Patients randomized to the placebo plus S-1 and oxaliplatin arm received the same S-1 and oxaliplatin dosage as well as placebo on days 1 and 8 in part A. Eligible patients received second-line paclitaxel, 80 mg/m2, on days 1, 8, and 15 and ramucirumab, 8 mg/kg, on days 1 and 15 in part B (28-day cycle)., Main Outcomes and Measures: The primary end point was progression-free survival, analyzed using the stratified log-rank test; the hazard ratio (HR) was estimated using the stratified Cox proportional hazards regression model. Secondary end points included overall survival and adverse events., Results: In total, 189 patients were randomized and received treatment: 96 to the ramucirumab plus S-1 and oxaliplatin arm and 93 to the placebo plus S-1 and oxaliplatin arm. Among the 189 patients, 121 (64.0%) were male, and the median (range) age was 62.0 (26-84) years. Median progression-free survival was not prolonged in the ramucirumab plus S-1 and oxaliplatin arm compared with the placebo plus S-1 and oxaliplatin arm (6.34 [80% CI, 5.65-6.93] vs 6.74 [80% CI, 5.75-7.13] months; HR, 1.07; 80% CI, 0.86-1.33; P = .70). Median overall survival was 14.65 (80% CI, 12.39-15.67) months in the ramucirumab plus S-1 and oxaliplatin arm and 14.26 (80% CI, 13.83-17.31) months in the placebo plus S-1 and oxaliplatin arm (HR, 1.11; 80% CI, 0.89-1.40; P = .55). The most commonly reported grade 3 or higher treatment-emergent adverse events in the ramucirumab plus S-1 and oxaliplatin arm in part A were decreased neutrophil count (14 patients [14.6%]), hypertension (10 patients [10.4%]), and anemia (10 patients [10.4%])., Conclusions and Relevance: In this randomized clinical trial, the addition of ramucirumab to first-line S-1 and oxaliplatin treatment did not prolong progression-free survival or overall survival compared with S-1 and oxaliplatin alone among East Asian patients with advanced gastric cancer; no new safety signals for ramucirumab were identified., Trial Registration: ClinicalTrials.gov identifier: NCT02539225.

Background/aim: Dysgeusia is one of the adverse events frequently affecting patients undergoing cancer chemotherapy. Dysgeusia-induced anorexia could decrease patient's quality of life. The present study was designed to determine whether the zinc-containing compound polaprezinc improves chemotherapy-induced dysgeusia., Patients and Methods: The incidence of grade 2 dysgeusia was assessed in 634 patients receiving cancer chemotherapy in outpatient settings during January 2013 and June 2017. Polaprezinc was administered to patients showing grade 2 dysgeusia and the effect was compared with that in patients subjected to follow-up observation., Results: Grade 2 dysgeusia appeared in 80 patients (12.6%), in whom pancreatic cancer and treatment with fluoropyrimidines were significant risks for dysgeusia. Polaprezinc, when administered to patients with grade 2 dysgeusia, significantly shortened the duration of dysgeusia compared with that in the follow-up observation group. Subgroup analysis indicated that polaprezinc was less effective in patients with pancreatic cancer, those receiving gemcitabine, or those whose age was 65 year-old and over., Conclusion: Chemotherapy-induced dysgeusia occurred with high frequency in patients with pancreatic cancer or in those receiving fluoropyrimidines. Polaprezinc was highly effective in improving the symptom of dysgeusia, except for patients with pancreatic cancer, those receiving gemcitabine and the elderly., (Copyright© 2018, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Background: According to the Response Evaluation Criteria in Solid Tumors (RECIST), progressive disease (PD) is diagnosed under two conditions: an increase in size of pre-existing lesions (IS) and the appearance of new lesions (NL). We retrospectively investigated the difference in the prognosis between IS and NL., Methods: Patients receiving drug therapies for metastatic breast cancer between 2004 and 2015 at our institution were reviewed. The survival time after NL and IS was compared and the frequency of NL with each drug calculated., Results: For the 107 eligible patients, the survival time after NL at second-line chemotherapy was significantly worse than after IS (median survival time 4.3 months vs. 20.3 months, p = 0.0048). Maintenance therapy with bevacizumab or trastuzumab had a high frequency of NL (88.9%), and third-line eribulin had a low frequency of NL (16.7%). A multivariate analysis showed that NL at second-line chemotherapy was not an independent risk factor (hazard ratio 1.02, 95%; confidence interval 0.54-1.93, p = 0.95) for the total survival time., Conclusions: Patients with IS had a better survival after PD than those with NL. We may be able to avoid changing drug therapy for patients without NL and allow them to continue drug therapy for longer.

Objectives: Chemotherapy is an indispensable therapeutic approach for colorectal cancer both in the adjuvant and metastatic setting. Although chemotherapy-induced nausea and vomiting (CINV) is one of the most crucial adverse events, many aspects of CINV in patients with colorectal cancer remain unclear., Methods: This multicenter, prospective, observational study analyzed the data of 190 colorectal cancer patients scheduled for moderately emetogenic chemotherapy (MEC). The patients recorded the incidence of CINV and severity of nausea by visual analogue scales daily for 7 days after receiving chemotherapy., Results: All 190 patients received MEC and 99% of patients received antiemetic therapy in compliance with guidelines. Acute CINV was well controlled. 13 (6.8%) patients suffered from acute nausea and 4 (2.1%) experienced acute vomiting, whereas the prevalence of delayed CINV was relatively high. Delayed nausea occurred in 71 (37.4%) patients and delayed vomiting in 24 (12.6%). History of motion sickness was a significant independent risk factor for delayed nausea (Odd ratio 3.89, 95% confidence interval 1.49-10.19, p = 0.0056)., Conclusions: The compliance with CINV guidelines in colorectal cancer chemotherapy was quite high and led to good control of chemotherapy-induced vomiting in Japan. However, the incidence of delayed nausea remained high in patients receiving MEC.

Background: We conducted a nationwide survey on chemotherapy-induced nausea and vomiting (CINV) in Japan and demonstrated good compliance with Japanese CINV guidelines, resulting in good control of vomiting. However, almost half the patients experienced breakthrough CINV. We analyzed the survey results in relationship to the management of patients with breakthrough CINV., Methods: This multicenter, prospective, observational study analyzed data for 1910 patients in Japan scheduled for moderately or highly emetogenic chemotherapy (MEC and HEC, respectively). Patients who developed CINV despite prophylactic use of antiemetics were administered rescue drugs. Patients who received cisplatin-based HEC (C-HEC), non-cisplatin-based HEC (N-HEC), or MEC were evaluated separately., Results: A total of 989 patients experienced CINV, of whom 412 (44%) received rescue antiemetics during the study period. The rate at which patients with breakthrough CINV were started on rescue drugs ranged from 13% to 24%. Rescue drugs were given more frequently on days 2-4 for C-HEC and MEC and on days 1-2 for N-HEC. Eighty-six percent of patients received metoclopramide or domperidone. 5-HT 3 receptor antagonists, antipsychotics, and anti-anxiety drugs were used for 11-5% of patients. The mean duration of antiemetic use was 2.6 days., Conclusions: Fewer than half of the patients with breakthrough CINV were treated with rescue antiemetics, suggesting that CINV was mild in the remaining patients. However, CINV was sufficiently severe to prevent eating in other patients, indicating the need for new drugs with different mechanisms to control CINV.

Background: Chemotherapy with moderate emetic risk (MEC), including irinotecan-based and oxaliplatin-based chemotherapy regimens, are predominantly used for colorectal cancer chemotherapy. Chemotherapy-induced nausea and vomiting (CINV) remain unsatisfactorily controlled., Patients and Methods: The rates of prevalence of antiemetic medication and the control of CINV were investigated from medical records in patients with colorectal cancer who received the first cycle of irinotecan-based or oxaliplatin-based regimens. Risks for CINV were determined by multivariate logistic regression analysis., Results: A total of 179 patients received the first cycle of MEC regimens and the number of overall cycles was 2,176 during the study period from January 2013 to December 2015. Guideline-consistent antiemetic medication was performed in most cases. The rate of no-CINV was nearly 90% during the overall period. Female sex and age under 50 years were significant risks for CINV. Comparison considering only the group aged 50 years or more indicated that the control of CINV was significantly worse in irinotecan-based regimens than in the oxaliplatin-based regimens., Conclusion: Female sex and age younger than 50 years were significant risks for CINV in patients receiving MEC for colorectal cancer. Moreover, the control of CINV was less sufficient for irinotecan-based than for oxaliplatin-based regimens., (Copyright© 2016 International Institute of Anticancer Research (Dr. John G. Delinassios), All rights reserved.)

Although standard chemotherapy for esophageal cancer patients is fluorouracil and cisplatin, the prognosis is still unsatisfactory. A new therapeutic regimen combining docetaxel, cisplatin, and 5-fluorouracil was recently developed to improve both local and distant tumor control. We developed a new regimen of docetaxel, nedaplatin, and S1 (DGS) and previously reported the recommended dose in a phase I dose-escalation study. We then undertook a phase II study of DGS for advanced esophageal squamous cell carcinoma. Patients with clinical stage IB/II/III disease were eligible. Patients received two courses of chemotherapy: docetaxel 35 mg/m(2) with nedaplatin 40 mg/m(2) on day 8, 80 mg/m(2) S1 on days 1-14, and 2 weeks off. After completion of chemotherapy, patients underwent esophagectomy. The primary endpoint was the completion rate of protocol treatment (completion of two courses of preoperative chemotherapy and R0 surgery [no residual tumor]). We enrolled 32 patients. The completion rate of protocol treatment was 96.9%. During chemotherapy, the most common grade 3 or 4 toxicity was neutropenia (25.0%). No treatment-related deaths were observed, and the incidence of operative morbidity was tolerable. The overall response rate after chemotherapy was 83.3%. This DGS regimen was well tolerated and highly active. This trial is registered with the University Hospital Medical Information Network (UMIN ID: 000014626)., (© 2016 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.)

Resistance to chemotherapy is a crucial problem in the clinical situation. To overcome this issue, many mechanisms of chemoresistance have been elucidated so far. However, this problem still has not been solved completely. In this study, we investigated the mechanism of chemoresistance from the view of cancer metabolism-related genes, especially focusing on the expression profile of pyruvate kinase muscle (PKM) isoforms, which are rate-limiting enzymes in cancer-specific metabolism (Warburg effect). Herein, we showed that PKM1, which promotes oxidative phosphorylation (OXPHOS), was commonly up-regulated in various chemoresistant cells. To clarify the functions of PKM1 in chemoresistance, we investigated effects of PKM1 expression in DLD-1 parental, 5-FU-resistant and oxaliplatin-resistant DLD-1 cells. The overexpression of PKM1 resulted in resistance of the parental cells to 5-FU and oxaliplatin. Moreover, gene-silencing of PKM1 induced apoptosis in these cells including the resistant cells by causing a decrease in the mitochondrial membrane potential. Furthermore, combination therapy using 5-FU or oxaliplatin with siR-PKM1 was also effective against the resistant cells. Our findings should lead to the development of new agents that can cancel the chemoresistance from the view of cancer energy metabolism., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Targeted molecular therapy is an effective anticancer strategy. Anti-EGFR monoclonal antibodies such as cetuximab (CTX) have been approved for the treatment of various malignancies, including colorectal cancer (CRC) with wild-type KRAS. However, their efficacy in patients with KRAS mutations has not been established. Therefore, we investigated whether CTX treatment was effective as a single agent or in combination with zoledronic acid (ZOL) in human CRC cell lines with different KRAS status. CRC cell lines SW48 (wild-type KRAS) and LS174T (mutant KRAS) were treated with ZOL, CTX and a combination of both drugs. Cytotoxicity was measured using the MTT assay. Changes in the levels of intracellular signaling proteins were evaluated using western blot analysis. Finally, we evaluated the efficacy of the combination treatment in an in vivo xenograft model. We observed that ZOL apparently inhibited growth in both cell lines, whereas CTX showed little effect. ZOL also increased the levels of unprenylated RAS. Combined ZOL and CTX treatment was synergistic in both cell lines and was associated with inhibition of the RAS-MAPK and AKT-mTOR signaling pathways. Furthermore, the combination treatment was more effective in suppressing the growth of xenografts derived from both SW48 and LS174T cells; this effect was associated with increased apoptosis. These results demonstrate that ZOL inhibits the growth of colon cancer cells regardless of KRAS status, and combination therapy using ZOL and CTX enhances this growth suppression. These findings suggest a novel strategy for the treatment of CRC independent of KRAS mutational status., (© 2015 The Authors International Journal of Cancer published by John Wiley & Sons Ltd on behalf of UICC.)

Purpose: Although anti-EGFR monoclonal antibodies, including cetuximab and panitumumab, are highly effective in KRAS wild-type advanced colorectal cancer, these drugs frequently cause several adverse events. These events include hypomagnesemia and acneiform rash, which may lead to the dose reduction or discontinuation of therapy. In the present study, we retrospectively investigated the incidence of hypomagnesemia and acneiform rash in patients with metastatic colorectal cancer (mCRC). We examined the relationship between the incidence of such adverse events and the therapeutic effect., Methods: Thirty-four mCRC patients receiving anti -EGFR monoclonal antibody as a first-line therapy during April 2012 to March 2015 were the subjects of the present study. The symptoms of hypomagnesemia and acneiform rash were graded in accordance with the Common Terminology Criteria for Adverse Events, v4.0., Results: The incidence rates of hypomagnesemia (all grades) and the acneiform rash (≥grade 2) were 29%and 50%, respectively. Eight patients (24%) exhibited both of these adverse events. The tumor response rate was notable, as it was significantly higher in patients who experienced both of these adverse events compared to those who did not(88% vs 38% for complete response plus partial response, p=0.039). However, the tumor response rate tended to be higher, although not significantly, in patients with either of these adverse events compared to those without it., Conclusion: Concurrent onset of hypomagnesemia and acneiform rash may become a reliable factor capable of predicting the therapeutic effect of anti-EGFR monoclonal antibody.

Multidisciplinary therapy is essential in the treatment of borderline resectable pancreatic cancer involving the superior mesenteric artery (BR-SMA). We analyzed the outcomes of multidisciplinary treatment for BR-SMA and evaluated the efficacy of neoadjuvant therapy (NAT). We reviewed the clinical courses of 10 patients with BR-SMA. Seven patients were treated with preoperative neoadjuvant therapy (NAT group), and 3 patients underwent radical pancreaticoduodenectomy first (SF group). In the NAT group, the rate of R0 was 7/7 (100%), the induction rate of postoperative adjuvant chemotherapy (AC) was 6/7 (86%), and the first recurrence sites were the lung in 4 patients, and the liver and peritoneum in one patient each, respectively. In the SF group, the rate of R0 was 2/3 (67%) because of a positive pathological dissecting peripancreatic margin in 1 case. The induction rate of AC was 3/3 (100%), and the first recurrence sites were the liver in 2 patients, the peritoneum in 1, and a local site in 1. The disease free survival of the NAT group (median survival time [MST] 19.3 months) was significantly better than that of the SF group (MST 5.7 months) (log rank test, p=0.002). The median overall survival of the NAT and SF groups was 51.6 months and 19.5 months, respectively (p=0.128). An R0 resection could be performed in all cases in the NAT group. The NAT extended disease-free survival. We conclude that NAT is recommended in the treatment of BR-SMA.

Our previous study showed that administering oxaliplatin as first-line chemotherapy increased ERCC1 and DPD levels in liver colorectal cancers (CRCs) metastases. Second, whether the anti-VEGF monoclonal antibody bevacizumab alters tumoral VEGFA levels is unknown. We conducted this multicenter observational study to validate our previous findings on ERCC1 and DPD, and clarify the response of VEGFA expression to bavacizumab administration. 346 CRC patients with liver metastases were enrolled at 22 Japanese institutes. Resected liver metastases were available for 175 patients previously treated with oxaliplatin-based chemotherapy (chemotherapy group) and 171 receiving no previous chemotherapy (non-chemotherapy group). ERCC1, DPYD, and VEGFA mRNA levels were measured by real-time RT-PCR. ERCC1 mRNA expression was significantly higher in the chemotherapy group than in the non-chemotherapy group (P = 0.033), and were significantly correlated (Spearman's correlation coefficient = 0.42; P < 0.0001). VEGFA expression level was higher in patients receiving bevacizumab (n = 51) than in those who did not (n = 251) (P = 0.007). This study confirmed that first-line oxaliplatin-based chemotherapy increases ERCC1 and DPYD expression levels, potentially enhancing chemosensitivity to subsequent therapy. We also found that bevacizumab induces VEGFA expression in tumor cells, suggesting a biologic rationale for extending bevacizumab treatment beyond first progression.

Background: Many cancer patients suffer from the common side effect of chemotherapy-induced nausea and vomiting (CINV). Guidelines recommend a combination of two prophylactic antiemetics for moderately emetogenic chemotherapy (MEC) and three for highly emetogenic chemotherapy (HEC) and certain MEC regimens., Methods: This multicenter, prospective, observational study analyzed data for 1,910 patients in Japan scheduled for MEC or HEC. Use of antiemetic prophylaxis in relation to type of chemotherapy, incidences of and risk factors for nausea, vomiting, and acute versus delayed CINV, and estimated incidence of CINV by staff were analyzed using Fisher's exact test and multivariate logistic regression. The patients recorded the incidence of CINV and severity of nausea by visual analogue scales daily for 7 days after receiving chemotherapy., Results: A total of 240 (20.1 %) HEC and 476 MEC patients (66.6 %) received 2 antiemetics, compared with 883 (73.9 %) and 200 (28.0 %), respectively, who received 3 antiemetics. Approximately 74 % of HEC and 95 % of MEC patients received antiemetic therapy in compliance with guidelines. Acute nausea and vomiting were well controlled, but high incidences of delayed nausea occurred in both HEC and MEC patients. Delayed vomiting (p < 0.0001) was significantly less frequent in patients receiving three compared with 2 antiemetics. Female sex was a major risk factor for CINV. Medical staff tended to overestimate the incidence of CINV. Among HEC regimens, the incidence of CINV and the degree of nausea on day 1 of anthracycline-cyclophosphamide combination therapy were higher than with a cisplatin-based regimen., Conclusions: Adherence to antiemetic guidelines effectively controls vomiting but is less effective against delayed nausea in HEC and MEC patients. Identification of individual risk factors, such as female sex, will assist in the development of personalized treatments for CINV. More intensive antiemetic therapy or a different modality of prophylaxis should be considered for the control of acute CINV in an anthracycline-cyclophosphamide regimen.

To evaluate a novel therapy for triple-negative breast cancer (TNBC), the biological responses to vitamin K3 (VK3) should be considered with the understanding of the features of breast cancer. In human breast cancer cell lines, the effects of VK3 on cell growth inhibition and the cellular signaling pathway were determined by MTT assay and western blotting. In the in vivo study, a subcutaneous tumor model of breast cancer was created, VK3 was injected into the subcutaneous tumors, and tumor size was measured. The IC50 of VK3 for breast cancer cells was calculated to be 11.3-25.1 µM. VK3 induced phosphorylation of whole tyrosine and epidermal growth factor receptor. VK3 mediated phosphorylation of extracellular signal-regulated kinase (ERK) and c-Jun NH2-terminal kinase (JNK) for 30 min. ERK but not JNK phosphorylation was maintained for at least 6 h. In contrast, another antioxidant agent, catalase, showed no effect on either ERK phosphorylation or growth inhibition. On built-up tumors under the skin of mice, local treatment with VK3 was effective in a time- and dose-dependent manner, and the experiments for total tumor volume also showed a dose-dependent effect of VK3. The expression of phosphorylated ERK was clearly detected at 10.9 times the control in tumor tissue, whereas ethanol itself showed no effect. In conclusion, ERK plays a critical role in VK3-induced growth inhibition, and it will be the focus of next steps in the development of molecular therapy for TNBC.

Prevention of chemotherapy-induced nausea and vomiting (CINV) according to the clinical practice guidelines is particularly important. In the present study, we investigated the adherence to the guidelines for antiemetic medication and the control of CINV in 61 patients with colorectal cancer receiving the first course of chemotherapy of moderate emetic risk at our outpatient cancer chemotherapy clinic. Furthermore, we carried out intervention to improve evidence-based antiemetic medication in another 64 patients. The rate of adherence to the antiemetic guidelines was only 6.6%; non-adherence was due mostly to the lack of dexamethasone treatment on days 2 and 3. In the interventional group, antiemetic medication adherence was markedly enhanced to 89%, which led to a significant enhancement of complete protection from nausea and vomiting during-delayed period (days 2-5 after chemotherapy) from 54% to 74% (p<0.05), although the daily dose of dexamethasone was 4 mg, lower than that recommended by the guidelines (8 mg). Finally, we evaluated the effect of dexamethasone at a daily dose of 4 mg, since little is known about the efficacy of such dose. Dexamethasone at this dose was found to be effective at elevating the rate of complete protection from nausea and vomiting during-delayed period (increase of 20%, p<0.05). These findings suggest that medication intervention to reduce the gap between guidelines and clinical practice improves the emetic control in patients with colorectal cancer receiving moderately-emetic chemotherapy.

Rationale, Aims and Objectives: Outpatient cancer chemotherapy is increasing with the development of anticancer agents, and roles of medical staff are becoming more and more important in cancer chemotherapy. We showed here roles of pharmacists with experience in oncology and evaluated outcomes of their activities in medical practices in cancer chemotherapy clinic., Methods: Two pharmacists were newly assigned to the outpatient cancer chemotherapy clinic, where they were in charge of verification of prescription orders, mixing of anticancer injections, monitoring adverse drug reactions, implementation of supportive care and provision of information about cancer chemotherapy to medical staff and patients. The number of patients, amounts of mixing of anticancer injections and hospital revenue were compared before and after assignment of pharmacists. Management of chemotherapy-induced nausea and vomiting in breast cancer patients receiving the combination chemotherapy with anthracycline and cyclophosphamide were also compared., Results: Pharmacists spent 75 hours per month in patient education and adverse drug reactions monitoring, which led to the reduction of the workload of physicians. As a consequence, the number of outpatients and the resultant hospital revenue markedly increased. In addition, facilitation of proper use of anti-emetic drugs led to the improved control of chemotherapy-induced nausea with reducing the cost for anti-emesis by 16%., Conclusions: Pharmacists contributed to the improved efficiency of medical practices., (© 2011 Blackwell Publishing Ltd.)

Aim: More effective regimens are urgently needed for treatment of esophageal carcinoma; therefore, we conducted a phase I trial of a combination of docetaxel, nedaplatin, and S-1 (DGS) to determine the optimal dose in patients with advanced esophageal carcinoma., Patients and Methods: We studied 14 patients with previously untreated advanced cervical esophageal carcinoma with T3-4 tumors and/or M1 staging and esophageal carcinoma with cervical lymph node metastasis. The patients received an infusion of docetaxel at different dose levels (levels 1, 2, 3, 4: 25, 30, 35, 40 mg/m(2), respectively) and an infusion of nedaplatin (40 mg/m(2)) on day 8 plus oral administration of S1 (80 mg/m(2)/day) for two consecutive weeks at two-week intervals., Results: Dose-limiting toxicities (DLTs) included febrile neutropenia and leukopenia. DLTs occurred in 2 out of 5 patients at level 4. The response rate was 78.6 (11/14)%, including a complete response rate of 35.7(5/14)%., Conclusion: The DGS regimen reported here was well tolerated and toxicities were manageable. The maximum tolerated dose was level 4, and the recommended dose was determined to be docetaxel at 35 mg/m(2) with nedaplatin at 40 mg/m(2) plus S1 at 80 mg/m(2). We found that our regimen, administered on an outpatient basis, showed high activity and tolerance. A phase II study has been started.

Purpose: The purpose of this study was to evaluate the efficacy of(adjuvant)surgery following the response to chemotherapy for advanced gastric cancer., Subjects and Methods: The subjects were 20 advanced gastric cancer patients who had undergone gastrectomy following the response to combination chemotherapy with docetaxel and S-1 from September 2003 to December 2008. They consisted of 14 men and 6 women, with a median age of 58. 8, who received combination chemotherapy with docetaxel and S-1 according to the following regimen: S-1, 80 mg/m2, was administered on 14 consecutive days followed by a 7-day rest period, and docetaxel, 40 mg/m2, was administered on day 1., Results: The average treatment was 4. 4 courses. They consisted of 17 PR and 3 SD. The median overall survival was 855 days. 2-year and 3-year survival was seen in 80% and 54. 9% of patients, respectively, following macroscopically curative operation. Median survival of patients with liver metastasis and peritoneal dissemination was 865 days and 510 days, respectively., Conclusion: Adjuvant surgery might be effective in advanced gastric cancer patients except for cases of peritoneal dissemination.

To elucidate the mechanism of resistance to 5-fluorouracil (5-FU) in human gastric cancer cells, we established a cell line MKN45/F2R, which acquired 5-FU resistance as a result of continuous exposure to increasing dosages of 5-FU over a year. The cell line showed 157-fold elevated 5-FU resistance compared to the MKN45 human gastric cancer parental cell line. Furthermore, the cells acquired crossresistance to paclitaxel and docetaxel. To identify the mechanism of 5-FU resistance, the expressions of 5-FU metabolic enzymes were examined. Although protein expression and activity of thymidylate synthase and dihydropyrimidine dehydrogenase did not change, orotate phosphoribosyl-transferase (OPRT) protein expression and activity significantly decreased in the 5-FU resistant MKN45/F2R cells. Interestingly, expression of proteins related to taxane resistance including P-glycoprotein, class III beta-tubulin and Bcl-2 increased in MKN45/F2R cells. OPRT-knockout MKN45 parent cells using small interfering RNA demonstrated 15.8-fold increased resistance to 5-FU compared to the control cells. However, resistance to paclitaxel and docetaxel was not observed. These results strongly indicate that decreased activity of OPRT plays an important role in the acquired resistance of gastric cancer cells towards 5-FU; however, it does not play a direct role in paclitaxel and docetaxel resistance. Further studies are now underway to identify genes related to crossresistance to these chemotherapeutic agents.

Prior laboratory prediction of individual drug response is of key importance in esophageal squamous cell carcinoma (ESCC), because of the extremely narrow therapeutic index of chemotherapy. However, very few critical markers have been validated to date for ESCC. We previously demonstrated that simultaneous performance of two different types of comprehensive gene expression analysis might provide a way to identify potent marker genes for drug sensitivity from the expression-sensitivity correlation analysis alone, but the screening method appeared not to be always effective. Therefore, we attempted to identify novel potent marker genes using a new statistical analysis of oligonucleotide microarray expression data, based on a two-dimensional mixed normal model, and selected 3 and 7 novel candidates for 5-fluorouracil (5-FU) and cis-platinum (CDDP), respectively. Interferon induced transmembrane protein 1 (IFITM1) gene alone, being suggested as a key gene of Wnt pathway, was commonly selected in both screening methods. The transfection analyses and siRNA-mediated knock-down experiments revealed that expression of IFITM1 closely related to cellular sensitivity to CDDP. Considering the fact that drug sensitivity is determined by multiple genes, we established the best linear model using quantified expression data of a set of all the selected marker genes including IFITM1, which converted the quantified expression data of ESCC cell lines into an IC50 value of each drug. In the same way, using the representative genes selected in vitro, we developed highly predictive formulae for disease-free survival (DFS) of the CDDP/5-FU combination after curative operation in esophageal cancer patients (R=0.917). A two-dimensional mixed normal model can be a powerful tool to identify novel drug-response determinants, and the IFITM1 gene selected by the statistical method a novel critical biomarker of CDDP response in ESCC.

The effect of conjugated linoleic acid (CLA) on pre-existent peritoneal metastasis was examined by mouse peritoneal metastasis models. The cell growth of LL2 mouse cancer cells was suppressed by CLA in a dose-dependent manner. CLA-induced growth inhibition was recovered by the exposure to antisense S-oligodeoxynucleotide for peroxisome proliferator-activated receptor (PPAR)-gamma. C57B6 mice were inoculated with LL2 cells into their peritoneal cavity. Two weeks after inoculation, colonized peritoneal cancer foci (2.2+/-0.4 mm in diameter) were treated with CLA administrated intraperitoneally (200 or 600 pmol/mouse, twice a week). CLA treatment decreased the number of peritoneal tumors: 8.7+/-0.6, 5.7+/-0.6, and 2.3+/-0.6 in untreated, 200 pmol/mouse CLA, and 600 pmol/mouse CLA groups, respectively (P<0.0001). CLA treatment decreased the size of peritoneal tumors: 3.7+/-1.5, 1.3+/-0.5, and 1.0+/-0.4 mm in untreated, 200 pmol/mouse CLA, and 600 pmol/mouse CLA groups, respectively (P<0.0001). In CLA-treated tumors, proliferating cells were decreased (P<0.0001), whereas apoptotic cells were increased (P=0.0010). CLA-treated LL2 tumors showed decrease of PPARgamma and EGFR proteins and increase of BAX protein in comparison with untreated tumors. These findings suggest that CLA possesses anti-tumor capability to peritoneal metastasis.

The effect on peritoneal metastasis of linoleic acid (LA) was examined using in vitro treatment of cancer cells and mouse peritoneal metastasis models. Firstly, cell growth of MKN28 human gastric cancer cells and Colo320 human colon cancer cells was suppressed by LA in a dose-dependent manner with increment of apoptosis. LA-induced growth inhibition was recovered by the exposure to antisense S-oligodeoxynucleotide for peroxisome proliferator-activated receptor gamma (PPARgamma) or 15-lipoxygenase-1, which converts LA to PPARgamma ligands. LA significantly inhibited invasion into type-IV collagen-coated membrane of MKN28 and Colo320 cells (p<0.05). BALB/c nu/nu mice inoculated with MKN28 and Colo320 cells into their peritoneal cavities were administrated with LA intraperitoneally (weekly, four times). The LA treatment significantly diminished the number of metastatic foci of both cells in the peritoneal cavity (p<0.05). Protein production in MKN28 and Colo320 cells treated with LA showed a decrease of epidermal growth factor receptor and an increase of Bax. These findings suggest that LA inhibits invasion and metastasis of human gastric and colon cancer cells by nondietary administration.

We developed concise, accurate prediction models of the in vitro activity for 8 anticancer drugs (5-FU, CDDP, MMC, DOX, CPT-11, SN-38, TXL and TXT), along with individual clinical responses to 5-FU using expression data of 12 genes. We first performed cDNA microarray analysis and MTT assay of 19 human cancer cell lines to sort out genes which were correlative in expression levels with cytotoxicities of the 8 drugs; we selected 13 genes with proven functional significance to drug sensitivity from a huge number of potent prediction marker genes. The correlation significance of each was confirmed using expression data quantified by real-time RT-PCR, and finally 12 genes (ABCB1, ABCG2, CYP2C8, CYP3A4, DPYD, GSTP1, MGMT, NQO1, POR, TOP2A, TUBB and TYMS) were selected as more reliable predictors of drug response. Using multiple regression analysis, we fixed 8 prediction formulae which embraced the variable expressions of the 12 genes and arranged them in order, to predict the efficacy of the drugs by referring to the value of Akaike's information criterion for each sample. These formulae appeared to accurately predict the in vitro efficacy of the drugs. For the first clinical application model, we fixed prediction formulae for individual clinical response to 5-FU in the same way using 41 clinical samples obtained from 30 gastric cancer patients and found to be of predictive value in terms of survival, time to treatment failure and tumor growth. None of the 12 selected genes alone could predict such clinical responses., (Copyright 2004 Wiley-Liss, Inc.)

In the present study, we examined the expression of peroxisome proliferator-activated receptor gamma (PPARgamma) and the growth-inhibitory effects of Troglitazone and Pioglitazone, selective ligands for PPARgamma, using a series of human esophageal carcinoma cell lines (TE-1, -3, -7, -8, -12 and -13). PPARgamma expression was detected in all six human esophageal carcinoma cell lines. The esophageal carcinoma cell line TE-13 showed marked growth inhibition in response to Troglitazone and Pioglitazone. Flow cytometry performed on TE-13 cells exposed to Troglitazone showed that the cell cycle was arrested at the G1-phase. This result was confirmed by the finding of reduced cyclin D and cyclin E expression by Western blot analysis. DNA ladder formation was also detected, as was the induction of apoptosis-related proteins. Our results suggested that Troglitazone inhibited the growth of human esophageal carcinoma cell lines via G1 arrest and apoptosis and that PPARgamma ligands should be considered as possible target molecules in the treatment of human esophageal carcinomas.

Background: It has been reported recently that the antidiabetic thiazolidinediones not only induce fibroblast differentiation but also inhibit the growth of carcinoma cells., Materials and Methods: In the present study, in order to elucidate the further mechanism of growth inhibition by troglitazone, the expression of cell cycle regulators and apoptotic regulators were examined by cDNA microarrays and Western blot analysis by gastric carcinoma cells., Results: Six gastric carcinoma cell lines (TMK-1, MKN-1,7,28,45,74) were treated with 0.1, 1, 10, 100 microM of troglitazone in vitro. The growth of 5 cell lines were inhibited by troglitazone in a time- and dose-dependent manner. Interestingly, the expression of cyclin D mRNA and protein was decreased and that of p27 was increased in TMK-1 cells at 12 hours after troglitazone treatment, suggesting the induction of cell cycle arrest of the cells. On the other hand, DNA ladder formation was observed at 12 hours after treatment. Moreover, the expression of cytochrome C, caspases 3 and 8 and PARP genes was increased after treatment and the gradual reduction of Bcl-XL protein was observed, which indicate that the apoptotic signals were induced after treatment by troglitazone., Conclusion: These results suggest that the thiazolidinediones can be a new therapeutic tool for gastric carcinoma via cell cycle regulation and apoptosis.

Objective: TAS‐102 is effective for treating patients with metastatic colorectal cancer (mCRC). This study determined whether combining bevacizumab (Bmab) with TAS‐102 improves clinical outcomes in refractory mCRC. Patients and Methods: We retrospectively analyzed data from Japanese patients with refractory mCRC who received TAS‐102 (35 mg/m2, twice a day) with (T‐B group) or without Bmab (TAS‐102 monotherapy; T group) between July 2014 and December 2018. The primary endpoint was median overall survival (OS), and secondary endpoints were median time to treatment failure, overall response rate, and the incidence of adverse events. Clinical outcomes were compared using propensity score matched analysis. Results: Data from 57 patients were analyzed (T‐B group: 21 patients, T group: 36 patients). Median OS was significantly longer in the T‐B group than the T group (14.4 months vs. 4.5 months, p <.001). Cox proportional hazard analysis showed that combination therapy with Bmab was significantly correlated with OS. Propensity score matched analysis confirmed that the median OS was significantly longer in the T‐B group than the T group (14.4 months vs. 6.1 months, p =.006) and that there was a significant correlation between Bmab and OS. The incidence of hypertension (grade ≥2) as an adverse event was significantly higher in the T‐B group than the T group (23.8% vs. 0.0%, p =.005), whereas other adverse events were comparable between the two groups. Conclusion: Treatment with Bmab in combination with TAS‐102 is significantly associated with improved clinical outcomes in patients with mCRC refractory to standard therapies. Implications for Practice: Combining bevacizumab (Bmab) with TAS‐102 significantly improved overall survival and several prognostic indicators in patients with metastatic colorectal cancer (mCRC) refractory to standard therapies, with manageable toxicities. Treatment with Bmab in combination with TAS‐102 is significantly associated with improved clinical outcomes in patients with mCRC. To determine whether combined treatment with bevacizumab improves clinical outcomes, this retrospective study compared the efficacy and safety of treatment with or without bevacizumab in patients receiving TAS‐102 for metastatic colorectal cancer. [ABSTRACT FROM AUTHOR]

Purpose: Anti-epidermal growth factor receptor antibody therapy alone or in combination with irinotecan is recognized as a standard third-line treatment for KRAS wild-type unresectable metastatic colorectal cancer. However, in some cases, it is difficult to administer irinotecan after third-line treatment. Therefore, we examined the efficacy and safety of the combination of cetuximab and S-1 in patients with KRAS wild-type unresectable metastatic colorectal cancer who were previously treated with irinotecan, oxaliplatin, and fluoropyrimidines.Methods: The study was designed as a phase II, non-randomized, open-label, multicenter trial. Cetuximab was initially administered at 400 mg/m(2), followed by weekly infusion at 250 mg/m(2). S-1 was administered at a fixed dose of 80 mg/m(2) orally twice daily for 28 days followed by a 14-day break, resulting in a 6-week treatment course. The primary endpoint was progression-free survival (PFS). The secondary endpoints were the overall response rate (ORR), overall survival (OS), disease control rate (DCR), time to treatment failure, dose intensity, safety, and BRAF mutation status.Results: Thirty-seven patients were eligible. The median PFS was 5.5 months, the median OS was 13.5 months, the ORR was 29.7 %, and the DCR was 73.0 %. The relative dose intensity was 86.8 % for cetuximab and 88.1 % for S-1. Grade 3-4 adverse events that occurred in >10 % of the patient population included rash, dry skin, diarrhea, paronychia, anorexia, fatigue, mucositis, and neutropenia.Conclusions: Combination therapy with cetuximab and S-1 was effective and well tolerated in patients with irinotecan-, oxaliplatin-, and fluoropyrimidine-refractory metastatic colorectal cancer. [ABSTRACT FROM AUTHOR]

The prognosis of esophageal cancer patients is still unsatisfactory. Although a docetaxel, cisplatin, and 5-Fu (DCF) regimen has been reported, it is often difficult to accomplish because of severe toxicity. Therefore, we developed a new biweekly DCF (Bi-DCF) regimen and previously reported the recommended dose in a phase I dose-escalation study. We then performed a phase II study of Bi-DCF for advanced esophageal squamous cell carcinoma (SCC). Patients with clinical stage II/III were eligible. Patients received 2 courses of chemotherapy: docetaxel 35 mg/m(2) with cisplatin 40 mg/m(2) on days 1 and 15 and 400 mg/m(2) 5-fluorouracil on days 1-5 and 15-19 every 4 weeks. After completion of the chemotherapy, patients received esophagectomy. The primary endpoint was the completion rate of protocol treatment. Thirty-two patients were enrolled. The completion rate of protocol treatment (completion of two courses of preoperative chemotherapy and R0 surgery) was 100 %. During chemotherapy, the most common grade 3 or 4 toxicities were neutropenia (31.3 %). No treatment-related death was observed, and the incidence of operative morbidity was tolerable. The overall response rate after the chemotherapy was 90.3 %. This Bi-DCF regimen was well tolerated and highly active. This trial was registered with the University Hospital Medical Information Network (No. UMIN 000014625). [ABSTRACT FROM AUTHOR]

Purpose: Anti-EGFR monoclonal antibody is effective for KRAS wild-type metastatic colorectal cancer (mCRC), but frequently causes several adverse reactions, including hypomagnesemia and skin disorders. The present study was designed to investigate the relationship between the incidence of adverse reactions and therapeutic effects in mCRC patients receiving anti-EGFR monoclonal antibody in combination with first-line chemotherapy. Methods: Forty-three mCRC patients who received cetuximab or panitumumab between April 2012 and December 2015 were the subjects of the present study. All patients were pretreated with oral minocycline in combination with skin treatment using moisturizer for prevention of skin rash. Hypomagnesemia and acneiform rash were graded according to the Common Terminology Criteria for Adverse Events, version 3.0. Overall response rate (ORR) and time to treatment failure (TTF) were compared between patients with and without these adverse events. Results: The incidence rates of hypomagnesemia and acneiform rash were 32.6 % (grade 1: 20.9 %, grade 2: 11.6 %) and 93.0 % (grade 1: 41.9 %, grade 2: 41.9 %, grade 3: 9.3 %), respectively. ORR was significantly higher in patients with hypomagnesemia than in those without it (71.4 vs 34.5 %, P = 0.048). Median TTF tended to be longer, though not significantly, in patients with hypomagnesemia than in those without it. However, no significant difference in both ORR and median TTF was observed between patients with and without acneiform rash. Conclusion: Hypomagnesemia may become a predicting factor for therapeutic effects of anti-EGFR monoclonal antibody in mCRC patients. [ABSTRACT FROM AUTHOR]

In 2006, the Adjuvant Chemotherapy Trial of S-1 for Gastric Cancer (ACTS-GC) demonstrated that S-1 is an effective adjuvant therapy for gastric cancer. Following that study, S-1 has been used as the standard adjuvant therapy for gastric cancer in Japan. However, the 1-year completion rate was only 65.8% in the ACTS-GC study and feasibility remains a critical issue. We conducted a study to evaluate the feasibility of 2 weekly administration regimens of S-1 as adjuvant chemotherapy in gastric cancer. The criteria for eligibility included histologically proven stage II (excluding T1), IIIA or IIIB gastric cancer with D2 lymph-node dissection. The patients were randomly assigned to either arm A (S-1 administration for 4 weeks followed by 2 weeks of rest) or arm B (S-1 administration for 2 weeks followed by 1 week of rest). In each arm, treatment was continued for 12 months unless recurrence or severe adverse events were observed. The primary endpoint was feasibility (protocol treatment completion rate). The secondary endpoints were safety, relapse-free survival and overall survival. A total of 47 patients were assigned to arms A or B between May, 2008 and February, 2010. During the first interim analysis, the protocol treatment completion rates in arms A and B were 83 and 100%, respectively, at 6 months and 49 and 89%, respectively, at 12 months (P=0.0046). Therefore, S-1 administration for 2 weeks followed by 1 week rest was more feasible as adjuvant chemotherapy in gastric cancer. Grade 3 adverse events in arm A included fatigue (8.0%), anorexia (8.0%), nausea (4.0%), vomiting (4.0%) and hand-foot syndrome (4.0%), whereas none were observed in arm B. There were no reported grade 4 adverse events in either arm. In conclusion, the 2-week S-1 administration followed by 1-week rest regimen appears to be a more feasible oral administration regimen for S-1 as adjuvant chemotherapy in gastric cancer. [ABSTRACT FROM AUTHOR]

5-fluorouracil (5-FU) is widely used in chemotherapy for gastric and colorectal cancer, but gemcitabine (GEM), and not 5-FU, is approved as a standard drug for use in pancreatic cancer. Interindividual variation in the enzyme activity of the GEM metabolic pathway can affect the extent of GEM metabolism and the efficacy of GEM chemotherapy. Human equilibrative nucleoside transporter 1 (hENT1) is recognized as a major transporter of GEM into cells. In addition, a factor that activates hENT1 is the inhibition of thymidylate synthase (TS), one of the 5-FU metabolic enzymes; TS inhibition mediates depleting intracellular nucleotide pools, resulting in the activation of the salvage pathway mediated through hENT1. In this paper, the role of 5-FU in GEM-based chemotherapy for pancreatic cancer is discussed with special emphasis on enzymes involved in the 5-FU and GEM metabolic pathways and in the correlation between GEM responsiveness and the expression of 5-FU and GEM metabolic enzymes. [ABSTRACT FROM AUTHOR]

Background: We performed a single-institution retrospective study to evaluate the efficacy and toxicities of combination therapy with docetaxel and S-1 in patients with advanced or recurrent gastric cancer. Methods: Eighty-six patients with advanced or recurrent gastric cancer were enrolled. Patients received docetaxel, 40 mg/m2, on day 1 and oral S-1, 80 mg/m²/day, on days 1 to 14 every 3 weeks. Results: All 84 patients were assessable for response. The overall response rate was 52.4% (44/84) and the disease control rate was 96.4% (81/84). Median time to progression (TTP) and overall survival (OS) were 6.5 (95% CI, 4.8-8.1 months) and 15.1 months (95% CI, 11.7-18.5 months), respectively. The major toxicities were neutropenia, leukopenia, alopecia and anorexia. Grade 3 or 4 hematologic toxicities included neutropenia in 31 patients (36.0%), leukopenia in 27 (31.7%), febrile neutropenia in four (4.7%), and anemia in one (1.2%). Other grade 3 toxicities included anorexia in five patients (5.8%), and stomatitis, diarrhea and nausea in one each (1.2%). There was one treatment-related death (1.2%). Conclusion: The combination of docetaxel and S-1 had good clinical activity with acceptable toxicity in patients with advanced or recurrent gastric cancer. [ABSTRACT FROM AUTHOR]

To establish the maximum tolerated dose and dose-limiting toxicity of chemoradiation with paclitaxel (PTX) and cisplatin (CDDP) for patients with local symptoms due to unresectable primary advanced or locally recurrent gastric adenocarcinoma located at left-upper abdomen. Chemotherapy consisted of PTX at escalating doses of 40–80 mg/m2 per day and CDDP at escalating doses of 20–25 mg/m2 per day on days 1, 15, and 29. Concurrent radiation was administered up to a dose of 45 Gy for 5 weeks. A total of nine patients were enrolled, of which six were into level 1 (PTX 60 mg/m2 and CDDP 20 mg/m2) and three into level −1 (PTX 50 mg/m2 and CDDP 20 mg/m2). At level 1, one patient developed grade 3 fatigue, and the other experienced grade 5 DIC, grade 5 pneumonia, grade 4 thrombocytopenia, grade 3 hyponatremia, and grade 3 esophagitis as dose-limiting toxicities. A palliative effect was observed in eight of nine patients; six of six patients at level 1 and two of three at level −1. PTX 50 mg/m2 and CDDP 20 mg/m2 given biweekly with concurrent radiation therapy of 45 Gy were well tolerated. [ABSTRACT FROM AUTHOR]

The KEYNOTE-659 study evaluated the efficacy and safety of pembrolizumab in combination with chemotherapy as the first-line treatment in Japanese patients with advanced gastric/gastroesophageal junction (G/GEJ) cancer. In this paper, we report results from cohort 1 (S-1 plus oxaliplatin [SOX] with pembrolizumab). This was a non-randomised, multicentre, open-label phase IIb study in patients with advanced programmed death-ligand 1 (PD-L1)-positive, human epidermal growth factor receptor 2-negative G/GEJ tumours. The primary endpoint was the objective response rate (ORR) assessed by blinded independent central review (BICR). Secondary endpoints were duration of response (DOR), disease control rate (DCR), time to response (TTR), progression-free survival (PFS), overall survival (OS) and safety. Exploratory analyses were performed based on the PD-L1 combined positive score (CPS) status. Fifty-four patients were evaluated. The median follow-up was 10.1 months. ORR and DCR by BICR were 72.2% (95% confidence interval [CI] 58.4–83.5) and 96.3% (95% CI 87.3–99.5), respectively. Median DOR, TTR, PFS and OS were as follows: not reached, 1.5 months, 9.4 months and not reached. The ORR was 73.9% in patients with CPS ≥1 to <10 and 71.0% in those with CPS ≥10. Grade ≥3 treatment-related adverse events (TRAEs) were reported by 57.4% of patients. The most common grade ≥3 TRAEs were decreased platelet count (14.8%), decreased neutrophil count (13.0%), colitis (5.6%) and adrenal insufficiency (5.6%). SOX with pembrolizumab showed encouraging efficacy and a manageable safety profile for the first-line treatment of advanced G/GEJ cancer. NCT03382600/JapicCTI-183829. • This study was conducted for gastric/gastroesophageal junction (G/GEJ) cancer. • Efficacy and safety of S-1 + oxaliplatin (SOX) with pembrolizumab were assessed. • Overall response rate assessed by blinded independent central review was 72.2%. • No increase in treatment-related adverse events occurred with this combination. • First-line SOX with pembrolizumab warrants further evaluation for G/GEJ cancer. [ABSTRACT FROM AUTHOR]

Recent gastric cancer clinical trials have aimed to establish the efficacy of combination therapy over monotherapy, however, the role for genomic biomarkers in these trials has remained largely unexplored. Here, using the NanoString expression platform, we analyzed 105 gastric tumors from a randomized phase III Japanese clinical trial (GC0301/TOP002) testing the efficacy of irinotecan plus S-1(IRI-S) versus S-1 therapy. We found that previously established proliferative subtype signatures, were associated with older patients (>65 years) and liver metastasis while mesenchymal subtype signatures were associated with younger patients (≤65 years) and peritoneal metastasis. Genes associated with tumor microenvironment (CD4, CD14, ADAMTS1, CCL5, CXCL12, CCL19), therapeutic implications (DPYD) and oncogenic signaling (Wnt5A, PTRF) were significantly associated with patient age, histology, tumor status, measurable lesions and metastasis. We identified Wnt5A downregulation as a candidate predictor of improved progression free survival (>8 weeks) in S-1 but not in IRI-S treatment. Although statistical significance was not achieved, mesenchymal subtype showed a trend for treatment interaction with IRI-S for efficacy. These findings highlight promising genomic markers that could be useful predictors of chemotherapy efficacy for better prognosis and survival outcome in gastric cancer. [ABSTRACT FROM AUTHOR]