Large-scale prospective genome-wide association study of oxaliplatin in stage II/III colon cancer and neuropathy.

BACKGROUND: The severity of oxaliplatin (L-OHP)-induced peripheral sensory neuropathy (PSN) exhibits substantial interpatient variability, and some patients suffer from long-term, persisting PSN. To identify single-nucleotide polymorphisms (SNPs) predicting L-OHP-induced PSN using a genome-wide association study (GWAS) approach. PATIENTS AND METHODS: A large prospective GWAS including 1379 patients with stage II/III colon cancer who received L-OHP-based adjuvant chemotherapy (mFOLFOX6/CAPOX) under the phase II (JOIN/JFMC41) or the phase III (ACHIVE/JFMC47) trial. Firstly, GWAS comparison of worst grade PSN (grade 0/1 versus 2/3) was carried out. Next, to minimize the impact of ambiguity in PSN grading, extreme PSN phenotypes were selected and analyzed by GWAS. SNPs that could predict time to recovery from PSN were also evaluated. In addition, SNPs associated with L-OHP-induced allergic reactions (AR) and time to disease recurrence were explored. RESULTS: No SNPs exceeded the genome-wide significance (P < 5.0 × 10-8) in either GWAS comparison of worst grade PSN, extreme PSN phenotypes, or time to recovery from PSN. An association study focusing on AR or time to disease recurrence also failed to reveal any significant SNPs. CONCLUSION: Our results highlight the challenges of utilizing SNPs for predicting susceptibility to L-OHP-induced PSN in daily clinical practice.

Oxaliplatin-based adjuvant chemotherapy duration (3 versus 6 months) for high-risk stage II colon cancer: the randomized phase III ACHIEVE-2 trial.

BACKGROUND: Oxaliplatin-based adjuvant chemotherapy may be associated with debilitating peripheral sensory neuropathy (PSN) in patients with high-risk stage II colon cancer. This open-label, multicenter, randomized phase III trial was conducted as a prospective pooled analysis to investigate the non-inferiority of 3 versus 6 months of adjuvant oxaliplatin-based chemotherapy. PATIENTS AND METHODS: From 12 February 2014 to 31 January 2017, 525 Asian patients with high-risk stage II colon cancer were randomly assigned to 3- and 6-month treatment arms. The treatment consisted of either modified fluorouracil, leucovorin, and oxaliplatin (mFOLFOX6) or capecitabine combined with oxaliplatin (CAPOX). The primary end point was disease-free survival (DFS). The secondary end points were treatment compliance and safety. RESULTS: Of the 525 randomized patients, 11 were not treated. Among the 514 participating patients (255 in the 3-month arm; 259 in the 6-month arm), 432 (84%) received CAPOX, and 184 (36%) presented with T4 as a high-risk factor for recurrence. The 3-year DFS rate was 88.2% in the 3-month arm and 87.9% in the 6-month arm [hazard ratio (HR), 1.12; 95% confidence interval (CI), 0.67-1.87]. With CAPOX, the 3-year DFS rate was 88.2% in the 3-month arm and 88.4% in the 6-month arm (HR, 1.13; 95% CI, 0.65-1.96). The discontinuation rate in the 3- and 6-month arms was 10% and 31% for mFOLFOX6 (P = 0.0193), and 15% and 35% for CAPOX (P < 0.0001), respectively. The incidence of grade ≥2 PSN was significantly lower in the 3-month arm than in the 6-month arm (16% and 43%, respectively, P < 0.0001). CONCLUSIONS: Three months of combination therapy presented significantly less grade ≥2 PSN than the respective 6-month regimen. The shortened therapy duration did not affect the 3-year DFS rate, suggesting that a 3-month course of CAPOX can be an effective treatment option. CLINICAL TRIAL INFORMATION: UMIN Clinical Trials Registry, UMIN000013036 and Japan Registry of Clinical Trials, jRCTs031180128.

Pan-Asian adapted ESMO Clinical Practice Guidelines for the diagnosis treatment and follow-up of patients with localised colon cancer.

The most recent version of the European Society for Medical Oncology (ESMO) Clinical Practice Guidelines for the diagnosis, treatment and follow-up of localised colon cancer was published in 2020. It was decided by both the ESMO and the Japanese Society of Medical Oncology (JSMO) to convene a special virtual guidelines meeting in March 2021 to adapt the ESMO 2020 guidelines to take into account the ethnic differences associated with the treatment of localised colon cancer in Asian patients. These guidelines represent the consensus opinions reached by experts in the treatment of patients with localised colon cancer representing the oncological societies of Japan (JSMO), China (CSCO), India (ISMPO), Korea (KSMO), Malaysia (MOS), Singapore (SSO) and Taiwan (TOS). The voting was based on scientific evidence and was independent of the current treatment practices and drug availability and reimbursement situations in the different Asian countries.

Neutropenia and survival outcomes in metastatic colorectal cancer patients treated with trifluridine/tipiracil in the RECOURSE and J003 trials.

BACKGROUND: The phase II J003 (N = 169) and phase III RECOURSE (N = 800) trials demonstrated a significant improvement in survival with trifluridine (FTD)/tipiracil (TPI) versus placebo in patients with refractory metastatic colorectal cancer. This post hoc analysis investigated pharmacokinetic data of FTD/TPI exposure and pharmacodynamic markers, such as chemotherapy-induced neutropenia (CIN) and clinical outcomes. PATIENTS AND METHODS: A total of 210 patients from RECOURSE were enrolled in this substudy. A limited sampling approach was used, with three pharmacokinetic samples drawn on day 12 of cycle 1. Patients were categorized as being above or below the median area under the plasma concentration-time curve (AUC) for FTD and TPI. We conducted a post hoc analysis using the entire RECOURSE population to determine the correlations between CIN and clinical outcome. We then carried out a similar analysis on the J003 trial to validate the results. RESULTS: In the RECOURSE subset, patients in the high FTD AUC group had a significantly increased CIN risk. Analyses of the entire population demonstrated that FTD/TPI-treated patients with CIN of any grade in cycles 1 and 2 had significantly longer median overall survival (OS) and progression-free survival (PFS) than patients who did not develop CIN and patients in the placebo group. Patients who required an FTD/TPI treatment delay had increased OS and PFS versus those in the placebo group and those who did not develop CIN. Similar results were obtained in the J003 cohort. CONCLUSIONS: In RECOURSE, patients with higher FTD drug exposure had an increased CIN risk. FTD/TPI-treated patients who developed CIN had improved OS and PFS versus those in the placebo group and those who did not develop CIN. Similar findings were reported in the J003 cohort, thus validating the RECOURSE results. The occurrence of CIN may be a useful predictor of treatment outcomes for FTD/TPI-treated patients. CLINICALTRIALS. GOV IDENTIFIER: NCT01607957 (RECOURSE). JAPAN PHARMACEUTICAL INFORMATION CENTER NUMBER: JapicCTI-090880 (J003).

Pan-Asian adapted ESMO consensus guidelines for the management of patients with metastatic colorectal cancer: a JSMO-ESMO initiative endorsed by CSCO, KACO, MOS, SSO and TOS.

The most recent version of the European Society for Medical Oncology (ESMO) consensus guidelines for the treatment of patients with metastatic colorectal cancer (mCRC) was published in 2016, identifying both a more strategic approach to the administration of the available systemic therapy choices, and a greater emphasis on the use of ablative techniques, including surgery. At the 2016 ESMO Asia Meeting, in December 2016, it was decided by both ESMO and the Japanese Society of Medical Oncology (JSMO) to convene a special guidelines meeting, endorsed by both ESMO and JSMO, immediately after the JSMO 2017 Annual Meeting. The aim was to adapt the ESMO consensus guidelines to take into account the ethnic differences relating to the toxicity as well as other aspects of certain systemic treatments in patients of Asian ethnicity. These guidelines represent the consensus opinions reached by experts in the treatment of patients with mCRC identified by the Presidents of the oncological societies of Japan (JSMO), China (Chinese Society of Clinical Oncology), Korea (Korean Association for Clinical Oncology), Malaysia (Malaysian Oncological Society), Singapore (Singapore Society of Oncology) and Taiwan (Taiwan Oncology Society). The voting was based on scientific evidence and was independent of both the current treatment practices and the drug availability and reimbursement situations in the individual participating Asian countries.

Meta-analysis of individual patient safety data from six randomized, placebo-controlled trials with the antiangiogenic VEGFR2-binding monoclonal antibody ramucirumab.

BACKGROUND: Ramucirumab, the human immunoglobulin G1 monoclonal antibody receptor antagonist of vascular endothelial growth factor receptor 2, has been approved for treating gastric/gastroesophageal junction, non-small-cell lung, and metastatic colorectal cancers. With the completion of six global, randomized, double-blind, placebo-controlled, phase III trials across multiple tumor types, an opportunity now exists to further establish the safety parameters of ramucirumab across a large patient population. MATERIALS AND METHODS: An individual patient meta-analysis across the six completed phase III trials was conducted and the relative risk (RR) and associated 95% confidence intervals (CIs) were derived using fixed-effects or mixed-effects models for all-grade and high-grade adverse events (AEs) possibly related to vascular endothelial growth factor pathway inhibition. The number needed to harm was also calculable due to the placebo-controlled nature of all six registration standard trials. RESULTS: A total of 4996 treated patients (N = 2748 in the ramucirumab arm and N = 2248 in the control, placebo arm) were included in this meta-analysis. Arterial thromboembolic events [ATE; all-grade, RR: 0.8, 95% CI 0.5-1.3; high-grade (grade ≥3), RR: 0.9, 95% CI 0.5-1.7], venous thromboembolic events (VTE; all-grade, RR: 0.7, 95% CI 0.5-1.1; high-grade, RR: 0.7, 95% CI 0.4-1.2), high-grade bleeding (RR: 1.1, 95% CI 0.8-1.5), and high-grade gastrointestinal (GI) bleeding (RR: 1.1, 95% CI 0.7-1.7) did not demonstrate a definite increased risk with ramucirumab. A higher percentage of hypertension, proteinuria, low-grade (grade 1-2) bleeding, GI perforation, infusion-related reaction, and wound-healing complications were observed in the ramucirumab arm compared with the control arm. CONCLUSIONS: Ramucirumab may be distinct among antiangiogenic agents in terms of ATE, VTE, high-grade bleeding, or high-grade GI bleeding by showing no clear evidence for an increased risk of these AEs in this meta-analysis of a large and diverse patient population. Ramucirumab is consistent with other angiogenic inhibitors in the risk of developing certain AEs. Clinical Trial Numbers: NCT00917384 (REGARD), NCT01170663 (RAINBOW), NCT01168973 (REVEL), NCT01183780 (RAISE), NCT01140347 (REACH), and NCT00703326 (ROSE).

Bone metabolic microarray analysis of ligature-induced periodontitis in streptozotocin-induced diabetic mice.

BACKGROUND AND OBJECTIVE: Periodontal disease is a chronic infectious disease that results in bone loss. Many epidemiological studies have reported the progression of periodontal tissue destruction in patients with diabetes; however, the associated mechanism remains unclear. In this study, we comprehensively investigated how diabetes affects the periodontal tissue and alveolar bone loss using a ligature-induced periodontitis model in streptozotocin-induced diabetic (STZ) mice. MATERIAL AND METHODS: Diabetes was induced by intraperitoneal injection with streptozotocin in 6-wk-old C57/BL6J male mice. A silk ligature was tied around the maxillary left second molar in 9-wk-old wild-type (WT) and STZ mice. Bone loss was evaluated at 3 and 7 d after ligation. mRNA expression levels in the gingiva between the two groups were examined by DNA microarray and quantitative polymerase chain reaction at 1, 3 and 7 d post-ligation. Tartrate-resistant acid phosphatase and alkaline phosphatase staining of the periodontal tissue was performed for evaluation of osteoclasts and osteoblasts in histological analysis. RESULTS: In the gingiva, hyperglycemia upregulated the osteoprotegerin (Opg) mRNA expression and downregulated Osteocalcin mRNA expression. In the ligated gingiva, tumor necrosis factor-α (Tnf-α) mRNA expression was upregulated at 1 d post-ligation in STZ mice but not in WT mice. At 3 d post-ligation, alveolar bone loss was observed in STZ mice, but not in WT mice. Significantly severe alveolar bone loss was observed in STZ mice compared to WT mice at 7 d post-ligation. Bone metabolic analysis using DNA microarray showed significant downregulation in the mRNA expression of glioma-associated oncogene homologue 1 (Gli1) and collagen type VI alpha 1 (Col6a1) at the gingiva of the ligated site in STZ mice compared to that in WT mice. Quantitative polymerase chain reaction showed that Gli1 and Col6a1 mRNA expression levels were significantly downregulated in the gingiva of the ligated site in STZ mice compared to WT mice. Histological analysis showed lower alkaline phosphatase activity in STZ mice. In addition, an increased number of tartrate-resistant acid phosphatase-positive multinucleated cells were observed at the ligated sites in STZ mice. CONCLUSIONS: These results suggest that an imbalance of bone metabolism causes osteoclastosis in insulin-deficient diabetes, and that alveolar bone loss could occur at an early phase under this condition.

Comprehensive analyses using next-generation sequencing and immunohistochemistry enable precise treatment in advanced gastric cancer.

BACKGROUND: In advanced gastric cancer (AGC), most clinical trials are designed on the basis of protein expression or gene amplification of specific genes. Recently, next-generation sequencing (NGS) allowed us to comprehensively profile the tumor gene status. This study aimed to elucidate the profiling between gene alterations and protein expression in AGC to aid in future clinical trials on AGC. PATIENTS AND METHODS: Formalin-fixed, paraffin-embedded tumor samples from 121 stage III/IV gastric cancer patients were examined for protein expression of tyrosine kinase receptors (RTKs; ERBB2, EGFR, c-MET, and FGFR2) using immunohistochemistry (IHC). Furthermore, 409 cancer-related genes were sequenced to detect mutations and copy number variations using NGS. RESULTS: Most ERBB2 overexpression (IHC 3+) cases (80.0%) had ERBB2 amplification and did not have other RTK amplification or oncogene mutations. However, one-fourth of MET overexpression cases (25.0%) had ERBB2 alterations. EGFR and FGFR2 overexpression cases had ERBB2 alterations or other gene alterations such as KRAS or PIK3CA. On the other hand, most of the four RTK amplification cases (88.2%) were mutually exclusive with each amplification. However, RTK amplification did not simply correlate with protein overexpression, whereas cases with RTK high-level amplification had protein overexpression and rarely showed other co-existing gene alterations. CONCLUSION: AGC involves a complicated arrangement of protein expression and gene alterations. Comprehensive analyses of NGS and IHC will be necessary to design the optimal therapy for treating the appropriate population of patients in future clinical trials.

Large-scale prospective pharmacogenomics study of oxaliplatin-induced neuropathy in colon cancer patients enrolled in the JFMC41-1001-C2 (JOIN Trial).

BACKGROUND: Peripheral sensory neuropathy (PSN) is a dose-limiting toxicity of oxaliplatin-based chemotherapy. Several genetic markers have been shown to predict oxaliplatin-induced PSN; however, results remain to be validated in a large-scale and prospective pharmacogenomics study. PATIENTS AND METHODS: Among 882 patients enrolled in the JFMC41-1001-C2 (JOIN trial), which was designed to investigate the tolerability of adjuvant-modified FOLFOX6 (mFOLFOX6) in Japanese Patients with stage II or III colon cancers undergoing curative resection, 465 patients were eligible for this pharmacogenomics analysis. Twelve single-nucleotide polymorphisms (SNPs) were selected based on published data. The effect of each genotype on time to PSN onset was evaluated in all patients (n = 465) using the Cox proportional hazard model. For the association analysis between severity of PSN and 12 SNP markers, 84 patients who failed to complete 12 cycles of mFOLFOX6 from grade 0/1 PSN group were excluded because the termination of the protocol treatment had been caused by reasons other than PSN. RESULTS: Comparison of grade 0/1 PSN with grade 2/3 PSN or grade 3 PSN showed no significant associations with any of the 12 SNP markers after adjustment for total dose of oxaliplatin. Time-to-onset analysis also failed to reveal any significant differences. CONCLUSIONS: Our large-scale and prospective pharmacogenomics study of Japanese patients receiving protocol treatment of adjuvant mFOLFOX6 could not verify a role for any of the 12 SNP markers reported as being significantly associated with PSN. Considering the OR observed in this study (range: 0.76-1.89), further evaluation of these 12 SNP markers in the context of L-OHP-induced PSN is unlikely to be clinically informative.

Quality-of-life and performance status results from the phase III RAINBOW study of ramucirumab plus paclitaxel versus placebo plus paclitaxel in patients with previously treated gastric or gastroesophageal junction adenocarcinoma.

BACKGROUND: The phase III RAINBOW trial demonstrated that the addition of ramucirumab to paclitaxel improved overall survival, progression-free survival, and tumor response rate in fluoropyrimidine-platinum previously treated patients with advanced gastric/gastroesophageal junction (GEJ) adenocarcinoma. Here, we present results from quality-of-life (QoL) and performance status (PS) analyses. PATIENTS AND METHODS: Patients with Eastern Cooperative Oncology Group PS of 0/1 were randomized to receive ramucirumab (8 mg/kg i.v.) or placebo on days 1 and 15 of a 4-week cycle, with both arms receiving paclitaxel (80 mg/m(2)) on days 1, 8, and 15. Patient-reported outcomes were assessed with the QoL/health status questionnaires EORTC QLQ-C30 and EQ-5D at baseline and 6-week intervals. PS was assessed at baseline and day 1 of every cycle. Time to deterioration (TtD) in each QLQ-C30 scale was defined as randomization to first worsening of ≥10 points (on 100-point scale) and TtD in PS was defined as first worsening to ≥2. Hazard ratios (HRs) for treatment effect were estimated using stratified Cox proportional hazards models. RESULTS: Of the 665 patients randomized, 650 (98%) provided baseline QLQ-C30 and EQ-5D data, and 560 (84%) also provided data from ≥1 postbaseline time point. Baseline scores for both instruments were similar between arms. Of the 15 QLQ-C30 scales, 14 had HR < 1, indicating similar or longer TtD in QoL for ramucirumab + paclitaxel. Treatment with ramucirumab + paclitaxel was also associated with a delay in TtD in PS to ≥2 (HR = 0.798, P = 0.0941). Alternate definitions of PS deterioration yielded similar results: PS ≥ 3 (HR = 0.656, P = 0.0508), deterioration by ≥1 PS level (HR = 0.802, P = 0.0444), and deterioration by ≥2 PS levels (HR = 0.608, P = 0.0063). EQ-5D scores were comparable between treatment arms, stable during treatment, and worsened at discontinuation. CONCLUSION: In patients with previously treated advanced gastric/GEJ adenocarcinoma, addition of ramucirumab to paclitaxel prolonged overall survival while maintaining patient QoL with delayed symptom worsening and functional status deterioration. CLINICALTRIALSGOV: NCT01170663.

Impact of excision repair cross-complementing gene 1 (ERCC1) on the outcomes of patients with advanced gastric cancer: correlative study in Japan Clinical Oncology Group Trial JCOG9912.

BACKGROUND: Since the best chemotherapy regimen for each patient with advanced gastric cancer is uncertain, we aimed to identify molecular prognostic or predictive biomarkers from biopsy specimens in JCOG9912, a randomized phase III trial for advanced gastric cancer. PATIENTS AND METHODS: Endoscopic biopsy specimens from primary lesions were collected in 445 of 704 randomized patients in JCOG9912. We measured the mRNA expression of excision repair cross-complementing group 1 (ERCC1), thymidylate synthase, dihydropyrimidine dehydrogenase, and five other genes, then, categorized them into low and high groups relative to the median, and examined whether gene expression was associated with efficacy end point. RESULTS: Multivariate analyses showed that high ERCC1 expression [HR 1.37; 95% confidence interval (CI) 1.08-1.75; P = 0.010], performance status ≥ 1 (HR 1.45; 95% CI 1.13-1.86; P = 0.004), and number of metastatic sites ≥ 2 (HR 1.66; 95% CI 1.28-1.86; P < 0.001) were associated with a poor prognosis, and recurrent disease (versus unresectable; HR 0.75; 95% CI 0.56-1.00; P = 0.049) was associated with a favorable prognosis. None of these molecular factors were a predictive marker for choosing irinotecan plus cisplatin or 5-fluorouracil rather than S-1. CONCLUSION: These correlative analyses suggest that ERCC1 is an independent prognostic factor for overall survival in the first-line treatment of gastric cancer. CLINICAL TRIAL NUMBER: C000000062, www.umin.ac.jp.

Phase I study of TAS-102 treatment in Japanese patients with advanced solid tumours.

BACKGROUND: TAS-102 consists of α, α, α-trifluorothymidine (TFT) and an inhibitor of thymidine phosphorylase (TPI). We conducted a dose-escalation phase I study in Japanese patients with advanced solid tumours. METHODS: TAS-102 was administered twice daily on days 1-5 and days 8-12 in a 28-day cycle to patients with solid tumours refractory to standard chemotherapy, to determine its maximum tolerated dose (MTD), dose-limiting toxicities (DLTs), and pharmacokinetics (PKs). MTD was evaluated in cycle 1. RESULTS: Safety and PKs were evaluated in 21 patients treated with TAS-102 at 30, 40, 50, 60, or 70 mg m(-2) per day. DLTs, such as grade 4 leucopenia, grade 4 neutropenia, and grade 4 thrombocytopenia, were observed in two patients at doses of 30 and 70 mg m(-2). α, α, α-trifluorothymidine and TPI exposures increased dose dependently, and the percentage of decrease in neutrophil count and TFT exposure were significantly correlated. The disease control rate was 50.0% with a median progression-free survival of 2.4 months in 18 colorectal cancer patients. The dose of TAS-102 was not increased above 70 mg m(-2) per day because of the increased tendency for grade 3 and 4 neutropenia, and 70 mg m(-2) per day was the recommended dose for phase II studies. CONCLUSIONS: TAS-102 at 70 mg m(-2) per day was tolerated in Japanese patients with advanced solid tumours. Phase II studies are ongoing in patients with colorectal cancer.

Phase I first-in-human study of TAK-285, a novel investigational dual HER2/EGFR inhibitor, in cancer patients.

BACKGROUND: This phase I first-in-human study was conducted in Japanese patients to investigate the safety, pharmacokinetics (PKs), and determine the maximum tolerated dose (MTD) of oral TAK-285, a novel dual erbB protein kinase inhibitor that specifically targets human epidermal growth factor receptor (EGFR) and HER2. METHODS: The TAK-285 dose was escalated until MTD was determined. A second patient cohort received TAK-285 at the MTD for at least 4 weeks. RESULTS: In all, 26 patients received TAK-285 at doses ranging from 50 to 400 mg once daily (q.d.) or twice daily (b.i.d.); 20 patients made up the dose escalation cohort and the remaining 6 patients were the repeated administration cohort. TAK-285 was well tolerated. Dose-limiting toxicities noted in two patients who received 400 mg b.i.d. were grade 3 increases in aminotransferases and grade 3 decreased appetite. Consequently, the MTD was determined to be 300 mg b.i.d. Absorption of TAK-285 was rapid after oral dosing, and plasma exposure at steady-state increased in a dose-proportional fashion for doses ranging from 50 to 300 mg b.i.d. A partial response was observed for one patient with parotid cancer who received 300 mg b.i.d. CONCLUSION: The toxicity profile and PK properties of oral TAK-285 warrant further evaluation.

KRAS mutations in primary tumours and post-FOLFOX metastatic lesions in cases of colorectal cancer.

BACKGROUND: KRAS mutations are predictive markers for the efficacy of anti-EGFR antibody therapies in patients with metastatic colorectal cancer. Although the mutational status of KRAS is reportedly highly concordant between primary and metastatic lesions, it is not yet clear whether genotoxic chemotherapies might induce additional mutations. METHODS: A total of 63 lesions (23 baseline primary, 18 metastatic and 24 post-treatment metastatic) from 21 patients who were treated with FOLFOX as adjuvant therapy for stage III/IV colorectal cancer following curative resection were examined. The DNA samples were obtained from formalin-fixed paraffin-embedded specimens, and KRAS, NRAS, BRAF and PIK3CA mutations were evaluated. RESULTS: The numbers of primary lesions with wild-type and mutant KRAS codons 12 and 13 were 8 and 13, respectively. The mutational status of KRAS remained concordant between the primary tumours and the post-FOLFOX metastatic lesions, irrespective of patient background, treatment duration and disease-free survival. Furthermore, the mutational statuses of the other genes evaluated were also concordant between the primary and metastatic lesions. CONCLUSION: Because the mutational statuses of predictive biomarker genes were not altered by FOLFOX therapy, specimens from both primary tumours and post-FOLFOX tumour metastases might serve as valid sources of DNA for known genomic biomarker testing.

Pooled safety analysis from phase III studies of trifluridine/tipiracil in patients with metastatic gastric or gastroesophageal junction cancer and metastatic colorectal cancer.

BACKGROUND: Trifluridine/tipiracil (FTD/TPI) showed clinical benefit, including improved survival and manageable safety in previously treated patients with metastatic colorectal (mCRC) or gastric/gastroesophageal junction (mGC/GEJC) cancer in the phase III RECOURSE and TAGS trials, respectively. A pooled analysis was conducted to further characterize FTD/TPI safety, including management of haematologic toxicities and use in patients with renal or hepatic impairment. PATIENTS AND METHODS: Adults with ≥2 prior regimens for advanced mGC/GEJC or mCRC were randomized (2 : 1) to FTD/TPI [35 mg/m2 twice daily days 1-5 and 8-12 (28-day cycle); same dosage in both trials] or placebo plus best supportive care. Adverse events (AEs) were summarized in the safety population (patients who received ≥1 dose) and analysed by renal/hepatic function. RESULTS: TAGS and RECOURSE included 335 and 533 FTD/TPI-treated and 168 and 265 placebo-treated patients, respectively. Overall safety of FTD/TPI was similar in TAGS and RECOURSE. Haematologic (neutropenia, anaemia) and gastrointestinal (nausea, diarrhoea) AEs were most commonly observed. Laboratory-assessed grade 3-4 neutropenia occurred in 37% (TAGS)/38% (RECOURSE) of FTD/TPI-treated patients (median onset: 29 days/55 days), and 96% (TAGS)/97% (RECOURSE) of cases resolved regardless of renal/hepatic function. Supportive medications for neutropenia were received by 17% (TAGS) and 9% (RECOURSE); febrile neutropenia was reported in 2% and 4%, respectively. Overall grade ≥3 AEs were more frequent in patients with moderate renal impairment [81% (TAGS); 85% (RECOURSE)] versus normal renal function (74%; 67%); anaemia and neutropenia were more common in patients with renal impairment. FTD/TPI safety (including haematologic AEs) was consistent across patients with normal and mildly impaired hepatic function. CONCLUSIONS: These results support FTD/TPI as a well-tolerated treatment in patients with mGC/GEJC or mCRC, with a consistent safety profile. Safety was largely similar in patients with normal or mildly impaired renal/hepatic function; however, patients with renal impairment should be monitored for haematologic toxicities.

Effect of KRAS codon 12 or 13 mutations on survival with trifluridine/tipiracil in pretreated metastatic colorectal cancer: a meta-analysis.

BACKGROUND: KRAS gene mutations can predict prognosis and treatment response in patients with metastatic colorectal cancer (mCRC). METHODS: We undertook a meta-analysis of three randomized, placebo-controlled trials (RECOURSE, TERRA and J003) to investigate the impact of KRAS mutations in codons 12 or 13 on overall survival (OS) and progression-free survival in patients receiving trifluridine/tipiracil (FTD/TPI) for refractory mCRC. RESULTS: A total of 1375 patients were included, of whom 478 had a KRAS codon 12 mutation and 130 had a KRAS codon 13 mutation. In univariate analyses, the absence of a KRAS codon 12 mutation was found to significantly increase the OS benefit of FTD/TPI relative to placebo compared with the presence of the mutation {hazard ratio (HR), 0.62 [95% confidence interval (CI): 0.53-0.72] versus 0.86 (0.70-1.05), respectively; interaction P = 0.0206}. Multivariate analyses showed that taking confounding factors into account reduced the difference in treatment effect between the presence and the absence of KRAS codon 12 mutations, confirming that treatment benefit was maintained in patients with [HR, 0.73 (95% CI: 0.59-0.89)] and without [HR, 0.63 (95% CI: 0.54-0.74)] codon 12 mutations (interaction P = 0.2939). KRAS mutations in codon 13 did not reduce the OS benefit of FTD/TPI relative to placebo, and, furthermore, KRAS mutations at either codon 12 or codon 13 did not affect the progression-free survival benefit. CONCLUSIONS: Treatment with FTD/TPI produced a survival benefit, relative to placebo, regardless of KRAS codon 12 or 13 mutation status in patients with previously treated mCRC.

KRAS mutations detected by the amplification refractory mutation system-Scorpion assays strongly correlate with therapeutic effect of cetuximab.

BACKGROUND: We aimed to compare the sensitive and quality-controlled KRAS testing with direct sequencing and to assess the impact on decision making of treatment. PATIENTS AND METHODS: We analysed genomic DNA isolated from macrodissected formalin-fixed paraffin-embedded specimens by direct sequencing and an amplification refractory mutation system-Scorpion assay (ARMS/S) method. Cetuximab was administered to patients identified as having wild-type (WT) KRAS using direct sequencing. Therapeutic effects were evaluated according to their KRAS status as determined by ARMS/S. RESULTS: Among the 159 patients, the overall mutation rate was determined to be 37.0% by direct sequencing and 44.0% by ARMS/S. For the patients diagnosed as WT by direct sequencing and treated with cetuximab (n=47), a response rate of 16.0% was observed for 38 ARMS/S WT patients, whereas 9 ARMS/S mutant (MUT) patients failed to respond. The ARMS/S WT patients showed significant improvement in progression-free survival (PFS) and overall survival (OS) compared with ARMS/S MUT patients (PFS median 5.0 vs 1.7 months, hazards ratio (HR)=0.29, P=0.001; OS median 12.1 vs 3.8 months, HR=0.26, P=0.001). CONCLUSION: Sensitive and quality-controlled KRAS testing may provide improved predictive power to determine the efficacy of anti-epidermal growth factor antibodies.

Phase I trial of combination chemotherapy with docetaxel, cisplatin and S-1 (TPS) in patients with locally advanced or recurrent/metastatic head and neck cancer.

BACKGROUND: we investigated the maximum tolerated dose (MTD) of combination therapy with docetaxel, cisplatin, and S-1 (TPS) in patients with locally advanced or recurrent/metastatic head and neck cancer (HNC). PATIENTS AND METHODS: treatment consisted of docetaxel (Taxotere) at doses of 50, 60, and 70 mg/m(2); cisplatin at 70 mg·m(2)/day on day 1; and S-1 twice daily on days 1-14 at doses of 40, 60, and 80 mg·m(2)/day, repeated every 3 or 4 weeks. RESULTS: forty patients were enrolled. MTD was not reached until level 4. Subjects at expanded dose were limited to patients with locally advanced disease. Two dose-limiting toxic effects (DLTs) were observed at dose level 5 (TPS: 70/70/80 mg·m(2)/day, every 3 weeks), namely one grade 3 infection and one grade 3 hyperbilirubinemia, establishing this as the MTD. Of 12 patients treated at dose level 6 (TPS: 70/70/60 mg·m(2)/day, every 3 weeks), 2 DLTs were seen. Six achieved a complete response and 22 a partial response, giving a response rate of 70%. CONCLUSIONS: TPS was well tolerated. The recommended phase II dose as induction chemotherapy for locally advanced HNC was determined as 70/70/60 mg·m(2)/day every 3 weeks. Antitumor activity was highly promising and warrants further investigation.

The diagnosis and management of gastric cancer: expert discussion and recommendations from the 12th ESMO/World Congress on Gastrointestinal Cancer, Barcelona, 2010.

Well-recognized experts in the field of gastric cancer discussed during the 12th European Society Medical Oncology (ESMO)/World Congress Gastrointestinal Cancer (WCGIC) in Barcelona many important and controversial topics on the diagnosis and management of patients with gastric cancer. This article summarizes the recommendations and expert opinion on gastric cancer. It discusses and reflects on the regional differences in the incidence and care of gastric cancer, the definition of gastro-esophageal junction and its implication for treatment strategies and presents the latest recommendations in the staging and treatment of primary and metastatic gastric cancer. Recognition is given to the need for larger and well-designed clinical trials to answer many open questions.

Long-term results of salvage photodynamic therapy for patients with local failure after chemoradiotherapy for esophageal squamous cell carcinoma.

BACKGROUND AND STUDY AIMS: Local failure after chemoradiotherapy (CRT) remains a major problem for patients with esophageal squamous cell carcinoma (ESCC). The aim of this study was to clarify the long-term results of salvage photodynamic therapy (PDT) for local failure. PATIENTS AND METHODS: Patients were treated with CRT, consisting of more than 50 Gy irradiation and concurrent chemotherapy. The indications for salvage PDT were as follows: 1) absence of lymph-node or distant metastasis after CRT; 2) failure lesion limited to T2; 3) refusal by patient to undergo salvage esophagectomy; 4) written informed consent. PDT was performed using an excimer dye laser at 48 and 72 hours after administration of Photofrin. RESULTS: A total of 37 consecutive patients underwent salvage PDT. The baseline stage before CRT was as follows: T1/T2/T3/T4 in 3/4/24/6 and N0/1 in 13/24 patients, respectively. Prior to PDT, 20 patients had a uT1 lesion, and 17 had a uT2 lesion; 24 patients had histologically proven local failure. A complete response was achieved in 22 patients (59.5%) following PDT. Esophageal fistulae, stenosis, and phototoxicity occurred in 4 (10.8%), 20 (54.1%), and 2 (5.4%) patients, respectively. Over a median follow-up period of 55 months, the 5-year progression-free (PFS) and overall survival rates of 37 patients following PDT were 20.7% and 36.1%, respectively. The 5-year PFS and overall survival of 24 patients with proven local failure were 17.6% and 34.6%, respectively. CONCLUSION: Salvage PDT is a curative treatment option for patients with local failure after CRT for ESCC.