Definitive chemoradiotherapy with paclitaxel for locally advanced esophageal squamous cell carcinoma in older patients (PARADISE-1): a phase I trial.

BACKGROUND: In older patients, esophageal squamous cell carcinoma (ESCC) is difficult to treat using standard therapies, including surgery and cisplatin-based chemoradiotherapy. Paclitaxel (PTX) has radiosensitizing activity. We conducted a phase I trial of PTX combined with radiotherapy to establish a standard therapy for locally advanced ESCC in older patients. METHODS: Enrollment was conducted at six centers in Japan from April 2016 to September 2019. The participants were aged ≥ 70 years, had locally advanced ESCC, and were intolerant to surgery or unwilling. A fixed 60-Gy radiation dose was administered in 30 fractions. PTX dosing levels started at 30 mg/m2 weekly for 6 weeks. Depending on the number of DLTs, the dose was set to be increased by 10 mg/m2 or switched to biweekly. A geriatric assessment was performed before treatment using the Geriatric-8 screening tool. The primary endpoint was dose-limiting toxicity (DLT). RESULTS: We enrolled 24 patients (6 per group); DLT was observed in one (grade 4 hypokalemia), one (grade 3 aspiration), two (grade 3 radiodermatitis, grade 3 esophageal hemorrhage), and two (grade 3 anorexia, grade 5 pneumonitis) patients in the weekly PTX 30, 40, 50, and 60 mg/m2 groups, respectively. All adverse events, except death in the 60 mg/m2 group, showed reversible improvement, and the safety profile was considered acceptable. The 2-year survival and complete response rates were 40.0% and 54.2%, respectively. There was a significant difference in survival between favorable and unfavorable Geriatric-8 scores. CONCLUSIONS: The recommended PTX dose with concomitant radiation was determined to be 50 mg/m2 weekly. Phase II trials at this dose are underway.

Risk factors for early recurrence after radical gastrectomy followed by adjuvant chemotherapy for stage II or III gastric cancer: a multicenter, retrospective study.

BACKGROUND: Radical gastrectomy followed by adjuvant chemotherapy is the standard treatment for stage II or III gastric cancer in Asian countries. Early recurrence during or after adjuvant chemotherapy is associated with poor prognosis; however, risk factors for early recurrence remain unclear. METHODS: In this multicenter, retrospective cohort study including six institutions, we evaluated the clinicopathological factors of 553 patients with gastric cancer undergoing gastrectomy followed by adjuvant chemotherapy between 2012 and 2016. Patients were divided into the following groups: early recurrence (recurrence during adjuvant chemotherapy or within 6 months after adjuvant chemotherapy completion) and non-early recurrence, which was further divided into late recurrence and no recurrence. Early-recurrence risk factors were investigated using multivariate Cox proportional hazard model. The chronological changes in the recurrence hazard were also examined for each factor. RESULTS: Early recurrence and late recurrence occurred in 83 (15.0%) and 73 (13.2%) patients, respectively. Based on the Cox proportional hazards model, a postoperative serum carcinoembryonic antigen level of ≥5 ng/mL (hazard ratio: 2.220, 95% confidence interval: 1.089-4.526) and a neutrophil-to-lymphocyte ratio of >1.8 (hazard ratio: 2.408, 95% confidence interval: 1.479-3.92) were identified as independent risk factors of early recurrence, but not late recurrence. The recurrence hazard ratios for neutrophil-to-lymphocyte ratio significantly decreased over time (P < 0.001) and carcinoembryonic antigen also had the same tendency (P = 0.08). CONCLUSIONS: A carcinoembryonic antigen level of ≥5 ng/mL and a neutrophil-to-lymphocyte ratio of >1.8 are predictors of early recurrence after radical gastrectomy and adjuvant chemotherapy for stage II or III gastric cancer.

Pattern of disease progression during third-line or later chemotherapy with nivolumab associated with poor prognosis in advanced gastric cancer: a multicenter retrospective study in Japan.

BACKGROUND: Accelerated tumor growth during immunotherapy in pre-existing measurable lesions, hyperprogressive disease (HPD), has been reported. However, progression of non-measurable lesions and new lesions are frequently observed in patients with advanced gastric cancer (AGC). METHODS: This retrospective study involved AGC patients at 24 Japanese institutions who had measurable lesions and received nivolumab after ≥ 2 lines of chemotherapy. HPD was defined as a ≥ two-fold increase in the tumor growth rate of measurable lesions. The pattern of disease progression was classified according to new lesions in different organs and ascites appeared/increase of ascites. RESULTS: Of 245 patients, 147 (60.0%) showed progressive disease (PD) as the best response and 41 (16.7%) showed HPD during nivolumab monotherapy. There was no significant difference in overall survival (OS) between patients with HPD and those with PD other than HPD (median OS 5.0 vs 4.8 months; hazard ratio [HR] 1.0, 95% confidence interval [CI] 0.6-1.5; p = 1.0). Fifty-three patients developed new lesions in different organs and 58 had appearance/increase of ascites; these patients showed shorter OS than those without each of these features (median OS 3.3 vs 7.1 months, HR 1.8, 95% CI 1.2-2.7, p = 0.0031 for new lesions, and 3.0 vs 7.8 months, HR 2.6, 95% CI 1.8-3.8, p < 0.0001 for ascites). Thirty-one patients who had both features showed the worst prognosis (median OS 2.6 months). CONCLUSIONS: New lesions in different organs and appearance/increase of ascites, rather than the original definition of HPD, are the patterns of disease progression associated with poor prognosis in AGC patients receiving nivolumab whose best response was PD.

Evaluating the efficacy of post-operative chemotherapy after curative resection of stage IV gastric cancer with synchronous oligo metastasis: a multicenter retrospective study.

BACKGROUND: Surgical resection of oligo-metastasis in gastric cancer (GC) is weakly recommended for patients without other incurable factors in the Japanese GC Treatment Guidelines. While post-operative chemotherapy is the standard treatment in patients with stage II or III GC, its efficacy for resected stage IV GC is unclear. This study aimed to evaluate the efficacy of post-operative chemotherapy after curative resection of GC with oligo-metastasis. METHODS: We retrospectively reviewed the medical records of patients with GC who were diagnosed with synchronous oligo-metastasis at 20 institutions in Japan between 2007 and 2012. The selection criteria were: adenocarcinoma, stage IV with oligo-metastasis at liver or lymph node without other distant metastasis, curative resection including synchronous oligo-metastasis, and no prior treatment of GC before surgery. RESULTS: A total of 110 patients were collected. Of the 94 eligible patients, 84 underwent gastrectomy with surgical resection of oligo-metastasis (39 [41%] liver metastasis and 55, [59%] distant lymph node metastasis), followed by post-operative chemotherapy with S-1 (S1: n = 55), S1 plus cisplatin (CS: n = 22), or Others (n = 7). Moreover, 10 patients did not receive post-operative chemotherapy (Non-Cx). The median overall survival (OS) was 35.2 and 11.1 months in the post-operative chemotherapy and Non-Cx groups (hazard ratio, 3.56; 95% confidence interval, 1.74-7.30; p < 0.001), respectively. In multivariable analysis, Non-Cx and age over 70 years were identified as poor prognostic factors for OS (p < 0.05). CONCLUSIONS: Curative resection followed by post-operative chemotherapy in patients with GC with synchronous oligo-metastasis showed favorable survival.

Phase I dose-escalation study on irinotecan, cisplatin, and S-1 combination in chemotherapy-naïve patients with HER2-negative advanced gastric cancer (HERBIS-4B, OGSG 1106).

BACKGROUND: The development of triplet regimens for advanced gastric cancer is challenging. The aim of this phase I dose-escalation study was to determine the maximum tolerated dose and recommended dose of the combination of irinotecan, cisplatin, and S-1 in chemotherapy-naïve patients with HER2-negative advanced gastric cancer. METHODS: The 3 + 3 design was adopted. Every 4 weeks, patients received an escalating dose of intravenous irinotecan (100-150 mg/m2) on day 1 and fixed doses of intravenous cisplatin (60 mg/m2) on day 1 and oral S-1 (80 mg/m2) on days 1 to 14. RESULTS: Twelve patients were enrolled in two dose level cohorts. In the level 1 cohort (irinotecan 100 mg/m2, cisplatin 60 mg/m2, and S-1 80 mg/m2), dose-limiting toxicity including grade 4 neutropenia and febrile neutropenia occurred in one of six patients, whereas in the level 2 cohort (irinotecan 125 mg/m2, cisplatin 60 mg/m2, and S-1 80 mg/m2), dose-limiting toxicities including grade 4 neutropenia developed in two of six patients. Thus, the level 1 and 2 doses were determined to be the recommended and maximum tolerated doses, respectively. Common grade 3 or higher adverse events were neutropenia (75%; n = 9), anemia (25%; n = 3), anorexia (8%; n = 1), and febrile neutropenia (17%; n = 2). Irinotecan, cisplatin, and S-1 combination therapy achieved an overall response rate of 67% with a median progression-free survival and overall survival of 19.3 and 22.4 months, respectively. CONCLUSIONS: The potential treatment efficacy of this triplet regimen in HER2-negative advanced gastric cancer warrants further evaluation, especially in patients requiring intensive chemotherapy.

Protocol of OGSG 1901: a phase II trial of ramucirumab plus irinotecan for patients with early relapsed gastric cancer during or after adjuvant docetaxel plus S - 1 therapy.

BACKGROUND: Although docetaxel plus S-1 adjuvant chemotherapy after gastrectomy with D2 lymphadenectomy has been a standard of treatment for stage III gastric cancer, there is no established chemotherapy for patients with recurrence during or within six months after the completion of adjuvant docetaxel plus S-1 therapy. METHODS: The OGSG 1901 trial is a prospective, open-label, multicenter, phase II trial evaluating ramucirumab plus irinotecan for gastric cancer patients with early relapse after adjuvant docetaxel plus S-1 therapy. The key eligibility criteria were: 1) histologically confirmed gastric adenocarcinoma 2) patients who were on docetaxel plus S-1 adjuvant chemotherapy after the confirmation of pathological stage III, 3) patients with early relapse, i.e., recurrence during or within 6 months after the completion of docetaxel plus S-1 therapy, and 4) patient with Eastern Cooperative Oncology Group performance status of 0-1. Irinotecan (150 mg/m2, day 1) and ramucirumab (8 mg/kg, day 1) will be administered every 2 weeks. The primary endpoint is overall survival, and the secondary endpoints are overall response rate, progression-free survival, and safety. The number of patients has been set at 40 based on the threshold and expected median survival times of 7 and 11 months, respectively, with a one-sided alpha error of 0.05 and power of 0.80. The enrollment and follow-up periods are 2 and 1.5 years, respectively. DISCUSSION: The results of this trial will indicate whether the ramucirumab with irinotecan regimen has the potential to be a recommended treatment regimen for patients with recurrence gastric cancer during or within 6 months after the completion of adjuvant docetaxel plus S-1 therapy. TRIAL REGISTRATION: This study was registered in the Japan Registry of Clinical Trials ( jRCTs05119071 , October 6, 2019).

TRESBIEN (OGSG 2101): encorafenib, binimetinib and cetuximab for early recurrent stage II/III BRAF V600E-mutated colorectal cancer.

The BRAF V600E mutation accounts for approximately 5% of colorectal cancer (CRC) cases and is an extremely poor prognostic factor. However, there are no clear recommendations regarding first-line therapy for patients with early recurrent BRAF V600E-mutated CRC, during or after adjuvant chemotherapy. Recently, a novel combination of encorafenib, binimetinib and cetuximab, showed a higher response rate than standard chemotherapy in patients with BRAF V600E-mutated CRC. Here we describe our plan for the TRESBIEN study (OGSG 2101), which is an open-label, multicenter, single-arm, phase II study designed to evaluate whether encorafenib, binimetinib and cetuximab are effective for patients with early recurrent BRAF V600E-mutated colorectal cancer, during or after adjuvant chemotherapy. The planned number of subjects is 25.

An ongoing study to evaluate encorafenib, binimetinib and cetuximab for people with early recurrent BRAF V600E-mutated colorectal cancer. BRAF V600E-mutated colorectal cancer (CRC) is a type of cancer caused by change (mutation) in a gene called BRAF. It is one of the most difficult types of CRC to treat because currently available drugs do not effectively treat the disease. Recently, two novel treatments, encorafenib and cetuximab, have been approved for use together in several countries for the treatment of advanced or metastatic BRAF V600E-mutated CRC. In Japan, these drugs are also approved to be given with another treatment called binimetinib, an approach called triplet therapy. This article describes the ongoing TRESBIEN study that is looking at how effective and how safe triplet therapy is for the treatment of people with early recurrent BRAF V600E-mutated CRC, during or after they have additional (adjuvant) chemotherapy. This study is ongoing, and the researchers are currently recruiting new participants. TRESBIEN will evaluate the percentage of participants whose tumors shrink with triplet therapy. The study will also look at any side effects. Clinical Trial Registration: jRCTs051210152 (ClinicalTrials.gov) (Japan Registry of Clinical Trials https://jrct.niph.go.jp/search?language=en&page=1).

Impact of preoperative chemotherapy as initial treatment for advanced gastric cancer with peritoneal metastasis limited to positive peritoneal lavage cytology (CY1) or localized peritoneal metastasis (P1a): a multi-institutional retrospective study.

BACKGROUND: Gastric cancer (GC) patients with peritoneal metastasis are defined as stage IV in the Japanese classification of GC. For patients with peritoneal metastasis limited to positive peritoneal lavage cytology (CY1) and/or localized peritoneal metastasis (P1a), gastrectomy followed by S1 monotherapy is one of the most widely accepted therapeutic strategy in Japan. This study investigated the efficacy of preoperative chemotherapy as initial treatment in GC patients with CY1 and/or P1a. METHODS: We retrospectively reviewed GC patients diagnosed with CY1 and/or P1a at 34 institutions in Japan between 2008 and 2012. Selection criteria were: adenocarcinoma, no distant metastasis except CY1 or P1a, and no prior treatment. The subjects were divided into an Initial-Chemotherapy group and an Initial-Surgery group, according to the initial treatment. RESULTS: A total of 824 patients were collected and 713 eligible patients were identified for this study. As the initial treatment, 150 patients received chemotherapy (Initial-Cx), and 563 patients underwent surgery (Initial-Sx). Initial-Cx regimens were cisplatin plus S1/docetaxel plus cisplatin plus S1/others (n = 90/37/23). Both overall survival (OS) and progression-free survival (PFS) were similar between the Initial-Cx and Initial-Sx groups (median OS 24.8 and 24.0 months, HR 1.07, 95% CI 0.87-1.3; median PFS 14.9 and 13.9 months, HR 1.04, 95% CI 0.85-1.27). The 5-year OS rates were 22.3% in the Initial-Cx group and 21.5% in the Initial-Sx group. CONCLUSIONS: Although, the preoperative chemotherapy did not show a survival benefit for GC patients with CY1 and/or P1a, initial-Cx showed favorable survival in patients who converted to P0 and CY0.

Impact of sarcopenia in patients with advanced or recurrent colorectal cancer treated with regorafenib.

BACKGROUND: Regorafenib is a key agent for patients with advanced or recurrent colorectal cancer. Sarcopenia represented by skeletal muscle depletion is closely related to frailty and predicts oncological prognoses. We hypothesized that sarcopenia negatively affects the time to treatment failure (TTF) or overall survival (OS) of patients treated with regorafenib. METHODS: We retrospectively reviewed the medical records of all patients treated with regorafenib between May 2013 and April 2019 at our institution. The cross-sectional area of the psoas muscle at the level of the third lumbar vertebra on baseline computed tomography (CT) was assessed to calculate the psoas muscle index (PMI). Sarcopenia was defined based on PMI cut-off values for Asian adults (6.36 cm2/m2 for males and 3.92 cm2/m2 for females). RESULTS: Thirty-four patients were analyzed. The prevalence of sarcopenia was 44.1%. Sarcopenia was significantly associated with poorer OS (median 3.2 vs. 5.3 months, p = 0.031). Less 75% 1-Month Relative Dose Intensity patients experienced significantly shorter TTF and OS than the rest, as did patients receiving total regorafenib dose of < 3360 mg (median 3.1 and 9.4 months, p < 0.001). Multivariate analysis showed that sarcopenia was a significant predictor of prognosis. CONCLUSION: Sarcopenia was a predictive marker of negative outcome for patients with advanced or recurrent colorectal cancer treated with regorafenib. Screening for sarcopenia can be used to identify patients more likely to benefit from regorafenib in routine clinical practice.

Efficacy of Postoperative Chemotherapy After Resection that Leaves No Macroscopically Visible Disease of Gastric Cancer with Positive Peritoneal Lavage Cytology (CY1) or Localized Peritoneum Metastasis (P1a): A Multicenter Retrospective Study.

BACKGROUND: Gastric cancer (GC) patients with positive peritoneal lavage cytology (CY1) and/or localized peritoneum metastasis (P1a) are defined as stage IV in the 15th edition of the Japanese Classification of Gastric Cancer. In Japan, the most common treatment for patients with CY1 and/or P1a is gastrectomy followed by postoperative chemotherapy. PATIENTS AND METHODS: Subjects in this multi-institutional retrospective study were GC patients with CY1 and/or P1a who received surgical resection that leaves no macroscopically visible disease. Patients were selected from 34 institutions in Japan between 2007 and 2012. Selection criteria included adenocarcinoma, no distant metastasis except CY1 and P1a, and no prior treatment for GC before surgery. RESULTS: Among 824 patients registered, 506 were identified as eligible, with a background of P0CY1, P1aCY0, or P1aCY1 (72.5%, 16.0%, and 11.5% of subjects, respectively). Sixty-two patients had not received postoperative chemotherapy (no-Cx), whereas 444 patients had received postoperative chemotherapy: S-1 monotherapy (S-1; n = 267, 52.7%), cisplatin plus S-1 (CS; n = 114, 22.5%), and others (n = 63, 12.6%). Overall survival (OS) was 29.5, 24.7, 25.4 and 9.9 months in the S-1, CS, 'others', and no-Cx groups, respectively [CS vs. S-1: hazard ratio (HR) 1.15, 95% confidence interval (CI) 0.89-1.50; p = 0.275]. In multivariate analysis, OS was similar between the S-1 and CS groups (CS vs. S-1: HR 1.19, 95% CI 0.92-1.55; p = 0.18). CONCLUSIONS: Postoperative chemotherapy after gastrectomy that leaves no macroscopically visible disease may have some survival benefits for GC patients with CY1 and/or P1a. In contrast, S-1 plus cisplatin seems to have no additional benefit over S-1 treatment alone.

Endoscopic Evaluation of Neoadjuvant Chemotherapeutic Efficacy in Gastric Cancer before Gastrectomy Might be as Useful as Histological Assessment after Gastrectomy.

BACKGROUND: Neoadjuvant chemotherapy for advanced gastric cancer is expected to improve prognoses. However, as there is no method to evaluate neoadjuvant chemotherapeutic efficacy before gastrectomy, some patients at high risk for a poor prognosis undergo gastrectomy. The aim of the present study was to investigate whether endoscopy could be useful for assessing the efficacy of neoadjuvant chemotherapy. METHODS: In this retrospective study, we analyzed the data of 41 patients who received neoadjuvant chemotherapy followed by gastrectomy at our institution to investigate whether responsiveness to neoadjuvant chemotherapy, as assessed with endoscopy, can serve as a surrogate marker for histological grades 1b or higher in the Japanese Classification of Gastric Carcinoma (JCGC) scheme. RESULTS: There were 32 (78.0%) responders and 9 (22.0%) nonresponders to neoadjuvant chemotherapy, as observed in endoscopic evaluations. Among the endoscopic responders, 24 (75.0%) had cancer of histological grade 1b or higher, and 15 (46.9%) had cancer of grade 2 or higher. Among the endoscopic nonresponders, 1 (11.1%) patient had histological grade 1b cancer. Compared with endoscopic nonresponders, endoscopic responders were more likely to show a histological response (chi-square test: p = 0.0005 for JCGC grade 1b or higher; p = 0.0099 for JCGC grade 2 or higher). CONCLUSIONS: Most endoscopic responders showed JCGC histological responses. Evaluation of neoadjuvant chemotherapeutic efficacy by endoscopy in gastric cancer may be useful before gastrectomy. As this was a retrospective study, further investigations are required. The protocol was approved by the ethics review committee at Osaka Medical College (No. 2422) and was registered in the University Hospital Medical Information Network Clinical Trial Registry (UMIN000033088).

The Management of Recurrence within Six Months after Hepatic Resection for Colorectal Liver Metastasis.

BACKGROUND: Hepatectomy is currently recommended as the most reliable treatment for colorectal liver metastases. However, the association between the choice of treatment for recurrence and the timing of recurrence remains controversial. METHODS: Two-hundred ninety-five patients who underwent hepatectomy were retrospectively analyzed for the risk factors and the outcomes for early recurrence within 6 months. The remnant liver volumes (RLVs) and laboratory data were measured postoperatively using multidetector computed tomography on days 7 and months 1, 2, and 5 after the operation. RESULTS: Early recurrence developed in 88/295 patients (29.8%). Colorectal cancer lymph node metastasis, synchronous liver metastasis, and multiple liver metastases were independent risk factors for the occurrence of early recurrence (p < 0.001, 0.032, and 0.019, respectively). Patients with early recurrence had a poorer prognosis than did patients who developed later recurrence (p < 0.001). Patients who underwent surgery or other local treatment had better outcomes. The changes in RLV and laboratory data after postoperative month 2 were not significantly different between the 2 groups. CONCLUSION: Patients with early recurrence within 6 months had a poorer prognosis than did patients who developed later recurrence. However, patients who underwent repeat hepatectomy for recurrence had a better prognosis than did those who underwent other treatments, with good prospects for long-term survival.

[A Case of Remnant Gastric Cancer Occurring 12 Years after Surgery That Was Successfully Treated with Radiation Therapy].

A 59-year-old woman had a history of distal gastrectomy and D2 dissection in May 200X for advanced gastric cancer(GC) in the antrum area. The pathological stage was poorly differentiated, T2(SS), N2, H0, P0, CY0, M0, pStage ⅢA. After administration of S-1 for 1 year as adjuvant chemotherapy, the patient underwent surveillance with no recurrence. However, remnant GC was diagnosed in April 200X+12. Considering that there was no indication for curative resection due to severe invasion of the proper hepatic artery, gastrojejunostomy was performed for the anastomotic stenosis. Although the patient was administered 3 courses of S-1 plus oxaliplatin therapy as first-line treatment, partial response was not achieved. Therefore, chemoradiotherapy(CRT)with capecitabine was administered for local tumor control. Complete response was achieved, and the patient underwent surveillance with no recurrence 16 months after the recurrence. There were no serious acute adverse events(AEs)during CRT and late AEs after CRT. The patient was successfully treated with CRT for locally advanced remnant GC. Although there is no standard treatment for locally advanced remnant GC, this case showed the effectiveness of CRT.

Fluoropyrimidine-induced intestinal mucosal injury is associated with the severity of chemotherapy-related diarrhea.

BACKGROUND AND AIM: Although the fluoropyrimidines are effective chemotherapeutic agents for malignant gastrointestinal tumors, they sometimes cause enteritis with diarrhea. Severe treatment-related diarrhea may result in chemotherapy discontinuation. We investigated the relationship between diarrhea severity and fluoropyrimidine-induced small intestinal mucosal injury. METHODS: We performed small bowel capsule endoscopy in patients undergoing chemotherapy including fluoropyrimidine for a malignant tumor between May 2017 and June 2018 and analyzed the relationship between the endoscopic findings and diarrhea severity. We also performed a cross-sectional analysis of patient factors and routes of chemotherapy to identify risk factors of fluoropyrimidine-induced small intestinal injury. RESULTS: Small bowel capsule endoscopy was successfully completed in 16 eligible patients. The diarrhea grade (per the Common Terminology Criteria for Adverse Events, version 4.0) was significantly correlated with the percentage of patients with a small intestinal mucosal break (grade 0, 16.7%; grade 1, 57.1%; grade 2, 100%; p = .016, Cochran-Armitage trend test). Compared to patients receiving intravenous therapy, those receiving an orally administered fluoropyrimidine had a significantly greater number of small intestinal mucosal breaks (median number of breaks [range]; intravenous 5-fluorouracil, 0 [0-13]; oral fluoropyrimidine, 6.5 [1-20]; p = .0162, Mann-Whitney U test). CONCLUSIONS: Many patients with diarrhea caused by chemotherapy including fluoropyrimidine had small intestinal mucosal breaks. Additionally, small intestinal mucosal breaks were more severe in patients receiving a regimen of oral treatment than in those receiving a regimen of intravenous therapy. These outcomes have important implications for investigations of new strategies for preventing anti-cancer drug-induced diarrhea.

Association between UGT1A1 gene polymorphism and safety and efficacy of irinotecan monotherapy as the third-line treatment for advanced gastric cancer.

BACKGROUND: While uridine diphosphate glucuronosyltransferase (UGT) 1A1 is a key enzyme in the metabolism of irinotecan, relationship between UGT1A1 genotype and safety and efficacy of irinotecan monotherapy in patients with advanced gastric cancer is not clarified. METHODS: Efficacy and safety in advanced gastric cancer patients, who were tested for UGT1A1*6 and *28 genotype and treated with irinotecan monotherapy as third-line treatment from 2009 to 2014, were evaluated according to the UGT1A1*6 and *28 genotypes. RESULTS: Among 74 patients of the subjects, the genotypes of UGT1A1 were wild-type (WT) in 37 patients (50%), single heterozygosity (SH) in 27 (36.5%) and double heterozygosity or homozygosity (Homo/DH) in 10 (13.5%). The initial dose of irinotecan was reduced in 10 patients (27%) with WT, in 9 (33%) with SH, and in 7 (70%) with Homo/DH. Median overall survival was 6.9 months, 6.3 months, and 2.8 months in the WT, SH and Homo/DH genotypes, associated with median time to treatment failure of 2.4 months, 2.3 months, and 1.3 months, respectively. Among 36 patients with measurable lesion, disease control rates were 47.6%, 41.7% and 33.3% in the WT, SH and Homo/DH genotypes. Grade 3 or higher adverse events of special interest were neutropenia (13%, 22%, and 64% for the WT, SH and Homo/DH genotypes), febrile neutropenia (2%, 7%, and 50%) and diarrhea (6%, 5%, and 21%). CONCLUSIONS: The UGT1A1 polymorphism may be related to the clinical outcomes of irinotecan monotherapy as the third-line treatment for advanced gastric cancer.

Type of second primary malignancy after achieving complete response by definitive chemoradiation therapy in patients with esophageal squamous cell carcinoma.

BACKGROUND: While the standard treatment for stage II-III (non-T4) esophageal squamous cell carcinoma (ESCC) is neoadjuvant therapy followed by esophagectomy, definitive chemoradiation therapy (dCRT) is an option to treat ESCC patients who reject or may not tolerate surgical treatment. Second primary malignancy (SPM) is a problem for long-term survivors after achieving complete response (CR) by dCRT. METHODS: The source of the subjects in this study was the patients with stage II/III (excluding T4 disease) ESCC (UICC6th) who underwent dCRT from 2000 to 2011 at the National Cancer Center Hospital, Japan. SPM, defined as malignancy newly detected at different site from the initial disease, was checked in patients who achieved CR by the initial dCRT. RESULTS: Among the 285 patients with stage II/III (excluding T4 disease) ESCC who underwent dCRT, 185 patients achieved CR. SPM was detected in 49 patients (median time to developing SPM, 41.5 months), accounting for 19.3% (95% CI 0.137-0.257) as the 5-year cumulative risk of SPM. SPMs were head and neck cancer (n = 12), gastric cancer (n = 12), esophageal cancer (n = 7), lung cancer (n = 5), colon cancer (n = 4), diffuse large B-cell lymphoma (n = 3), bladder cancer (n = 2), small intestinal cancer (n = 1), cholangiocarcinoma (n = 1), malignant melanoma (n = 1), and breast cancer (n = 1). There were no significant differences in baseline characteristics between the patients who developed SPM (n = 49) and others (n = 136). CONCLUSIONS: Because second primary malignancy developed often after achieving CR by dCRT for ESCC, it should be followed carefully.

[A case of ruptured giant splenic artery aneurysm].

A 68-year-old woman presented with general malaise. Her vital signs were unstable, and abdominal computed tomography revealed giant (10 cm) splenic artery aneurysm with evidence of rupture. We first occluded the root of the splenic artery using a balloon catheter. Next, we resected the distal pancreas and spleen because of the aneurysm size and destruction of the related vasculature. After surgery, the patient's condition improved, and she was discharged from the hospital on postoperative day 18. Because ruptured giant splenic artery aneurysms are very rare, we report this case with a review of the literature.

Safety and Efficacy of Encorafenib, Binimetinib, and Cetuximab for BRAFV600E-Mutant Metastatic Colorectal Cancer: Results of the Japanese Expanded Access Program.

BACKGROUND: The phase 3 BEACON CRC study demonstrated the survival benefits of encorafenib and cetuximab, with or without binimetinib (the BEACON triplet or doublet regimen), for BRAFV600E-mutant metastatic colorectal cancer (mCRC). This expanded access program (EAP) and subsequent follow-up study assessed the efficacy and safety of the BEACON triplet regimen in Japanese patients with BRAFV600E-mutant mCRC. MATERIALS AND METHODS: The EAP was an open-label, single-arm study including Japanese patients with BRAFV600E-mutant mCRC whose disease progressed after 1 to 2 prior regimens. The patients received the BEACON triplet regimen with 28-day cycles. The subsequent follow-up study assessed the survival outcomes following EAP completion. Safety was assessed only during the EAP. RESULTS: Among the 86 enrolled patients, 81 received the BEACON triplet regimen. The objective response rate and median progression-free survival were 27.6% (95% confidence interval [CI], 18.0%-39.1%) and 5.26 (95% CI, 4.14-5.52) months, respectively. Grade 3 to 4 adverse events and treatment-related adverse events occurred in 43.2% and 28.4% of patients, respectively. No new safety signals were observed during the EAP. Among 58 patients with confirmed survival at EAP completion, 57 were included in the follow-up study. With a median observation period of 9.17 months through the EAP and follow-up study, the median overall survival was 10.38 (95% CI, 9.00-16.16) months. CONCLUSION: The efficacy and safety of the BEACON triplet regimen in Japanese patients with BRAFV600E-mutant mCRC were consistent with those reported in the BEACON CRC trial, supporting its use as a standard treatment for pretreated patients with BRAFV600E-mutant mCRC.

Localized colorectal cancer database integrating 4 randomized controlled trials; (JCOG2310A).

Although phase III randomized controlled trials (RCTs) represent the most robust statistical approach for answering clinical questions, they require massive expenditures in terms of time, labor, and funding. Ancillary and supplementary analyses using RCTs are sometimes conducted as alternative approaches to answering clinical questions, but the available integrated databases of RCTs are limited. In this background, the Colorectal Cancer Study Group (CCSG) of the Japan Clinical Oncology Group (JCOG) established a database of ancillary studies integrating four phase III RCTs (JCOG0212, JCOG0404, JCOG0910 and JCOG1006) conducted by the CCSG to investigate specific clinicopathological factors in pStage II/III colorectal cancer (JCOG2310A). This database will be updated by adding another clinical trial data and accelerating several analyses that are clinically relevant in the management of localized colorectal cancer. This study describes the details of this database and planned and ongoing analyses as an initiative of JCOG cOlorectal Young investigators (JOY).