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The triplet-agent (5-fluorouracil/leucovorin, oxaliplatin, and irinotecan; FOLFOXIRI) combined with an anti-epidermal growth factor receptor antibody as a first-line treatment of metastatic colorectal cancer (mCRC) has shown promising results in Western trials. This phase Ib study assessed the safety of FOLFOXIRI plus cetuximab in Japanese patients with RAS wild-type mCRC. Patients with previously untreated RAS wild-type mCRC received weekly cetuximab (400 mg/m2 at week 1 and subsequently 250 mg/m2) plus FOLFOXIRI that consisted of irinotecan (100, 120, and 150 mg/m2 defined as dose levels 0, 1, and 2), followed by oxaliplatin 85 mg/m2 and l-leucovorin 200 mg/m2 and then 5-fluorouracil 2400 mg/m2. The dose level of irinotecan was escalated starting at dose level 1 in a 3 + 3 manner. The primary endpoint was to determine the maximum-tolerated dose (MTD) and the recommended phase-2 dose (RP2D). Secondary endpoints included safety, overall response rate (ORR), progression-free survival (PFS) and overall survival (OS). Nine patients were enrolled. The MTD was not reached at dose level 2 and the RP2D was 150 mg/m2 irinotecan. The most frequent grade 3/4 adverse events were neutropenia (44%), fatigue (11%), paronychia (22%), and acneiform rash (11%). No dose-limiting toxicities occurred in any of the enrolled patients. No treatment-related death was observed. The ORR was 89% (95% confidence interval 52–100%). The safety profile of the combination of cetuximab and FOLFOXIRI was acceptable and promising anti-tumor activity was demonstrated, supporting further study in patients with RAS wild-type mCRC.

The introduction of immune checkpoint inhibitors has redefined the treatment strategy and changed the way tumor assessments are made because of its response pattern. Studies have suggested that initiating chemotherapy after checkpoint inhibitors may have high anti-tumor activity in some cancer types. This response pattern has not been reported in patients with gastric cancer, and particularly for the combination of trifluridine/tipiracil. A 69-year-old man presented at follow-up for metastatic gastric cancer being treated with nivolumab, an anti-PD-1 antibody. Computed tomography of the liver showed a rapid 4-fold growth of the metastasis compared with baseline measurements taken while receiving paclitaxel and ramucirumab. It met the definition of a phenomenon called hyperprogressive disease. Nivolumab was discontinued, and he was switched to trifluridine/tipiracil. The liver metastasis was shrunk markedly after 2 months with improvement in his performance status and laboratory data. Sequential therapy starting with immune checkpoint inhibitors followed by cytotoxic agents such as trifluridine/tipiracil may have an apparent efficacy in gastric cancer even though prior immunotherapy demonstrates hyperprogressive disease.

Trial Information Click here to access other published clinical trials. Lessons Learned The recommended S-1 dose was 40 mg/m2, twice daily on Monday, Wednesday, Friday, and Sunday, with oral leucovorin and bevacizumab. Compared with daily administration, the alternate-day administration of S-1 with oral leucovorin may reduce mucositis with promising antitumor activity in refractory metastatic colorectal cancer. Background Daily S-1 plus oral leucovorin administration in a 1-week-on/1-week-off schedule has promising efficacy in gastrointestinal cancer but is associated with high risk of mucositis and diarrhea. Methods This phase Ib, 3+3 dose-escalation trial included patients with chemorefractory metastatic colorectal cancer (mCRC) receiving S-1 (40 mg/m2) and leucovorin (25 mg) orally twice daily (level 1, even-numbered days; level 2, Monday, Wednesday, Friday, and Sunday) and intravenous bevacizumab (5 mg/kg) every 2 weeks. Enrollment continued at the recommended dose level in the expansion cohort. Results We enrolled 21 patients (3 and 18 patients in levels 1 and 2, respectively). Briefly, 12 and 9 patients had Eastern Cooperative Oncology Group (ECOG) performance status of 0 and 1, respectively, and 8 and 13 patients had 1–3 and ≥4 prior treatment lines, respectively. Dose-limiting toxicity (DLT) was not observed, and level 2 was confirmed as the recommended dose. Common grade 3–4 adverse events at level 2 were anemia (22%), anorexia (6%), and diarrhea (6%). In the entire cohort, response rate, disease control rate, and median progression-free survival were 10%, 71%, and 4.2 months, respectively. Conclusion The recommended S-1 dose was 40 mg/m2, twice daily on Monday, Wednesday, Friday, and Sunday, with 25 mg oral leucovorin twice daily and 5 mg/kg bevacizumab every 2 weeks. Compared with the daily administration, alternate-day administration of S-1 plus leucovorin may reduce mucositis with promising antitumor activity in refractory mCRC.

Background/aim Metastatic small bowel adenocarcinoma (SBA) is a rare disease with poor prognosis. This study aimed to explore the efficacy and safety of second-line chemotherapy for patients with SBA. Patients and methods We retrospectively reviewed the clinical characteristics of 27 metastatic patients with SBA after progression on first-line chemotherapy. The patients were divided into Cohort A, receiving second-line chemotherapy, and Cohort B, receiving best supportive care. Results Patients in Cohort B had higher age, worse performance status, and higher neutrophil-to-lymphocyte ratio compared with those in Cohort A. Cohort A showed significantly better overall survival (OS) compared with Cohort B (median OS, 15.6 vs. 3.4 months; p=0.002). Objective response rate, disease control rate, and median progression-free survival (PFS) for Cohort A were 7%, 74%, and 5.0 months, respectively. Patients who underwent irinotecan-based chemotherapy showed longer PFS and OS compared with those who underwent taxane-based chemotherapy. No significant adverse events were reported. Conclusion Second-line chemotherapy for metastatic SBA demonstrated clinical activity with acceptable toxicities.

Background Esophageal cancer is associated with synchronous or metachronous cancer at other primary sites. However, few studies have evaluated the second malignancies after the treatment of esophageal cancer. The present study aimed to clarify the frequency of and risk factors for the second malignancies after definitive therapy for esophageal cancer. Patients and Methods We included patients with esophageal cancer who received definitive therapy between 2000 and 2010. Exclusion criteria were synchronous cancer or a past history of cancer. Standardized incidence rate (SIR) was calculated using age‐ and sex‐specific incidence rates from the cancer registry data. To conduct risk analyses, we used the competing risk regression model, which defined death and the development of second malignancies as competing risks. Results A total of 758 patients were included, with 131 second malignancies occurring in 106 patients (14%), over a median follow‐up of 3.7 years. Cumulative incidences of second malignancies after 3, 5, and 8 years were 4.0%, 7.6%, and 13.8%, respectively. The risk of second malignancy was significantly elevated [SIR = 1.83, 95% confidence interval (CI): 1.50‐2.22]. The most common sites of primary tumor were the head and neck (20%), followed by the lung (17%), stomach (16%), colon and rectum (11%), and urinary tract (9%). Risk analyses revealed that age ≥ 65 years [subdistribution hazard ratio (sHR): 1.51, 95% CI: 1.01‐2.24, vs age, We conducted risk analyses using the competing risk regression model, which defined death and the development of second malignancies as competing risks. Our study revealed that risk of second primary malignancies was significantly higher compared with the general population. Age, clinical stage, and tumor location were identified as significant factors for the development of second primary malignancies.

PURPOSE We previously reported on the pilot study assessing the feasibility of using the Japanese translation of the Comprehensive Score for Financial Toxicity (COST) tool to measure financial toxicity (FT) among Japanese patients with cancer. In this study, we report the results of the prospective survey assessing FT in Japanese patients with cancer using the same tool. PATIENTS AND METHODS Eligible patients were receiving chemotherapy for a solid tumor for at least 2 months. In addition to the COST survey, socioeconomic characteristics were collected by using a questionnaire and medical records. RESULTS Of the 191 patients approached, 156 (82%) responded to the questionnaire. Primary tumor sites were colorectal (n = 77; 49%), gastric (n = 39; 25%), esophageal (n = 16; 10%), thyroid (n = 9; 6%), head and neck (n = 4; 3%), and other (n = 11; 7%). Median COST score was 21 (range, 0 to 41; mean ± standard deviation, 12.1 ± 8.45), with lower COST scores indicating more severe FT. On multivariable analyses using linear regression, older age (β, 0.15 per year; 95% CI, 0.02 to 0.28; P = .02) and higher household savings (β, 8.24 per ¥15 million; 95% CI, 4.06 to 12.42; P < .001) were positively associated with COST score; nonregular employment (β, −5.37; 95% CI, −10.16 to −0.57; P = .03), retirement because of cancer (β, −5.42; 95% CI, −8.62 to −1.37; P = .009), and use of strategies to cope with the cost of cancer care (β, −5.09; 95% CI, −7.87 to −2.30; P < .001) were negatively associated with COST score. CONCLUSION Using the Japanese version of the COST tool, we identified various factors associated with FT in Japanese patients with cancer. These findings will have important implications for cancer policy planning in Japan.

OBJECTIVES Insufficient oral intake in advanced gastric cancer (AGC) limits the use of several drugs. We aimed to determine the oral intake status of patients with AGC during later-line chemotherapy. MATERIALS AND METHODS We retrospectively evaluated data of patients with AGC who experienced disease progression during first-line chemotherapy administered from January 2012 to December 2018 in a single institution. We defined "insufficient oral intake" as requiring daily intravenous fluids or hyperalimentation. Multivariate logistic regression was performed to identify oral intake-related factors. RESULTS Among 589 included patients, at disease progression during first-line, second-line, and third-line chemotherapy, 78.3% (461), 53.3% (314), and 30.4% (179) of patients, respectively, exhibited sufficient oral intake. Fourth-line chemotherapy was initiated for 22.2% (131) of patients, with 20.0% (118) exhibiting sufficient oral intake. During second-line and third-line chemotherapy, 11/67 (16%) and 2/39 (5%) patients, respectively, exhibited improvements in oral intake; 85/428 (19.9%) and 70/259 (27.0%), respectively, exhibited deteriorations in oral intake. Factors correlated to deterioration in oral intake during second-line chemotherapy were poor Eastern Cooperative Oncology Group Performance Status (odds ratio, 4.32; P

Limited data are available regarding the efficacy of nutrition support in advanced gastric cancer (AGC) patients receiving a standard second-line combination chemotherapy. The BALAST study is conducted as a prospective, multicenter observational study to evaluate the efficacy of nutrition support for patients with AGC treated with ramucirumab plus taxane as second-line treatment. As part of the routine care, patients who are malnourished or at risk of malnutrition will receive nutrition support from dietitians. We will enroll a total of 26 patients to estimate weight control rate at 12 weeks as primary end point. This study will generate valuable data reinforcing the role of nutrition support therapy for AGC patients receiving second-line chemotherapy.Lay abstract Various guidelines recommend that nutrition support therapy should be considered if cancer patients are malnourished or at risk of malnutrition. Several studies have revealed that body weight loss, which is an important factor in determining the nutrition status, may predict survival during second-line standard chemotherapy with ramucirumab and a taxane for advanced gastric cancer (AGC) patients. However, limited data are available regarding the efficacy of nutrition support in AGC patients receiving ramucirumab and a taxane. This study is conducted as a prospective, multicenter observational study to evaluate the efficacy of nutrition support for Japanese patients with AGC treated with ramucirumab and a taxane. This study will generate valuable data reinforcing the role of nutrition support therapy for AGC patients in second-line treatment.

Background Nivolumab (NIVO) and irinotecan (IRI) are standard treatments for refractory advanced gastric cancer (AGC); however, it is unclear which drug should be administered first or in which cases. The tumor growth rate (TGR) during preceding treatment is reported to be associated with tumor response in metastatic colorectal cancer patients treated with regorafenib or trifluridine/tipiracil, suggesting that TGR may be useful for drug selection. Therefore, we evaluated the association between TGR during preceding treatment and the tumor response to NIVO or IRI. Patients and methods We retrospectively evaluated consecutive AGC patients treated with NIVO or IRI and divided them into slow-growing (Slow) and rapid-growing (Rapid) groups according to TGR and the presence or absence of new lesions (NL+/NL−, respectively) during preceding treatment (Slow group: NL− with low TGR, Highlights • NIVO and IRI are standard treatments for refractory AGC, although it is unclear which should be administered first. • TGR may be useful for drug selection, therefore we evaluated the association between TGR and the tumor response to NIVO or IRI. • In the Slow group, the response rate (RR) was significantly higher in patients treated with NIVO compared with IRI. • In the Rapid group, there was no significant difference in RR between the NIVO and IRI groups. • TGR and NL emergence during preceding treatment may be useful for drug selection.

Nivolumab is an increasingly used standard care treatment for heavily pretreated patients with advanced gastric cancer, with increasing clinical use in Japan. Data from retrospective studies on various tumors have shown the objective response rate to cytotoxic chemotherapy potentially improves after an exposure to immune checkpoint inhibitors. Based on these data, we conducted the multicenter observational REVIVE study to evaluate the efficacy and safety of cytotoxic chemotherapy in nivolumab-refractory or nivolumab-intolerant patients with advanced gastric cancer. Patients who are refractory or intolerant to nivolumab and scheduled to receive irinotecan monotherapy, oxaliplatin combination treatment or oral trifluridine/tipiracil hydrochloride therapy will be included. The primary end point is overall survival of nivolumab-pretreated patients with advanced gastric cancer after the cytotoxic chemotherapy. Clinical trial registration: UMIN000032182 ( umin.ac.jp )

Although immune checkpoint inhibitors are commonly less effective for patients with a poor general condition, they can be effective and should be considered for poor general conditions in the case of MSI‐H tumor.

In patients with advanced gastric cancer refractory to chemotherapy, the treatment options are limited. Via this phase II study, we aimed to assess the efficacy and safety of oxaliplatin in combination with 5-fluorouracil and l-leucovorin (modified FOLFOX6). Patients who had histologically confirmed metastatic gastric cancer refractory to ≥ two previous chemotherapy regimens were included. The primary endpoint was the overall response rate (ORR) by an independent central review. According to an assumption of a threshold ORR of 10% and expected ORR of 25%, with α = 0.05 and β = 0.20, at least 33 patients were required. The secondary endpoints included overall survival (OS), progression-free survival (PFS), quality of life measured by EQ-5D, and safety. Among the 35 enrolled patients, 33 were included in the primary analysis. All patients previously received fluoropyrimidines, cisplatin, and taxanes, and 24 (73%) were pretreated with irinotecan. The confirmed ORR was 27% [95% confidence interval (CI) 13–46]. The median PFS and OS were 2.2 (95% CI 1.2–3.2) and 5.6 (95% CI 4.1–7.0) months, respectively. In the multivariate analyses, immunotherapy within 90 days and a Glasgow Prognostic Score of 0 were associated with better treatment outcomes. The most common grade ≥ 3 adverse event was neutropenia (36%), and no febrile neutropenia was observed. The median EQ-5D scores did not change from baseline at 2, 4, and 8 weeks (p value = 0.38, 0.79, and 0.98, respectively). Modified FOLFOX6 (mFOLFOX6) showed substantial activity and acceptable toxicity for chemotherapy-refractory advanced gastric cancer. UMIN Clinical Trial Registry (UMIN000016416).

Background/aim The efficacy of treatment using the anti-programmed cell death-1 (anti-PD-1) antibody for metastatic gastric cancer (mGC) has been established previously. Exploratory analyses in various types of tumours suggest that prior exposure to immune checkpoint inhibitors can enhance the efficacy of subsequent cytotoxic chemotherapy (CTx). Our aim is to evaluate the efficacy and safety of CTx for mGC after progression on anti-PD-(ligand) 1 [anti-PD-(L)1] antibody. Patients and methods We retrospectively evaluated patients with mGC who underwent CTx. The patients received CTx after progression on anti-PD-(L)1 antibody (cohort A) or as a third-line treatment without prior exposure to anti-PD-(L)1 antibody (cohort B). We evaluated: i) clinical characteristics, ii) efficacies, iii) prognoses, and iv) adverse events (AEs). Results In cohorts A and B, 16 and 68 patients fulfilled the criteria, respectively. In the univariate analysis, the overall response rate was significantly higher in cohort A compared to cohort B (31% vs. 10%, respectively; Odds Ratio:3.96, 95% Confidence Interval:1.06-14.8, p=0.040). The multivariate analysis showed a similar trend. Immune-related AEs did not worsen and were manageable, while new immune-related AEs were not observed. Conclusion CTx after progression on anti-PD-(L)1 antibody demonstrated a favourable efficacy in intensively treated patients with mGC.

Background Anti-HER2 therapy has not demonstrated a survival advantage in the second-line setting of patients with HER2-positive gastric cancer. We conducted this study to assess changes in HER2 status and to identify possible biomarkers for acquired resistance after the use of trastuzumab as the first-line therapy. Patients and methods Patients with advanced or recurrent HER2-positive gastric adenocarcinoma who were diagnosed with progressive disease after the first-line trastuzumab-based therapy and developed pathologically confirmed adenocarcinoma within 3 months after completion of trastuzumab-based therapy were enrolled in this study. We collected re-biopsied samples from the HER2-positive patients who had developed resistance to trastuzumab and re-evaluated their HER2 status. Amplification of EGFR and c-met, as well as PIK3CA mutation, were comparatively analysed when samples were available. Results Among 33 eligible patients, loss of HER2 was identified in 20 patients (60.6%) with refractory disease. Immunohistochemistry showed that the rate of HER2 overexpression was greatly reduced after therapy (pre-HER2 3+: 24 [72.7%] vs. post-HER2 3+: 13 [39.4%]). We found that the use of fixatives other than 10% neutral buffered formalin significantly reduced the HER2-positive rate. EGFR amplification, c-met amplification and PIK3CA mutation before and after trastuzumab-based therapy were observed in 10.3% and 3.8%, 17.9% and 4.2% and 4.0% and 4.2% of cases, respectively. Conclusion Re-evaluation of HER2 status is needed to determine the appropriate use of anti-HER2–targeted therapy after disease progression. Our results also highlight the importance of formalin fixation conditions for HER2 testing.

Angiosarcoma of the heart is an uncommon soft tissue sarcoma. A few cases of disseminated intravascular coagulation (DIC) associated with angiosarcoma occurring in various organs, but not the heart, have been reported. Although taxane is commonly used in the treatment of metastatic angiosarcoma, data on the efficacy of nab-paclitaxel for angiosarcoma are limited. Here, we report probably the first case of a patient with primary cardiac angiosarcoma with coexisting DIC who was successfully treated with nab-paclitaxel. A 62-year-old female with chief complaints of nausea and shortness of breath was diagnosed as having cardiac angiosarcoma with liver metastases. Four months after the resection of her primary tumor, the hepatic metastatic lesions progressed rapidly accompanied by new metastatic lesions in the right iliac bone and signs of DIC. She received nab-paclitaxel as first-line chemotherapy. A response of stable disease was achieved after 2 treatment cycles and DIC was successfully controlled for at least 4 months. This report suggests potential utility of nab-paclitaxel for angiosarcoma complicated with DIC. We also review the literature for all cases of angiosarcoma with DIC reported so far.

Accumulating evidence suggests that response-related parameters such as depth of response (DpR) might be associated with survival in colorectal cancer, which has not been shown in gastric cancer. This study aimed to evaluate whether DpR was associated with clinical outcomes in HER2-positive AGC patients treated with trastuzumab-based chemotherapy. Fifty-seven HER2-positive AGC patients who were treated with trastuzumab in combination with fluoropyrimidines plus cisplatin therapy as first-line treatment were retrospectively enrolled. DpR was defined as the percent maximal tumor shrinkage of target lesions observed at the lowest point compared with baseline. The cutoff DpR level to discriminate better survival was based on receiver-operating characteristic curve analysis. Association of DpR with progression-free survival (PFS) and overall survival (OS) was assessed using the multivariable Cox proportional hazards model. Median DpR level was 56.8% (range −37.9 to 100%). In multivariate models adjusted for relevant variables, DpR, as a dichotomized variable with a cutoff level of 50% and a continuous variable, was significantly associated with PFS (hazard ratio [HR] 0.39 and 0.97; 95% confidence interval [CI] 0.22–0.68 and 0.96–0.98) and OS (HR 0.38 and 0.98; 95% CI 0.21–0.70 and 0.97–0.99). Clinically meaningful differences in PFS (median, 9.8 vs. 4.1 months; p

Taxane monotherapy is widely used for advanced gastric cancer (AGC) after failure of standard first-line chemotherapy with fluoropyrimidine and cisplatin. Triplet chemotherapy with docetaxel, cisplatin, and S-1 (DCS) is a promising regimen for first-line chemotherapy of AGC. The aim of this study was to evaluate the efficacy of taxane monotherapy in patients refractory to DCS. We retrospectively evaluated the efficacy and safety of taxane monotherapy in patients with AGC refractory to first-line therapy with DCS between January 2010 and April 2015. Selection criteria were as follows: ECOG PS of 0–2, treatment with taxane monotherapy in second-line or third-line therapy after failure of second-line irinotecan, absence of massive ascites, and adequate organ function. A total of 30 patients were included in this study. Of these, 15 patients received paclitaxel while another 15 received nanoparticle albumin-bound paclitaxel in either second- or third-line treatment. Median age for the second/third-line group was 64.0/62.0 (range 27–75/42–75); 14/13 (93.3/86.7%) had ECOG PS of 0 or 1. No patients achieved complete or partial response and stable disease was observed in 37.5/35.7% of the patients in the second/third line. Median progression-free survival and overall survival were 3.4 and 5.8 months in the second-line group, and 2.0 and 4.5 months in the third-line group, respectively. The incidences of any grade ≥3 adverse events in the second-line group and the third-line group were 60.0 and 33.3%, respectively. There was no treatment-related death. Taxane monotherapy after DCS failure had acceptable toxicities but was ineffective in AGC patients.

Background Regorafenib and trifluridine/tipiracil (TAS-102) both prolong survival for patients with refractory metastatic colorectal cancer. However, it is unclear which drug should be administered first. Materials and Methods We retrospectively evaluated the data from patients who had received regorafenib or TAS-102 at 2 institutions from May 2013 to March 2015. The inclusion criteria were disease refractory or intolerant to fluoropyrimidines, oxaliplatin, irinotecan, anti-vascular endothelial growth factor antibodies, and anti-epidermal growth factor receptor (EGFR) antibodies (if KRAS exon 2 wild-type), and no previous treatment with regorafenib or TAS-102. Results A total of 146 and 54 patients received regorafenib and TAS-102, respectively. The baseline characteristics were similar between the 2 groups, except for a history of irinotecan and anti-EGFR therapy and high alkaline phosphatase levels. The median progression-free survival and overall survival were 2.1 months and 6.7 months, respectively, with regorafenib and 2.1 months and 6.5 months, respectively, with TAS-102 (progression-free survival hazard ratio 1.20, P = .27; overall survival hazard ratio, 1.01, P = .97). The analysis of overall survival for patients after the approval of TAS-102 in Japan was similar to the overall survival for the entire population. The frequency of hand–foot syndrome and increased aspartate aminotransferase, alanine aminotransferase, and bilirubin levels was higher and the frequency of neutropenia, leukopenia, anemia, nausea, and febrile neutropenia was lower with regorafenib than with TAS-102. No remarkable differences were found in the efficacy and safety of TAS-102 between patients with and without previous regorafenib and vice versa. Conclusion Regorafenib and TAS-102 had similar efficacy but resulted in different toxicities, which could guide the agent choice.

Background TAS-102 significantly improves overall survival in patients with metastatic colorectal cancer. The most common treatment-related adverse event of TAS-102 is bone marrow suppression, which leads to neutropenia. The potential predictive value of neutropenia caused by cytotoxic drugs has been reported in various types of cancer. Methods We retrospectively analyzed 95 consecutive patients with metastatic colorectal cancer who received TAS-102 at 2 Japanese institutions between May 2014 and May 2015. To evaluate the association between efficacy and neutropenia, patients were divided into 4 categories according to the grade of neutropenia during the first cycle of TAS-102: Category A (grade 0-1), B (grade 2-4), C (grade 0-2), and D (grade 3-4). Results Patient characteristics were as follows: median age, 64 years; male, 58%; Eastern Cooperative Oncology Group performance status 0 to 1, 91%; primary site colon, 49%; KRAS exon 2 wild, 57%; and number of metastatic site ≥ 3, 55%. The disease control rate was significantly different between Category A and B (29.2% vs. 52.6%; P = .045) and between Category C and D (30.9% vs. 72.2%; P = .002). In multivariate analysis, Category D remained a significant predictive factor for progression-free survival compared with Category C (4.3 vs. 2.0 months; hazard ratio, 0.45; P = .01). Conclusion Neutropenia caused by TAS-102 during the first cycle was associated with better efficacy. Neutropenia may be a surrogate marker for adequate antitumor doses of TAS-102.

Purpose: Regorafenib improves survival in chemorefractory metastatic colorectal cancer (mCRC) patients. However, regorafenib induces various adverse events (AEs) that often impair patients' quality of life. Identification of early predictive markers of the efficacy is warranted. Methods: We retrospectively examined 146 consecutive mCRC patients who received regorafenib. Clinical parameters, including patient background, AEs, and changes in biochemical parameters until day 28, were evaluated to identify efficacy predictors. Results: Median progression-free survival (PFS) was 2.1 months, and median overall survival was 6.6 months. Major AEs in all cycles were hand-foot skin reaction, hypertension, and increased aspartate transaminase. We extracted 121 patients for prognostic analysis. In univariate analysis, decreased carcinoembryonic antigen (HR: 0.570, p = 0.012) and decreased carbohydrate antigen 19-9 (CA19-9) (HR: 0.422, p = 0.0012) were identified as prognostic markers of PFS. Patients in whom serum CA19-9 decreased after regorafenib exhibited significantly better PFS (median 3.7 vs. 2.0 months, p = 0.004) than those in whom serum CA19-9 did not decrease. Multivariate analysis revealed early CA19-9 decrease as an independent predictive factor (HR: 0.415, 95% CI: 0.210-0.818, p = 0.011). Conclusion: Early response of CA19-9 may predict the efficacy of regorafenib. Additional studies are needed for external validation.

Objective: Anti-epidermal growth factor receptor (EGFR) antibodies and bevacizumab are commonly used, sequentially, as palliative chemotherapies for patients with metastatic colorectal cancer. However, little is known about the efficacy of second-line treatments containing bevacizumab after first-line treatment with an anti-EGFR antibody. Methods: We retrospectively reviewed 128 patients who received second-line bevacizumab-containing chemotherapy and evaluated the effect of prior use of anti-EGFR antibody on the efficacy of the second-line treatment. Results: As first-line treatments, 35 of these patients received only cytotoxic chemotherapy (cohort A), 58 received bevacizumab-containing chemotherapy (cohort B), and 35 received anti-EGFR-containing chemotherapy (cohort C). The median progression-free survival (PFS) with the second-line bevacizumab-containing therapy was 8.3 months in cohort C, 6.9 months in cohort A (hazard ratio [HR], 1.43; 95% confidence interval [CI], 0.83-2.51), and 5.6 months in cohort B (HR, 1.95; 95% CI, 1.18-3.22). Multivariate analysis showed that PFS in cohort C was the same as that in cohort A, but better than that in cohort B. The overall response rate in cohort C (25.7%) was also similar to that in cohort A (20.0%), but better than that in cohort B (10.3%). Conclusions: Prior use of anti-EGFR antibody did not adversely affect the efficacy of subsequent bevacizumab-containing chemotherapy.

Background Disseminated intravascular coagulation (DIC) is a rare complication of advanced gastric cancer (AGC). Despite reports of the efficacy of chemotherapy for AGC with DIC, little is known of platinum-based doublet therapy. Patients and methods We conducted a single-institute, retrospective chart review of 500 consecutive chemotherapy-naive patients with advanced gastric adenocarcinoma (recurrent or metastatic) from November 2010 to November 2015. Results Six patients were diagnosed with AGC with DIC (1.2%); five (1.0%; 3 men, 2 women) received platinum-based doublet chemotherapy. All patients exhibited improved DIC and thrombocytopenia and survived for >100 days (range=114-313) with no therapy-related mortality. Grade ≥3 adverse effects included neutropenia, anemia, hyponatremia, catheter-related infection and diarrhea (maximum: 2 patients each). Conclusion Fluoropyrimidine plus platinum combination therapy was effective against DIC and yielded acceptable survival outcomes. Combination chemotherapy should be considered as a primary therapy for AGC with DIC.

e16045 Background: The ATTRACTION-3 trial showed that nivolumab (Nivo) significantly improved overall survival (OS) of patients (pts) with previously treated advanced esophageal squamous cell carcinoma (ESCC) regardless of tumor programmed cell death ligand-1 (PD-L1) expression assessed with tumor proportion score (TPS). On the other hand, pembrolizumab prolonged OS in advanced esophageal carcinoma pts with combined positive score (CPS) of ≥ 10 in the KEYNOTE-181 trial. Whether CPS can predict clinical outcome of Nivo in advanced ESCC pts remains unclear. Methods: We retrospectively evaluated advanced ESCC pts who received Nivo at a single institution between January 2014 and September 2020. The main eligibility criteria were as follows: refractory or intolerant to fluoropyrimidines and platinum, no prior anti-PD-1/PD-L1 antibody treatment, no comorbid malignancies, and available tissue specimens obtained before initiation of Nivo. PD-L1 immunostaining was performed using PD-L1 IHC 22C3 pharmDx assay, and the tumors were classified into three groups depending on CPS (≥ 10, 1–10, < 1). The adjusted hazard ratios (aHRs) for progression-free survival (PFS) and OS were calculated using a multivariate Cox model that contained variables with p values < 0.05 in the univariate analysis. Results: Among 69 pts, 50 were eligible (CPS ≥ 10/CPS 1–10/CPS < 1, 23/18/9). Patient characteristics were as follows (CPS ≥ 10/CPS 1–10/CPS < 1): age, ≥ 65, 70/67/67%; male, 83/67/78%; PS ≥ 1, 61/72/44%; second-line treatment, 65/61/56%; disease status, recurrent, 61/33/78%; prior esophagectomy, 65/33/44%; prior radiotherapy, 57/56/56%; prior taxane, 52/28/44%; the number of metastatic sites, ≥ 2, 48/61/89%; lymph node metastasis, 78/83/89%, lung metastasis, 26/22/56%; liver metastasis, 17/17/44%. Among 42 pts (84%) with disease progression after Nivo treatment, 24 pts received salvage-line chemotherapy. The adjustment factor for PFS was liver metastasis, while that for OS was not detected. The median PFS was 4.1 months (mo) in CPS ≥ 10 and 2.5 mo in CPS 1–10 (HR vs. CPS ≥ 10, 1.06; 95% CI, 0.51–2.17; p = 0.864; aHR, 1.15; 95% CI, 0.54–2.36; p = 0.713), and 1.4 mo in CPS < 1 (HR vs. CPS ≥ 10, 3,78; 95% CI, 1.53–8.92; p = 0.005; aHR, 1.91; 95% CI, 0.67–5.39; p = 0.223). The median OS was 12.3 mo in CPS ≥ 10, 10.2 mo in CPS 1–10 (HR vs. CPS ≥ 10, 1.72; 95% CI, 0.75–4.00; p = 0.201), and 9.0 mo in CPS < 1 (HR vs. CPS ≥ 10, 2.31; 95% CI, 0.92–5.69; p = 0.075). Objective response rate (CPS ≥ 10/CPS 1–10/CPS < 1) in 40 pts who had measurable lesions were 32/25/0%, respectively. Conclusions: The pts with CPS of < 1 did not respond to Nivo. Our study suggests that CPS is useful for predicting response to Nivo in pts with advanced ESCC.[Table: see text]

234 Background: Nivolumab (Nivo) is a standard therapy after ramucirumab (RAM)-based second-line chemotherapy in patients (pts) with advanced gastric cancer (AGC). However, the relationship between angiogenesis-related factors and the efficacies of immune-checkpoint inhibitors after anti-angiogenic chemotherapy is unclear. Methods: We retrospectively evaluated pts with AGCs who received Nivo after RAM-based second-line chemotherapy at a single institution from Nov 2017 to Aug 2019. Clinical benefit of Nivo was defined as CR, PR, or >4 months of SD and non-CR/non-PD. In addition, preserved serum samples at time points of pre-RAM, pre-Nivo, and post-Nivo (within 12 weeks from the start of Nivo) were analyzed by using the designated panel, containing vascular endothelial growth factor-A/D (VEGF-A/D), placental growth factor (PlGF), soluble vascular endothelial growth factor receptor-1/2/3 (sVEGFR-1/2/3), Interleukin-6/8 (IL-6/8), soluble intercellular adhesion molecule-1 (sICAM-1), soluble vascular cell adhesion molecule-1 (sVCAM-1), tissue inhibitor of metalloproteinase-1 (TIMP-1), angiopoietin-2, hepatocyte growth factor (HGF), interferon gamma (INF-γ), osteopontin (OPN), soluble neuropilin-1, and thrombospondin-2 (TSP-2). We investigated the association between angiogenesis-related factors and clinical outcomes with Nivo. Results: We evaluated 167 samples from 58 pts, including 10 pts (17.2%) exhibiting clinical benefit. Characteristics of pts were as follows: median age, 68; male, 74%; PS, 0/1-2, 17/83%; HER2 positive, 16%; prior gastrectomy, 40%; histology, intestinal/diffuse, 16/84%; disease status, metastatic/recurrent, 69/31%; lung metasstasis, 14%; liver metasstasis, 26%; peritoneum metastasis, 67%; lymph node metastasis, 31%. The median progression-free survival (PFS) and overall survival (OS) of Nivo were 1.7 and 6.2 months, respectively, with a median follow-up of 5.0 months. There were no correlations between pre-Nivo levels of angiogenesis-related factors and clinical benefit; however, the median post-Nivo/pre-Nivo VEGF-A ratio was significantly lower in pts with clinical benefit than in those without clinical benefit (0.44 versus 0.94, p = 0.008). By multivariate analysis using characteristics of pts and data from pre-Nivo samples, VEGF-A above the median level of 1400 pg/mL and sVCAM-1 below the median level of 1640000 pg/mL were independent prognostic factors for poor PFS (hazard ratio, 1.90, p = 0.033) and OS (hazard ratio, 2.02, p = 0.037), respectively. Conclusions: Our study suggests that rapid decline of serum VEGF-A level after Nivo and higher VEGF-A before Nivo were respectively associated with the clinical benefit of Nivo and poor survival in pts with AGC treated with Nivo after RAM-based second-line chemotherapy.

76 Background: FOLFIRI + bevacizumab (FOLFIRI + BEV) is a standard second-line chemotherapy (Cx) for metastatic colorectal cancer (mCRC) patients (pts) who are refractory or intolerant to fluoropyrimidines (FPs) and oxaliplatin (OX). However, the efficacy of continuing FPs as second-line Cx for pts who are refractory to FPs in first-line Cx remains unclear. Methods: We retrospectively evaluated mCRC pts who received irinotecan (IRI) + BEV or FOLFIRI + BEV as second-line Cx at a single institution from Jan 2010 to Apr 2020. The main eligibility criteria were ECOG performance status (PS) of 0-2, known KRAS status, a standard initial dose of fluorouracil (5-FU) (bolus 400 mg/m2, infusional 2400 mg/m2) in FOLFIRI + BEV and IRI (150 mg/m2), refractory to FPs, no prior use of IRI, and prior use of OX. We compared the efficacy and safety of IRI + BEV with those of FOLFIRI + BEV. The adjusted hazard ratios (aHRs) for progression-free survival (PFS) and overall survival (OS) were calculated using a multivariate Cox model that contained variables with p < 0.05 in the univariate analysis to reduce the imbalance between both the treatments. Results: Among the 261 pts, 107 were eligible (IRI + BEV/FOLFIRI + BEV, 31/76 pts). Pt characteristics were as follows (IRI + BEV/FOLFIRI + BEV): median age, 67/62; ECOG PS, 1–2, 55/46%; KRAS mutant, 45/50%; BRAF V600E mutant, 6/11%; right-sided tumor, 19/43%; lactate dehydrogenase (LDH) ≥ 400 U/L, 13/12%; PFS of first-line Cx < 6 month (m), 39/30%; prior use of BEV, 84/63%. Relative dose intensity (RDI) (IRI + BEV/FOLFIRI + BEV) of IRI and BEV was similar in the groups; median RDI (range) of IRI, 80 (44–100) /83 (49–100) %; p = 0.560; median RDI of BEV, 86 (35–100) /83 (20–100) %; p = 0.681. Efficacies (IRI + BEV/FOLFIRI + BEV) after a median follow-up of 13.1/14.3 m were as follows: median PFS, 6.4/5.8 m (HR, 0.90; 95% CI, 0.57–1.38; p = 0.64; aHR, 0.82; 95% CI, 0.50-1.34; p = 0.44); median OS, 16.6/16.5 m (HR, 0.83; 95% CI, 0.51-1.32; p = 0.44; aHR, 1.01; 95% CI, 0.59-1.69; p = 0.97); objective response rate, 25.9/11.3%. Adjustment factors for PFS were prior colorectomy, number of metastatic sites, ECOG PS, liver metastasis, and the level of LDH, while those for OS were prior colorectomy, number of metastatic sites, liver metastasis, peritoneal metastasis, and the level of LDH. All subgroup analyses for PFS and OS according to the pt characteristics also showed no significant differences in the groups. All grade nausea (32/58%) and stomatitis (13/36%) and grade 3–4 neutropenia (23/58%) and febrile neutropenia (0/3%) were less common in the IRI + BEV than in the FOLFIRI + BEV group. Conclusions: Our study suggests that omitting 5-FU from FOLFIRI + BEV as second-line Cx for mCRC pts who are refractory to FPs may lower the occurrence of adverse events without impairing the treatment efficacy.

Aim To investigate the efficacy and safety of olanzapine in combination with palonosetron and dexamethasone for patients receiving cisplatin (≥50 mg/m2), because this antiemetic therapy has not been sufficiently examined in patients receiving cisplatin. Methods We conducted a phase II study to evaluate the efficacy and safety of olanzapine in combination with palonosetron and dexamethasone for chemotherapy naive patients receiving cisplatin (≥50 mg/m2). Patients received prophylactic dexamethasone (20 mg IV, day 1), palonosetron (0.75 mg IV, day 1), and olanzapine (10 mg, days 1–4). The patients were monitored for emesis and nausea for 120 h after chemotherapy. The primary endpoint was the complete response (CR) rate, which was defined as no vomiting episodes and no use of rescue medication for the overall period. CR rates of 65% and 45% would indicate the potential usefulness and the lower limit of interest, respectively. Results Fifty-one patients, including 37 esophageal cancer patients were enrolled, of whom 41 (80%) completed the treatment protocol as planned. The complete response rate for the overall period was 43% (95% confidence interval: 29–58); the primary endpoint was not met. Vomiting was frequently observed, with the overall rate of 51%. Most events occurred during 24–72 h after chemotherapy. Somnolence was observed in 73% of the patients, but it was well tolerated in most cases. Conclusions Olanzapine combined with palonosetron and dexamethasone did not prevent chemotherapy-induced nausea and vomiting induced by cisplatin as expected. The safety of this antiemetic therapy was confirmed.

e16560 Background: Trifluridine/tipiracil, an oral drug, was approved in Japan for patients (pts) with advanced gastric cancer (AGC). Insufficient oral intake (INSUF) is one of the most common complications. We evaluated the clinical characteristics and impact of oral intake during 2nd line chemotherapy (CT). Methods: We retrospectively evaluated AGC pts receiving 2nd line CT from January 2012 to December 2018 at a single institution. We defined “INSUF” as a requirement for daily intravenous fluids or hyperalimentation and “improvement of oral intake (IMP)” as no such requirement for > 1 week. Exacerbation (EXA) was defined as a change from “sufficient oral intake (SUF)” to INSUF. Results: We enrolled 495 pts, of which 67 (13%) and 428 (87%) pts had INSUF and SUF at the start of 2nd line CT, respectively. Patient characteristics are summarized in the Table. There was no difference in the cytotoxic drugs of 2nd line CT. The causes of INSUF were peritoneal metastases (79%), cachexia (15%), and primary complications (3%). The objective response rates of INSUF and SUF pts were 9% and 26%, respectively. INSUF pts had poorer progression-free survival (PFS) (1.7 vs. 3.7 months [M]; adjusted HR [aHR], 1.51; p < 0.001) and overall survival (3.2 vs. 10.1 M; aHR, 2.01; p < 0.001) than SUF pts. At the end of 2nd line CT, 147 (32%) and 314 (68%) pts had INSUF and SUF, respectively. In SUF pts, the factors correlated with EXA were poor ECOG PS (odds ratio [OR], 5.26; p < 0.001), massive or moderate ascites (OR, 2.04; p = 0.031), palliative operation history (OR, 2.90; p = 0.007), and ramucirumab use (OR, 0.50; p = 0.034). Median PFS was shorter after CT in pts with EXA than in those without (1.7 vs. 4.2 M; aHR, 2.05; p < 0.001). Among INSUF pts, 11 pts (16%) achieved IMP; the rate of IMP did not differ according to regimen. Median PFS was shorter in pts without IMP than in pts with IMP (1.1 vs. 3.3 M; aHR, 4.97; p = 0.001). Subsequent CT was administered to 29% and 71% of INSUF and SUF pts, respectively. Conclusions: INSUF at the start of 2nd line CT was a poor prognostic factor. For appropriate use of oral drugs, CT should be changed in SUF pts with factors associated with EXA. [Table: see text]

126 Background: Sarcopenia and muscle loss during chemotherapy (Cx) have a poor prognosis in metastatic colorectal cancer (mCRC). It is unclear whether cachexia during Cx has a survival impact. Methods: mCRC patients (pts) receiving first-line Cx at a single institution between Jan 2010 and Jun 2018 were retrospectively evaluated. Pts receiving doublet Cx with bevacizumab or anti-EGFR agents, ECOG Performance Status (PS) 0–2, and abdominal computed tomography (CT) before and after initiating first-line Cx at least once were included and classified pts into those with (cachexia group) or without (non-cachexia group) cachexia. The skeletal muscle index (SMI) was calculated from the CT cross-section area at L3 divided by the length squared. Muscle loss was defined as a < 5% reduction in the SMI. The association between muscle loss and cachexia during Cx, time to treatment failure (TTF) and overall survival (OS) was determined by univariate and multivariate analysis including muscle loss, primary tumor location, ECOG PS, number of metastatic sites, ALP, WBC, LDH, KRAS status, and BRAF status as independent variables. Results: Of 562 included pts, 185 were eligible and 69 (37%) experienced cachexia. Differences in all patient characteristics such as muscle loss, ECOG PS 2, KRAS mutant, and BRAF mutant (28%, 8%, 32%, and 10% with cachexia group and 27%, 3%, 32%, and 8% with non-cachexia group) were not significant. Median follow-up was 26.8 months. Muscle loss was not associated with TTF (13.3 vs. 15.5 months, HR = 1.05; 95% CI: 0.76–1.45, p = 0.76). OS was shorter (24.4 vs. 29.9 months, HR = 1.23; 95% CI: 0.86–1.76, p = 0.25), but the difference was not significant in univariate and multivariate analysis. However, cachexia group presented significantly shorter TTF [median TTF 11.9 vs. 16.9 m; HR 1.52, 95% CI: 1.12-2.07, p < 0.01; adjusted HR (aHR) 1.53, 95% CI: 1.12-2.11, p < 0.01] and shorter OS (median OS 21.4 vs. 34.1 m; HR 1.81, 95% CI: 1.29-2.55, p < 0.01; aHR 1.97, 95% CI: 1.38-2.81, p < 0.01) than non-cachexia group. Conclusions: Cachexia during Cx may have a negative impact on survival in pts with mCRC.

396 Background: Although nivolumab (NIVO) and irinotecan (IRI) are currently used as third- or later-line therapy for advanced gastric cancer (AGC), few direct comparisons between them have been available. The present study therefore aims to compare the efficacy and safety of NIVO with IRI and explore clinical factors that predict efficacy. Methods: Patients with AGC who underwent NIVO or IRI treatment between November 2016 and June 2018 at three institution were retrospectively examined, subsequently evaluating response rates (RR), progression-free survival (PFS), overall survival (OS), and adverse events (AEs). The main inclusion criteria were patients pretreated with fluoropyrimidines and taxanes, Eastern Cooperative Oncology Group Performance Status (ECOG PS) of 0–2, and no previous NIVO or IRI treatment. Results: A total of 71 and 61 patients received NIVO and IRI, respectively, with both groups having similar baseline characteristics, except for gender. Efficacies were as follows (NIVO/IRI): RR, 20%/6% (p = 0.17); median PFS, 1.6 months (m)/1.8 m (HR 0.93, p = 0.67); median OS, 6.4 m/6.4 m (HR 0.91, p = 0.61); 1-year survival rate, 24.9%/19.3% (p = 0.61), respectively. Interaction analysis found no significant interaction between drugs and various factors such as ECOG PS (p = 0.59) and neutrophile/lymphocyte ratio (p = 0.33) related to OS. Subsequent chemotherapy agents were administered to 32 patients (45%) in the NIVO group (17 patients out of them received IRI) and 36 patients (59%) in the IRI group (23 patients out of them received NIVO) (p = 0.12). NIVO tended to have lower grade 3 or more AEs than IRI, especially neutropenia (3% vs. 28%, respectively; p < 0.01) and febrile neutropenia (1% vs. 8%, respectively; p = 0.09), as well as neutropenia, nausea, diarrhea, constipation, fatigue, and anorexia of any grade. Five patients developed immune-related adverse events in the NIVO group: pneumonitis (n = 1) and rash (n = 4). Conclusions: Although no remarkable differences in efficacy were found between NIVO and IRI for AGC, NIVO had a better safety profile compared to IRI. This study found no clinical factors that predicted efficacy.

The most recent version of the European Society for Medical Oncology (ESMO) Clinical Practice Guidelines for the diagnosis, treatment and follow-up of oesophageal cancer was published in 2016, and covered the management and treatment of local/ locoregional disease, limited disease, locally advanced disease and the management of advanced/metastatic disease. At the ESMO Asia Meeting in November 2017 it was decided by both ESMO and the Japanese Society of Medical Oncology (JSMO) to convene a special guidelines meeting immediately after the JSMO Annual Meeting in 2018. The aim was to adapt the ESMO 2016 guidelines to take into account the ethnic differences associated with the treatment of metastatic oesophageal cancer in Asian patients. These guidelines represent the consensus opinions reached by experts in the treatment of patients with metastatic oesophageal cancer representing the oncological societies of Japan (JSMO), China (CSCO), Korea (KSMO), Malaysia (MOS), Singapore (SSO) and Taiwan (TOS). 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.

BACKGROUND/AIM Anti-EGFR antibodies or bevacizumab comprise first-line treatment for patients with RAS wild-type colorectal liver metastases (CLM). Which marker better predicts efficacy, early tumor shrinkage or morphologic response, still remains unclear. PATIENTS AND METHODS We retrospectively evaluated 155 patients with KRAS exon 2 wild-type CLM treated with bevacizumab (BEV group) or anti-EGFR antibodies (EGFR group). Three radiologists independently assessed early tumor shrinkage (ETS) and early optimal morphologic response (EOMR) from baseline and first follow-up CT scan. RESULTS Patients with ETS had longer progression-free survival (PFS) than those without ETS [hazard ratio (HR)=0.69] and ETS tended to be observed in the EGFR group, while patients with EOMR had longer PFS than those without EOMR (HR=0.64) and EOMR tended to be observed in the BEV group. CONCLUSION Among patients with KRAS exon 2 wild-type CLM, EOMR and ETS may predict better PFS, especially in patients treated with bevacizumab and anti-EGFR antibodies, respectively.

Background Financial toxicity (FT) has a negative impact on the quality of life and survival of patients with cancer. The comprehensive score for FT (COST) questionnaire is a tool to measure FT which has already been validated in patients with cancer in the United States. However, the feasibility and validity of assessing FT using the COST questionnaire have not been established in non-US healthcare settings, including that in Japan. Methods This is a prospective pilot survey to ascertain the feasibility of using the COST questionnaire to evaluate FT in Japanese patients with advanced solid cancer who had been receiving chemotherapy for at least 2 months. The COST questionnaire was translated into Japanese using Functional Assessment of Chronic Illness Therapy methodology. Results Of the 12 patients approached, 11 (92%) responded to the questionnaire. The median COST score was 22 (range, 6-29; mean ± SD, 20.18 ± 8.17). Five (45%) and two (18%) patients suffered grade 1 (COST score 14-25) and grade 2 (COST score 1-13) FT, respectively. The COST measure demonstrated good internal consistency with a Cronbach α of 0.87. Conclusions The COST measure demonstrated good feasibility in measuring FT in the Japanese healthcare setting. Despite the existing universal health insurance system and ceiling amount for high-cost medical expenses, some Japanese patients experienced meaningful FT during chemotherapy. A prospective study is already underway to confirm the preliminary results (UMIN: 000025043).

Background: It remains unclear whether human epidermal growth factor receptor 2 (HER2) status is an outcome-associated biomarker independent of known prognostic factors for metastatic gastric cancer. Moreover, there are few reports about nomograms in inoperable locally advanced or metastatic gastric cancer (AGC), although several studies have been reported regarding other cancer types. This retrospective study aimed to develop nomograms that combine HER2 status and other prognostic factors to predict the survival outcomes of AGC patients starting first-line treatment. Methods: In this study, 838 consecutive AGC patients starting first-line chemotherapy at the Aichi Cancer Center Hospital (ACC) were included to establish the nomograms that calculated the predicted probability of survival at different time points, 6 months and 1 and 2 years for overall survival (OS) and 3 and 6 months, and 1 year for progression free survival (PFS). Nomograms were independently validated with 269 consecutive AGC patients at the Cancer Center Hospital (SCC) who underwent first-line chemotherapy. The discriminatory ability and accuracy of the models were assessed using Harrell’s c-index. IHC3+ or IHC2+/ISH+ tumors were defined as HER2 positive. Results: At a median follow-up of 12.3 (ACC) and 11.6 (SCC) months, the median OS was 12.5 and 12.4 months (P=1.00), and the median PFS was 4.8 and 5.8 months (P=0.03), respectively. The nomograms showed good C-index values: OS was respectively 0.688 and 0.576 and PFS was respectively for 0.643 and 0.544. Conclusions: The nomograms including HER2 status as covariate are crucial determinants of clinical care.

Aims Although platinum-based combination chemotherapies are commonly used for unfavourable subsets of cancer of unknown primary (CUP), the prognosis remains poor. Several studies have suggested that gene expression profiling or immunohistochemistry was useful for the prediction of primary sites in CUP, and site-specific therapy based on predicted primary sites might improve overall outcomes. In Japan, to identify primary sites, immunohistochemical tests were commonly used for CUP in clinical practice. However, it is unclear whether site-specific therapy based on predicted primary sites by pathological examination contributes survival benefit for unfavourable CUP subsets. Patients and methods In this study, 122 patients with unfavourable subsets of CUP were retrospectively reviewed. Ninety patients assigned to cohort A after July 2012 had received chemotherapy according to predicted primary sites; 32 patients assigned to cohort B before June 2012 had received platinum-based empiric chemotherapy. Results In cohort A, 56 patients (62.2%) with predicted primary sites by pathological examination received site-specific therapy; 34 patients (37.8%) with unpredictable primary sites received platinum-based empiric chemotherapy, the same as cohort B. The median overall survival was 20.3 months in patients with predictable primary sites in cohort A and 10.7 months in those of cohort B, with a significant difference between these cohorts (P = 0.03, adjusted hazard ratio = 0.57, 95% confidence interval 0.34–0.94). Conclusion Site-specific therapy based on predicted primary sites by pathological examination could improve prognosis in patients with an unfavourable subset of CUP.

To investigate the influence of addition of docetaxel to neoadjuvant chemotherapy (NAC) with cisplatin plus 5-fluorouracil (CF) in patients with clinical stage III or T3 esophageal squamous cell carcinoma. Information about 209 esophageal cancer patients with stage III or T3 disease, who underwent NAC consisting of CF with or without docetaxel, was reviewed. The survival outcomes were analyzed using the Kaplan–Meier method and propensity score-adjusted Cox proportional hazards models. The relevant variables were included in the propensity score model. NAC was administered to 149 patients in the CF group and 60 patients in the docetaxel plus CF (DCF) group. Overall, 129 patients treated with CF and 58 patients treated with DCF underwent surgery after NAC. The overall response rate was significantly higher in the DCF group compared with the CF group (61.0 vs. 43.2 %, p = 0.021). After matching, recurrence-free survival did not differ statistically between the CF and DCF groups [hazard ratio (HR) 0.83, 95 % confidence interval (CI) 0.50–1.37, p = 0.46]. After matching, the improvement in overall survival in the DCF group reached statistical significance (HR 0.49, 95 % CI 0.24–0.999, p = 0.050). No significant differences in rate of locoregional or distant recurrences were observed between the CF and DCF groups (53.0 vs. 48.3 %, p = 0.54). NAC with DCF is superior to CF in patients with clinical stage III or T3 esophageal squamous cell carcinoma.

Although nivolumab showed survival benefit in patients with advanced gastric cancer (AGC) progressing after standard chemotherapy, there is a lack of data regarding oxaliplatin-based chemotherapy in this clinical setting. We retrospectively evaluated the efficacy and safety of oxaliplatin with l-leucovorin and bolus/continuous infusion of 5-fluorouracil as salvage treatment in patients with AGC refractory or intolerant to fluoropyrimidines, cisplatin, taxanes, and irinotecan. Overall, 50 patients treated between December 2009 and December 2013 were included in this analysis. The overall response rate (ORR) was 21.2% among 33 patients with measurable disease. The median time to treatment failure (TTF) and overall survival (OS) were 2.4 and 4.2 months. In multivariate analysis, factors associated with OS included poor performance status [hazard ratio (HR) 3.20; 95% confidence interval (CI) 1.55–6.60], shorter time from the start of first-line therapy (HR 2.20; 95% CI 1.18–4.12), and higher neutrophil/lymphocyte ratio value (HR 4.87; 95% CI 2.32–10.25). In patients (n = 35) with at most one risk factor, the ORR, median TTF, and OS were 26.1%, 3.6, and 6.7 months, respectively. The most common grade 3 or 4 adverse events were neutropenia (30%), anemia (22%), febrile neutropenia (8%), and peripheral neuropathy (8%). Initial and subsequent dose reduction was performed in 18 (36%) and 23 (46%) patients. There was one treatment-related death caused by septic infection. Salvage chemotherapy with the combination of oxaliplatin, leucovorin, and 5-fluorouracil has a potential activity and is tolerable for heavily treated AGC with appropriate dose modification and patient selection.

Background/aim Severe peritoneal metastasis (PM) from advanced gastric cancer (AGC) causes massive ascites and inadequate oral intake. Because patients with severe PM are often not included in clinical trials, little is known regarding the efficacy and safety of oxaliplatin with l-leucovorin and bolus/continuous infusion of 5-fluorouracil (FOLFOX) for them. Patients and methods We retrospectively studied AGC patients with massive ascites and/or inadequate oral intake due to severe PM treated with FOLFOX as the first-line treatment. Results Only 39 (10%) of 378 AGC patients had severe PM; 10 received FOLFOX. The median progression-free and overall survivals were 7.5 and 13.2 months, respectively. Ascites decreased in seven of nine patients with ascites, and oral intake improved in four of seven patients with an inadequate oral intake. Common grade 3-4 adverse events included neutropenia and anemia. Conclusion This study suggests that FOLFOX is effective and manageable for AGC patients with severe PM.