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Whether trastuzumab use beyond disease progression is beneficial in second-line treatment for patients with unresectable human epidermal growth factor receptor 2 (HER2)-positive gastric cancer remains to be elucidated. We conducted this phase II study to assess whether trastuzumab plus docetaxel was effective for patients with previously treated advanced HER2-positive gastric cancer. This trial was a single-arm, open-label, multicenter, phase II study, conducted by Tohoku Clinical Oncology Research and Education Society (T-CORE). Patients aged 20 years or older who had advanced HER2-positive gastric cancer and were refractory to trastuzumab, fluoropyrimidine, and cisplatin were enrolled. Patients were treated with 6 mg/kg trastuzumab and 60 mg/m2 docetaxel every 3 weeks. The primary endpoint was the overall response rate. The threshold overall response rate was estimated to be at 15%. Secondary endpoints were progression-free survival, 6-month survival rate, overall survival, and toxicities. A total of 27 patients were enrolled from 7 hospitals. The median age was 67 years. Partial response was seen in 3 patients among the 26 evaluated patients. The overall response rate was at 11.5% (90% confidence interval 1.2%-21.8%). The median progression-free survival was 3.2 months, the 6-month survival rate was 85%, and the median overall survival was 11.6 months. Febrile neutropenia was observed in 14.8%. The most frequently observed grade 3 non-hematologic toxicity was anorexia (14.8%). The primary endpoint was not achieved. The results support a current consensus that the continuation of trastuzumab in second-line therapy for gastric cancer is not a recommended option.

Prophylactic percutaneous endoscopic gastrostomy (PEG) has been widely performed before concurrent chemoradiotherapy (CCRT) for locally advanced squamous cell carcinoma of the head and neck (LASCCHN) because severe oral mucositis and dysphagia induced by CCRT lead to difficulty with oral intake. However, it is controversial whether all patients require prophylactic PEG for adjuvant CCRT. This study evaluated predictive factors for the feasibility of oral intake in adjuvant CCRT for patients with LASCCHN. This study retrospectively analyzed 117 LASCCHN patients who underwent surgery followed by adjuvant CCRT with cisplatin at Shizuoka Cancer Center between April 2008 and December 2018. To investigate predictive factors for the feasibility of oral intake, tumor factors, treatment factors and social factors were included in multivariate analyses. Of the 117 patients, 25 received total laryngectomy and 92 received other surgery. In multivariate analysis, total laryngectomy [HR (hazard ratio) 0.09, P = 0.001] and oral cavity of primary tumor location (HR 0.21, P = 0.031) were significantly associated with the feasibility of oral intake. Difficulty obtaining adequate nutrition via oral intake from initiation of CCRT until 1 year after its completion was significantly rarer in the total laryngectomy group than in the other surgery group (16% vs. 57%, P

BACKGROUND: Although pathological response is a common endpoint used to assess the efficacy of neoadjuvant chemotherapy (NAC) for gastric cancer, the problem of a low rate of concordance from evaluations among pathologists remains unresolved. Moreover, there is no globally accepted consensus regarding the optimal evaluation. A previous study based on a clinical trial suggested that pathological response measured using digitally captured virtual microscopic slides predicted patients’ survival well. However, the pathological concordance rate of this approach and its usefulness in clinical practice were unknown. AIM: To investigate the prognostic utility of pathological response measured using digital microscopic slides in clinical practice. METHODS: We retrospectively evaluated pathological specimens of gastric cancer patients who underwent NAC followed by surgery and achieved R0 resection between March 2009 and May 2015. Residual tumor area and primary tumor beds were measured in one captured image slide, which contained the largest diameter of the resected specimens. We classified patients with < 10% residual tumor relative to the primary tumorous area as responders, and the rest as non-responders; we then compared overall survival (OS) and relapse-free survival (RFS) between these two groups. Next, we compared the prognostic utility of this method using conventional Japanese criteria. RESULTS: Fifty-four patients were evaluated. The concordance rate between two evaluators was 96.2%. Median RFS of 25 responders and 29 non-responders was not reached (NR) vs 18.2 mo [hazard ratio (HR) = 0.35, P = 0.023], and median OS was NR vs 40.7 mo (HR = 0.3, P = 0.016), respectively. This prognostic value was statistically significant even after adjustment for age, eastern cooperative oncology group performance status, macroscopic type, reason for NAC, and T- and N-classification (HR = 0.23, P = 0.018). This result was also observed even in subgroup analyses for different macroscopic types (Borrmann type 4/non-type 4) and histological types (differentiated/undifferentiated). Moreover, the adjusted HR for OS between responders and non-responders was lower in this method than that in the conventional histological evaluation of Japanese Classification of Gastric Carcinoma criteria (0.23 vs 0.39, respectively). CONCLUSION: The measurement of pathological response using digitally captured virtual microscopic slides may be useful in clinical practice.

Background Irinotecan (IRI) and oxaliplatin (Ox) are standard therapeutic agents of the first-line treatments for metastatic colorectal cancer (mCRC). Previous meta-analyses of randomized controlled trials (RCTs) showed that treatment with Ox-based compared with IRI-based regimens was associated with better overall survival (OS). However, these reports did not include trials of molecular targeting agents and did not take methods for the administration of concomitant drugs, such as bolus or continuous infusion of 5-fluorouracil, into account. A systematic literature review was performed to compare the efficacy and toxicity profiles between IRI- and Ox-based regimens as the first-line treatments for mCRC. Methods This meta-analysis used data from the Cochrane Central Register of Controlled Trials, PubMed, and SCOPUS. The primary endpoint was OS, and the secondary endpoints were progression-free survival (PFS), objective response rate (ORR), and adverse events (AEs). Results Nineteen trials involving 4571 patients were included in the analysis. No statistically significant difference was observed between the two groups in terms of OS, PFS, and ORR. There was no significant heterogeneity. Regarding ≥ grade 3 AEs, IRI-based regimens were associated with a high incidence of leukopenia, febrile neutropenia, and diarrhea. Moreover, there was a high incidence of thrombocytopenia and peripheral sensory neuropathy in patients who received Ox-based regimens. In a subgroup analysis, IRI combined with bevacizumab was correlated with a better PFS (HR = 0.90, 95% CI = 0.82–0.98, P = 0.02), but not with OS (pooled HR = 0.91, 95% CI = 0.80–1.03, P = 0.15). Conclusion Although the safety profiles of IRI- and Ox-based regimens varied, their efficacy did not significantly differ. The combination of anti-VEGF antibody and IRI was associated with better PFS compared with anti-VEGF antibody and Ox. Both regimens could be used as the first-line treatments for mCRC with consideration of the patients’ condition or toxicity profiles.

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 )

Background Ramucirumab monotherapy as a second-line treatment for advanced gastric cancer (AGC) prolongs survival compared to the best supportive care. However, in clinical practice, ramucirumab monotherapy is sometimes used as third- or later-line treatment for AGC refractory to fluoropyrimidine and taxanes. This study evaluated the efficacy and safety of salvage-line ramucirumab monotherapy for treating AGC. Methods The subjects of this retrospective study were advanced gastric or gastro-esophageal junction adenocarcinoma patients who received ramucirumab monotherapy after failure of 2 or more prior regimens containing fluoropyrimidine and taxanes but not ramucirumab. Results From June 2015 to April 2017, 51 patients were enrolled. The median progression-free survival (PFS) and overall survival (OS) were 1.8 (95% confidence interval [CI] = 1.6–2.2) and 5.1 (95% CI = 4.0–6.8) months, respectively. The objective response and disease control rates were 2 and 17%, respectively. Grade 3 adverse events (AEs; e.g., anemia, fatigue, hypertension, proteinuria, intestinal bleeding) occurred in seven (13%) patients, but no grade 4 AEs and treatment-related deaths were observed. A neutrophil–lymphocyte ratio (NLR) of Conclusions Salvage-line ramucirumab monotherapy has acceptable toxicity and comparable efficacy to second-line treatment; therefore, we consider physicians might choose this therapy as a salvage-line treatment option for AGC refractory to the standard therapies.

Although oxaliplatin 130 mg/m2 every 3 weeks was approved for advanced gastric cancer in Japan, data regarding S-1 plus oxaliplatin 130 mg/m2 (SOX130) are limited in Japanese patients with advanced gastric cancer. We investigated the feasibility and safety of SOX130 in Japanese patients with advanced gastric cancer. Patients with unresectable or recurrent gastric adenocarcinoma, no previous chemotherapy, and Eastern Cooperative Oncology Group Performance Status of 0–1 were treated with SOX130. The primary endpoint was the 3-cycle completion rate, defined as the proportion of patients who completed the first three cycles with ≥ 80% relative dose intensity of oxaliplatin. Twenty-five patients were enrolled from April 2015 to 2016. The 3-cycle completion rate was 72.0% (90% confidence interval: 53.8–86.1), which was higher than the predetermined threshold rate of 50%. With the median number of cycles being 6 (range, 1–19+), grade 3 or 4 adverse events occurred in 10 patients (40%). Major grade 3 adverse events were anorexia (24%), thrombocytopenia (16%), and neutropenia (12%). No febrile neutropenia or treatment-related deaths occurred. Among 12 patients with measurable lesions, the overall response rate was 58.3%. Median progression-free and overall survival were 5.7 months (95% confidence interval 2.9–8.5) and 13.1 months (95% confidence interval 7.4–19.0), respectively. Results indicated that SOX130 was feasible in Japanese patients with advanced gastric cancer.

The efficacy of primary prophylactic granulocyte colony-stimulating factor (G-CSF) in preventing febrile neutropenia (FN) in patients treated with docetaxel, cisplatin, and 5-fluorouracil (TPF) chemotherapy remains controversial. We compared the incidence of FN in patients treated with and without primary prophylactic G-CSF. We performed a retrospective analysis of 142 patients with locally advanced head and neck or esophageal cancer treated with TPF between January 2009 and March 2017. Among them, 116 patients started TPF without primary prophylactic G-CSF (control group) while 26 patients were given primary prophylactic G-CSF from day 7 of the first cycle of TPF (prophylactic group). The incidence of grade 4 neutropenia during the first cycle of TPF was significantly higher in the control group than in the prophylactic group [58.6% (n = 68) vs. 30.8% (n = 8), p = 0.02]. However, the incidence of FN in the first cycle was not significantly different between the two groups [32 patients (27.5%) in the control group and 8 patients (30.8%) in the prophylactic group (p = 0.62)]. In addition, the mean relative dose intensity throughout all cycles of TPF, as well as the survival time and response after TPF, were also not significantly different between the two groups. Primary prophylactic G-CSF from day 7 of the first cycle of TPF did not reduce the incidence of FN. Our findings suggest that the timing of primary prophylactic G-CSF, as recommended by the American Society of Clinical Oncology guidelines, should be modified to reduce the incidence of FN in TPF.

Background Recombinant human soluble thrombomodulin (rTM) has been established and introduced in the clinic as a standard treatment for disseminated intravascular coagulation (DIC). However, the efficacy and safety of rTM for DIC associated with solid tumors (DIC-STs) have not been fully established. Here, we performed a retrospective analysis of the clinical outcomes of rTM for DIC-STs and considered a treatment strategy with rTM for DIC-STs. Methods Patients with DIC-STs between November 2009 and March 2016 in 2 cancer core hospitals were retrospectively analyzed. Data, including patient background, treatment course, and clinical outcomes of rTM for DIC-STs, were extracted. The clinical outcomes were evaluated by comparing the DIC score, resolution rate, and overall survival (OS) duration. Results The study included 123 patients with DIC-STs. The median OS in all patients was 41 days. The DIC resolution rate was 35.2%. DIC scores and DIC-related blood test data (fibrin degradation product and prothrombin time-international normalized ratio) significantly improved at the end of rTM administration (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 demonstrated survival benefits as salvage therapy for patients with metastatic colorectal cancer. However, severe toxicities frequently occurred early in the treatment with the standard dose (160 mg/day), resulting in a dose reduction or interruption. To improve the tolerability and maintain sufficient efficacy, we conducted a phase II study of regorafenib with a lower starting dose (120 mg/day). Patients and Methods Regorafenib was initiated at 120 mg/day, and the dosage was increased to 160 mg/day on day 15 of the first cycle for patients who had met the dose escalation criteria. The primary endpoint was the disease control rate (DCR). The pharmacokinetics of the total and unbound regorafenib and its active metabolites (M2, M5) were assessed. Results A total of 70 patients were enrolled from September 2016 to December 2017. Only 6 patients achieved dose escalation to 160 mg on day 15 as planned. For the 68 evaluable patients, the DCR was 32.4% (95% confidence interval, 21.5%-44.8%), which was less than the threshold (30%) of our statistical hypothesis. The serum concentrations of total regorafenib for patients whose dose was escalated to 160 mg/day were significantly lower than those of the patients whose dose was not escalated (median, 3978 vs. 7244 nM; P = .027). The serum unbound concentrations of the sum of regorafenib and the active metabolites correlated significantly with the maximum grade of regorafenib-related symptomatic adverse events in the first cycle (11,138 vs. 19,096 pM; P = .035). Conclusion Regorafenib with a low starting dose of 120 mg/day did not achieve the expected DCR. A relationship of unbound exposure with toxicity was found.

Background The nutritional status of patients with esophageal squamous cell carcinoma (ESCC) harboring dysphagia is often poor. The efficacy and safety of enteral nutrition (EN) versus total parenteral nutrition (TPN) have not been addressed in patients with ESCC requiring nutritional support during definitive chemoradiotherapy (dCRT). Methods We performed a retrospective analysis of 51 locally advanced unresectable ESCC patients with dysphagia receiving EN (n = 28) or TPN (n = 23) during dCRT between 2009 and 2016. Results Patient characteristics in EN vs. TPN were as follows: median age (range), 67 (34 to 82) vs. 66 (57 to 83); ECOG performance status 0/1/2, 11/15/2 vs. 7/14/2; dysphagia score 2/3/4, 11/15/2 vs. 14/8/1; and primary tumor location Ce/Ut/Mt/Lt/Ae, 4/6/14/3/1 vs. 2/2/16/1/2. Median changes in serum albumin level one month after dCRT were +8.8% (−36 to 40) in EN and −12% (−64 to 29) in TPN (P = 0.00377). Weight, body mass index, and skeletal muscle area were not significantly different between the groups. Median durations of hospitalization were 50 days (18 to 72) in EN and 63 days (36 to 164) in TPN (P = 0.00302). Adverse events during dCRT in EN vs. TPN were as follows: catheter-related infection, 0 vs. 6 (27%); aspiration pneumonia, 3 (11%) vs. 2 (9%); mediastinitis, 3 (11%) vs. 1 (5%); grade ≥3 neutropenia, 6 (21%) vs. 14 (64%) (P = 0.00287); and febrile neutropenia, 0 vs. 6 (27%) (P = 0.00561). Conclusions EN may be advantageous for improving serum albumin level, and reducing hematological toxicity and duration of hospitalization compared with TPN during dCRT in ESCC patients.

Although oxaliplatin 130 mg/mPatients with unresectable or recurrent gastric adenocarcinoma, no previous chemotherapy, and Eastern Cooperative Oncology Group Performance Status of 0-1 were treated with SOX130. The primary endpoint was the 3-cycle completion rate, defined as the proportion of patients who completed the first three cycles with ≥ 80% relative dose intensity of oxaliplatin.Twenty-five patients were enrolled from April 2015 to 2016. The 3-cycle completion rate was 72.0% (90% confidence interval: 53.8-86.1), which was higher than the predetermined threshold rate of 50%. With the median number of cycles being 6 (range, 1-19+), grade 3 or 4 adverse events occurred in 10 patients (40%). Major grade 3 adverse events were anorexia (24%), thrombocytopenia (16%), and neutropenia (12%). No febrile neutropenia or treatment-related deaths occurred. Among 12 patients with measurable lesions, the overall response rate was 58.3%. Median progression-free and overall survival were 5.7 months (95% confidence interval 2.9-8.5) and 13.1 months (95% confidence interval 7.4-19.0), respectively.Results indicated that SOX130 was feasible in Japanese patients with advanced gastric cancer.

According to the REGARD and RAINBOW trials, ramucirumab(RAM)was introduced as second-line therapy for advanced or metastatic gastric cancer. RAM may impair wound healing due to the inhibition of angiogenesis; details on the postoperative course of patients who underwent surgery during RAM treatment remain unclear. Between 2011 and 2016, 93 patients with incurable gastric cancer were treated with RAM in our institute. Among them, 3 patients underwent surgery after RAM treatment. Case 1: A 74-year-old man with liver metastasis from gastric cancer was treated with a paclitaxel(PTX)plus RAM regimen. Perforation of the stomach was observed 3 days after final RAM administration. He was successfully treated with omental repair and discharged 19 days after surgery. Case 2: A 31-year-old woman with peritoneal recurrence after total gastrectomy received the PTX plus RAM regimen as second-line treatment. Stenting was performed for rectal stenosis. Perforation of the rectum just proximal of the stent was observed 5 days after final RAM administration. Ileostomy was performed. Closure of the perforation was not obtained until the patient died 210 days after surgery. Case 3: A 60-year-old man with remnant gastric cancer received the PTX plus RAM regimen. Accidentally, the enteral feeding tube was removed. Six weeks after the cessation of RAM administration, the enteral feeding tube was inserted under general anesthesia. He was discharged 4 days after surgery. If surgery is required in patients receiving RAM treatment, sufficient drug withdrawal is desirable. If emergency surgery is needed, less invasive procedures should be selected to the maximum extent possible.

Background/Objective Whether gastrojejunostomy (GJJ) or duodenal stent (DS) placement is preferable for treatment of gastric outlet obstruction (GOO) in patients with unresectable pancreatic cancer is unclear. We compared the usefulness of GJJ with that of DS placement in these patients. Methods We retrospectively reviewed 66 consecutive patients with unresectable pancreatic cancer who underwent GJJ or DS placement for symptomatic GOO. Results We analyzed 30 patients who underwent GJJ and 23 who underwent DS placement. Peritoneal metastasis was more common in the DS group. Median survival after the first intervention was similar in both groups. Although clinical success (maintaining a GOO Scoring System score ≥2 for more than 7 days) rate was significantly higher in the GJJ group (100% vs. 81%), clinical benefit (maintaining a score ≥2 for more than half of their survival after the first intervention) rate was similar between the GJJ and DS groups (66.7% vs. 69.7%), even among patients who survived for ≥90 days (73.3% vs. 75.0%). Further, the proportion of patients who could receive planned chemotherapy after the first intervention was higher and the time to administration of chemotherapy was significantly shorter in the DS group (9 vs. 32 days). Major complication rate was similar in both groups. Conclusions These findings suggest that DS placement is as effective as GJJ for the treatment of GOO in patients with unresectable pancreatic cancer, even in those with a long life expectancy. DS placement might be more beneficial than GJJ in patients for whom chemotherapy is planned.

Several studies have demonstrated the benefit of hepatectomy for treating gastric cancer (GC) with liver-limited metastases (LLM). The survival benefit of hepatectomy compared with that of systemic chemotherapy is unknown, particularly in patients with multiple LLM. This study investigated the survival benefit of hepatectomy compared with that of systemic chemotherapy administered to patients with GC with multiple LLM. We retrospectively reviewed the data of consecutive patients with GC with two or three LLM who underwent hepatectomy or received systemic chemotherapy as initial treatment at the Shizuoka Cancer Center between December 2004 and December 2015. Nine of 24 patients who met the inclusion criteria underwent hepatectomy, and 15 received chemotherapy. In the hepatectomy group, all patients achieved R0 resection and none died during hospitalization. Three patients received adjuvant chemotherapy. Disease recurred in eight patients (88.9%). In the chemotherapy group, three patients underwent hepatectomy following initial chemotherapy and did not experience recurrence or death during follow-up. Median follow-up was 47.9 months and median overall survival (OS) was 38.1 and 24.8 months in the chemotherapy and hepatectomy groups, respectively. Multivariate analysis of OS, including initial treatment, revealed that unilobar liver metastasis was the only independent favorable prognostic factor. Although hepatectomy for patients with GC with multiple LLM is not recommended as the initial therapy, it prolonged the survival of patients with tumors controlled using systemic chemotherapy.

Background Post-operative concurrent chemoradiotherapy (CCRT) with cisplatin (CDDP) for locally advanced squamous cell carcinoma of head and neck (LASCCHN) frequently induces severe oral mucositis and dysphagia, which lead to insufficient oral intake and negative impact on treatment outcomes. Therefore, prophylactic percutaneous endoscopic gastrostomy (PEG) has been widely performed. However, PEG placement often causes some complications such as bleeding or abscess. The aim of this study is to evaluate necessity of prophylactic PEG in adjuvant CCRT for high-risk patients with LASCCHN who underwent total laryngectomy. Methods This study retrospectively analyzed 117 LASCCHN patients who underwent either total laryngectomy or other surgery followed by adjuvant CCRT with CDDP at Shizuoka Cancer Center between April 2008 and December 2018. We evaluated the rate of patients unable to obtain sufficient nutrition via oral intake from initiation of CCRT until one year after completion of CCRT, and nutrition-support-free survival. The risk factors for inability of oral intake were determined by using the Cox proportional hazards model. Results Of 117 patients, 25 patients received total laryngectomy and 92 patients received other surgery. The rate of patients unable to obtain sufficient nutrition via oral intake was significantly lower in the total laryngectomy group (16% vs 57%, P Conclusion Prophylactic PEG for adjuvant CCRT may not be necessarily required for the LASCCHN patients who underwent total laryngectomy because of high feasibility of oral intake.

e17556 Background: The standard of care for oropharyngeal squamous cell carcinoma (OPSCC) is surgical (S) or non-surgical (NS) approach including chemoradiation (CRT). However, CRT is associated with significant long-term toxicity. Human papillomavirus (HPV) status are associated with improved prognosis for patients (pts) with OPSCC. The aim of this study was to explore the most promising treatment strategy with maintaining survival outcomes while improving QOL for locally advanced resectable HPV-positive OPSCC. Methods: A retrospective analysis of 96 pts with locally advanced resectable HPV-positive OPSCC in Shizuoka Cancer Center between 2004 and 2018 was performed. p16 immunohistochemistry was used to determine HPV tumor status. Clinical characteristics, acute and late toxicities, nutritional support, and survival were compared by treatment modalities. In pts who received S, surgical procedure and histological findings of the surgical specimens were additionally compared between pts who underwent upfront surgery (US) and those who did induction chemotherapy followed by surgery (ICT-S). Results: The median age was 62 years, with the majority having tonsil and base of the tongue as primary site. Thirty-six pts (38%) were current smokers, and 39 (41%) were former smokers. As an initial treatment, 62 (64.6%) and 34 (35.4%) pts underwent S and NS, respectively. Aspiration pneumonia more frequently occurred in NS (41.2%) than in S (8.1%) (p < 0.01). Nutritional support by gastrostomy tube or total parenteral nutrition was required in 20 pts (58.8%) of NS, compared with 15 pts (24.2%) of S (p < 0.01). S showed a trend toward longer overall survival (OS) than NS [HR = 0.204, p = 0.052], while progression free survival (PFS) was comparable between the groups. Of all S, 48 (50.0%) and 14 (14.6%) underwent US and ICT-S, respectively. Transoral surgery was performed in 78.6% of ICT-S, compared with 20.8% of US (p < 0.01). Histological examination of the surgical specimens revealed that positive surgical margins, involvement of ≥ 2 regional lymph nodes, and positive extracapsular extension were present in 7.1, 35.7, and 35.7% of ICT-S, compared with 31.3, 58.3, and 45.8% of US, respectively (N.S.). Pathologic complete response in the primary site and lymph nodes occurred in 43 % of ICT-S. Both OS and PFS was comparable between the groups. Conclusions: Our results suggest the impact of surgical approach on reduced long-term toxicity for HPV-positive OPSCC. ICT followed by surgery might be promising novel treatment strategy.

TPS178 Background: Immune checkpoint inhibitors are drugs that block specific proteins produced by the immune system cells, such as T-cells; these proteins prevent T-cells from killing cancer cells. NIV is a standard care for pretreated mGC patients (pts), with increasing clinical use in Japan. Data from retrospective studies on various tumors have shown that after exposure to immune checkpoint inhibitors, the objective response rate to CTx potentially improves; however, enough data have not been accumulated. Although there are no recommended CTx regimen following NIV therapy, in a clinical setting, an irinotecan or oxaliplatin combination regimen (limited to cisplatin-refractory or cisplatin-intolerant pts) is frequently used as post-NIV CTx. This multicenter observational study aims to evaluate the efficacy and safety of CTx in NIV-refractory or NIV-intolerant mGC pts. Methods: We prospectively collect clinical and imaging data from NIV-pretreated mGC pts; these pts will be treated with cytotoxic agents. Pts who meet inclusion criteria A (histologically proven mGC pretreated with NIV, prior administration of a combination therapy of fluoropyrimidine plus platinum and taxanes, and written informed consent) at primary registration are registered. After primary registration, pts who meet inclusion criteria B [Eastern Cooperative Oncology Group Performance Status (ECOG PS 0-2), refractory or intolerant to NIV; prior administration of irinotecan monotherapy or oxaliplatin combination regimens and prior use of cisplatin; evaluable lesions according to RECIST ver. 1.1] at formal registration are registered. The primary endpoint is overall survival of NIV-pretreated mGC pts after CTx. For this study, we require 146 pts, with bilateral alpha = 0.05 and beta = 0.10, with a median threshold survival of 4.0 months and an expected median survival of 6.0 months. Therefore, we plan to enroll 200 pts, considering exclusions from the analysis; since May 2018, we have enrolled 27 pts. Clinical trial information: UMIN000032182.

Background Chemoradiotherapy (CRT) and bio-radiotherapy (BRT) are recognized as standard therapies for head and neck cancer (HNC). Aspiration pneumonia after CRT or BRT is a common late adverse event. Our aim in this study was to evaluate the cause-specific incidence of aspiration pneumonia after CRT or BRT and to identify its clinical risk factors. Methods We performed a retrospective analysis of 305 patients with locally advanced HNC treated by CRT or BRT between August 2006 and April 2015. Results Of these 305 patients, 65 (21.3%) developed aspiration pneumonia after treatment. The median onset was 161 days after treatment. The two-year cause-specific cumulative incidence by CRT or BRT was 21.0%. Multivariate analysis revealed five independent risk factors for aspiration pneumonia, namely, habitual alcoholic consumption, use of sleeping pills at the end of treatment, poor oral hygiene, hypoalbuminemia before treatment, and the coexistence of other malignancies. A predictive model using these risk factors and treatment efficacy was constructed, dividing patients into low- (0–2 predictive factors), moderate- (3–4 factors), and high-risk groups (5–6 factors), the two-year cumulative incidences of aspiration pneumonia of which were 3.0, 41.6, and 77.3%, respectively. Aspiration pneumonia tended to be associated with increased risk of death, although this was not statistically significant (multivariate-adjusted hazard ratio 1.39, P = 0.18). Conclusion The cause-specific incidence and clinical risk factors for aspiration pneumonia after definitive CRT or BRT were investigated in patients with locally advanced HNC. Our predictive model may be useful for identifying patients at high risk for aspiration pneumonia.

Although irinotecan monotherapy is often used in third-line treatment after the failure of taxanes in Japanese clinical practice, its survival benefit is still unclear. The aim of this study is to investigate the efficacy and safety of irinotecan monotherapy as third-line treatment.Clinical data from consecutive patients in whom irinotecan had been initiated as third-line treatment between December 2003 and July 2015 in Shizuoka Cancer Center were retrospectively analyzed. Patients who were refractory or intolerant to fluoropyrimidine with or without platinum in first-line treatment and subsequent therapy with taxanes were included in this study. Irinotecan was administered at 150 mg/m(2) every 2 weeks.The data of 50 patients who met the inclusion criteria were analyzed. The overall response rate was 18.4 % (7/38) among the patients with measurable disease. The median progression-free survival time was 66 days, and the median survival time was 180 days from the initiation of irinotecan therapy. The major grade 3 or 4 adverse events including neutropenia, fatigue, and anorexia were observed in 12 (24 %), 8 (16 %), and 7 (14 %), respectively. No treatment-related deaths occurred. Thirteen patients (26 %) required a dose reduction to 120 mg/m(2) or less from the initiation of irinotecan.This study suggests that irinotecan as third-line treatment has an anti-tumor effect and is feasible with optimal dose modification for advanced gastric cancer.

Zoledronic acid suppresses osteoclastic changes and reduces the risk of cancer-induced skeletal-related events. Moreover, it has been reported to have antitumor effects. The authors here present a case of a male patient with large cell lung cancer who had an osteolytic lesion in the thoracic vertebrae. The cancer was moderately sensitive to radiation therapy but barely sensitive to chemotherapy with cytotoxic agents. However, it was markedly regressed after zoledronic acid monotherapy, and the patient’s symptoms almost disappeared. This remarkable response of large cell lung cancer to zoledronic acid monotherapy is rare.

e22185Background: Proper nutritional support affects the treatment outcome in cancer. However, the role of nutritional intervention (NI) in patients (pts) with metastatic esophageal squamous cell c...

261 Background: The 8th edition of the AJCC staging system for pancreatic cancer contains several changes. T and N classification incorporate tumor size and number of positive lymph node (LN). The aim of this study was to evaluate the impact on the outcomes of the new classification for the patients who underwent curative resection and received adjuvant treatment with S-1. Methods: We retrospectively reviewed 96 patients who underwent curative resection for pancreatic ductal adenocarcinoma and received adjuvant treatment with S-1 (40, 50, or 60 mg according to body-surface area, orally administered twice a day for 28 days followed by a 14-day rest, every 6 weeks [one cycle], for up to four cycles) at our institution between January 2007 and December 2015. Inclusion criteria were as follows: PS0/1, adequate-organ functions, no critical complication, start of adjuvant therapy within 10 weeks after resection, and no active concomitant malignancy. Results: 66 patients were satisfied with these criteria. Patients characteristics were as follows: median age 67 years (range, 43-83), male 40 (61%), Pancreatoduodenectomy / Distal / Total pancreatectomy 50/14/2, combined portal vein or superior mesenteric vein resection 25 (38%), no postoperative complication 25 (38%), Well/Moderately/Poorly differentiated type 23/41/2, the median tumor size 30mm (range, 13-130), the median number of dissected LN 25 (range, 10-60), the median number of positive LN 2 (range, 0-8), and the resection margin status (R0/1) 62/4. The distribution in the 8th edition (1A/1B/2A/2B/3) was 6(9%) / 10(15%) / 5(8%) / 36(54%) / 9(14%), respectively. 2-year overall survival (OS) and relapse-free survival (RFS) were 70% and 52%. In the 8th edition staging system (1A/1B/2A/2B/3), 2-year OS and RFS were 100/90/80/66/40% and 83/70/53/49/22%, respectively. 2-year OS and RFS by T classification according to AJCC 8th edition were 100/68/56% and 90/39/56% (T1/2/3), while those by N classification were 90/66/40% and 70/49/22% (N0/1/2), respectively. Conclusions: The survival was poor with progress of the stage in the new classification. Especially at N stage, it might be suggested an association with prognosis.

813 Background: UGT1A1 polymorphisms have been reported to be associated with increased irinotecan (IRI)-induced toxicity. However, influence of the polymorphisms on survival in metastatic colorectal cancer (mCRC) patients (pts) treated with IRI-containing therapy remains controversial. Methods: We retrospectively reviewed data of consecutive mCRC pts who received FOLFIRI/IRI with or without an anti-VEGF agent as 2nd line therapy at the Shizuoka Cancer Center between April 2008 and December 2015. The primary selection criteria were histologically confirmed adenocarcinoma, prior history of oxaliplatin-containing therapy, and adequate organ function. UGT1A1 polymorphisms were screened and pts with homozygous (*6/*6, *28/*28) or compound heterozygous (*6/*28) were excluded. Results: Among 103 pts found eligible for this analysis, 63 were wild type (W) (−/−) for UGT1A1, and 40 were heterozygous type (H) (-/*6, -/*28), with the following characteristics: median age (range), 60 (30–77) vs 67 (37–84); male/female, 41/22 vs 18/22; PS 0/1/2, 40/21/2 vs 21/18/1; tumor location right/left, 16/47 vs 9/31; peritoneal metastasis −/+, 49/14 vs 33/7; disease status metastasis/recurrence, 49/14 vs 23/17; RAS wild type/mutant, 25/37 vs 18/21; IRI regimen doublet/mono, 51/12 vs 33/7; anti-VEGF agent use −/+, 16/47 vs 12/28; and median IRI dose intensity, 63.7 vs 60 mg/m2/week. Incidences of grade 3/4 neutropenia, febrile neutropenia, and diarrhea in W/H pts were 36%/48%, 5%/9%, 5%/13% (initial IRI dose 180 mg/m2). Median PFS was 6.2 M in W, and 3.9 M in H (p = 0.36). Median OS was 12.1 M in W and 10.9 M in H (p = 0.86). RR was 13% in W, and 10% in H (p = 0.68). DCR was 81% in W, and 58% in H (p = 0.012). Multivariate analysis identified no liver-limited disease, disease status (metastatic), UGT1A1 H type, IRI monotherapy, and no anti-VEGF as independent predictors of poorer PFS (HR 1.76, 2.01, 1.67, 2.17, 2.58), and initial dose of CPT < 180mg/m2 and no anti-VEGF as independent predictors of poorer OS (HR 1.85 and 1.85). UGT1A1 polymorphism was not detected as an independent predictor of RR or DCR. Conclusions: UGT1A1 polymorphism may be useful in predicting PFS in mCRC pts treated with IRI-containing therapy.

156 Background: It has been suggested that nutritional indicators predict the prognosis of esophageal cancer. Nutritional risk (NR) as prognostic factor evaluated by NR index (NRI) in metastatic esophageal squamous cell cancer (ESCC) has not been clarified. Methods: We retrospectively reviewed the data of consecutive patients (pts) with metastatic ESCC who received chemotherapy (CTx) as initial treatment at Shizuoka Cancer Center between April 2008 and December 2015. The selection criteria were as follows: histologically confirmed squamous cell carcinoma; no indication for curative resection or definitive chemoradiotherapy (dCRT); adequate organ function; no prior CTx, radiotherapy (RT) or chemoradiotherapy; no other advanced malignancies. NR was calculated by following formula: NRI = (1.489*serum albumin) + (41.7*present body weight [BW] / ideal BW). NR was classified into 4 groups according to NRI: major (NRI < 83.5), moderate (NRI = 83.5-97.5), mild (NRI = 97.5-100), none (NRI > 100). Multivariate analysis was carried out using cox proportional hazard to estimate the hazard ratio for overall survival (OS). Results: The patients’ characteristics of 138 pts who met the selection criteria were as follows: median age (range), 67 (33-86) years; male/female, 123/15; performance status (PS) 0/1/2, 62/68/8; number of metastatic sites 1/2/3/4, 55/56/23/4; smoking history -/+, 19/119; previous esophagectomy -/+, 118/20; median skeletal muscle index (range), 44.5 (27.8-63.2); median body mass index (range), 20.3 (14.3-27.4); NR major/moderate/mild/none 22/37/26/53; median serum C-reactive protein (CRP) level (range), 0.75 (0.01-20.48) mg/dL. The most common chemotherapy regimen used was fluoropyrimidine plus cisplatin (93%), and 70 patients (50%) received concomitant RT. Median OS was 4.6 months in pts with major NR and 11.8 months in others (p < 0.001). Multivariate analysis for OS identified PS 2, female sex, metastatic sites > 2, CRP ≥ 1mg/dL, and major NR independently associated with poor survival. Conclusions: Major NR calculated by NRI formula associated with poor survival in pts with metastatic ESCC.

154 Background: While taxane-monotherapy following fluoropyrimidine plus platinum is recognized as the standard treatment strategy for advanced gastric cancer, triplet chemotherapy with docetaxel, cisplatin and S-1 (DCS) is another option for first-line therapy in Japan. However, efficacy of taxane after DCS therapy has not been sufficiently evaluated. Methods: We retrospectively evaluated the efficacy and safety of taxane-monotherapy after DCS between January 2010 and April 2015 for advanced gastric cancer. The taxane-monotherapy included weekly paclitaxel (PTX) (80 mg/m2, day 1, 8 and 15 of a 28-day cycle) and triweekly nab-PTX (260 mg/m2, day 1). Other selection criteria were: ECOG PS < 2; adequate organ function; no severe ascites; HER2-negative. Results: Thirty of 92 patients who had been treated with DCS received taxane-monotherapy. Fifteen and 15 patients received taxane-monotherapy as the second and third-line treatment, respectively. Patients characteristics of each group (2nd/3rd) were; median age: 64/62 (range 27-75/42-75); ECOG PS ≤ 1: 14/13; number of metastatic sites ≥ 2: 9/12; median taxane-free interval from first-line treatment: 1.6/3.4 (range 0.9-2.3/2.2-8.3) months; median total dose of prior DTX: 349/208 (range 39-844/141-685) mg/m2. Number of patients who received PTX/nab-PTX were 10/5 and 13/2 in the second and third line treatment. Median relative dose intensity of taxane was 96.4% (range 57.6-172.9%) in the second-line, 98.5% (44.0-166.8%) in the third-line group. Response rate and disease control rate were 0% and 37.5% in the second-line, and 0% and 38.5% in the third-line group. 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. Grade 3 or 4 neutropenia, anemia, and anorexia, occurred in 33%, 13% and 13% in the second-line group, and 6.7%, 13% and 6.7% in the third–line group, associated with no treatment related death. Conclusions: It is suggested that taxane-monotherapy has acceptable toxicities but insufficient efficacy in advanced gastric cancer patients after DCS therapy.

193 Background: Adjuvant S-1 therapy for pStage II/III gastric cancer (GC) patients (pts) after curative resection is standard treatment in Japan, however, prognosis of pStage III is still poor. There are few reports investigating the association of treatment exposure with survival. Therefore, we investigated the impact of dose modification or termination of S-1 as adjuvant therapy on overall survival (OS). Methods: The data of locally advanced GC pts who underwent gastrectomy with D2 lymph-node dissection in Shizuoka Cancer Center between Jan 2007 and Aug 2013 were retrospectively collected. Inclusion criteria were as follows: age 20 to 80 years; ECOG PS 0 or 1; histologically proven adenocarcinoma; pStage III under TNM 7th edition; R0 resection; initiation of S-1 within 56 days after surgery. S-1 was administered for 4 weeks followed by a 2 weeks rest. We defined completion of planned S-1 therapy as continuation of S-1 one year after surgery. Results: One hundred and six pts satisfied inclusion criteria. Pts’ characteristics were as follows: median age, 67 years (range, 38-78); male/female, 77/29 pts; ECOG PS 0/1, 72/34 pts; primary tumor location EGJ/U/M/L, 1/27/45/33 pts; and pStage IIIA/IIIB/IIIC, 25/41/40 pts. Fifty-five pts (51%) needed dose modification (dose reduction and/or schedule alteration). Eighty-two pts (77%) achieved completion of planned S-1 therapy. Five year OS rate was 59.9%. Among potential prognostic factors for OS in univariate analysis (age, PS, pStage, completion of planned S-1 therapy, dose modification), completion of planned S-1 therapy (HR 0.26; 95% CI 0.13-0.51; p < 0.001) and PS 0 (HR 0.52; 95% CI 0.27-0.99; p = 0.048) were good prognostic factors and dose modification was not prognostic factor (HR 1.06; 95% CI 0.53-2.12; p = 0.876) for OS. Conclusions: This study suggested that completion of planned adjuvant S-1 therapy and PS 0 were good prognostic factors for OS and appropriate dose modification might not worsen their prognosis.

113 Background: Several randomized trials demonstrated the survival benefit in advanced gastric cancer patients (AGC pts) receiving irinotecan or taxanes as second-line chemotherapy (SLC). Taxanes are used for SLC in daily clinical practice in Japan because of its less toxicity, especially in AGC pts with peritoneal dissemination, compared with irinotecan. Although irinotecan is often administered after refractory or intolerant to taxanes as SLC, the efficacy and safety of irinotecan as third-line chemotherapy (TLC) is still unclear. Methods: We retrospectively investigated the data of AGC pts administered irinotecan 150mg/m2 as TLC every two weeks until disease progression, unacceptable toxicity, or pts’ refusal between December 2002 and June 2015. Inclusion criteria were (1) age 75 years or less (2) refractory or intolerant to fluoropyrimidine with or without platinum as first-line chemotherapy (3) refractory or intolerant to taxanes as SLC. Results: A total of 52 pts were analyzed. Pts’ characteristics were as follows: median age, 66 (range, 33-75) years; male/female, 35/17 pts; ECOG PS 0-1/2, 42/10 pts; peritoneal dissemination +/-, 32/20 pts; ascites +/-, 22/30 pts, number of metastatic sites 1-2/3-4, 44/8 pts. Median follow-up period was 548 (141-1931) days. Median progression-free survival was 70 days (95%CI 49-137) and median overall survival was 144 days (95%CI 120-231) from the initiation of irinotecan administration. Response rate and disease control rate was 10.8% and 50.4%, respectively. Relative dose intensity was 74.7% (56 mg/m2/week); 14 pts needed dose reduction in the first course, and 22 pts after the second course. Grade 3 or 4 neutropenia, anemia, diarrhea, nausea, and febrile neutropenia were observed in 13 (25%), 21 (40.4%), 5 (9.6%), 3 (5.8%) and 3 (5.8%) pts, respectively. No treatment-related death was observed. Conclusions: This study suggests that irinotecan monotherapy as TLC has acceptable anti-tumor effect and has manageable toxicity in appropriately selected AGC pts.

Lewis Y (LeY) antigen is an oligosaccharide that is highly expressed at the cell surface in various human cancers. Increased LeY expression activates epidermal growth factor receptor (EGFR) and human epidermal growth factor receptor 2 (HER2) and promotes cell proliferation in EGFR-overexpressing cells. However, the effect of downregulation of LeY expression on cell proliferation in HER2-overexpressing cells remains unknown. FUT1 encodes α1,2-fucosyltransferase, a key enzyme for LeY synthesis. We knocked down FUT1 by short interfering RNA (siRNA) in four HER2-overexpressing human cancer cell lines, including NCI-N87, MKN7, SKBr3 and BT474. We investigated whether downregulation of LeY and alteration in the glycosylation status of these cells affect cell proliferation and HER2 activation. Knocking down FUT1 expression markedly inhibited proliferation of NCI-N87, which highly expressed EGFR and was sensitive to EGFR deprivation. Furthermore, FUT1 siRNA downregulated the total amount of HER2 protein, phosphorylation of HER2 and EGFR, and phosphorylation of extracellular signal-regulated kinase (ERK) in this cell line. Moreover, the marked downregulation of phosphorylation of HER2 and ERK was observed following short-time EGF-stimulation. These effects were not observed in the other three cell lines. Our results suggest that knockdown of FUT1 downregulates HER2 signaling via EGFR downregulation. FUT1 may serve as a new molecular target for HER2-overexpressing human cancers with activated EGFR signaling.

Background: Chemotherapy-induced lung toxicity is one of the critical side effects in cancer treatment, and it has great influence on the prognosis and treatment. Here, we analyzed the clinical features of the patients who were suffered from the chemotherapy-induced lung toxicity in our hospital for three years. Methods: We analyzed the cause drugs, treatments, and clinical pathways of the patients who had the chemotherapy-induced lung toxicities between May 2011 and Dec 2013. Results: 17 patients had the chemotherapy-induced lug toxicities. 6 patients were Irinotecan, which were the most cases, 5 patients were Gemcitabine, 3 patients were Pemetrexed, 2 patients were Fluorouracil, and other drugs. All patients were treated by steroid treatment as soon as possible. Two patients died owing to the respiratory failure. And one patient needed the mechanical ventilation. Other patients were successfully recovered. One fatal patient had the interstitial pneumonia and the other fatal patient could not discriminate the carcinomatous lymphangiosis. Conclusions: Our result was superior to the results of past reported. Our patients were treated when light respiratory symptom appeared. It is proposed that early diagnosis and early treatment are important.

Background: Opportunities to give chemotherapy for elderly advanced gastric cancer (AGC) patients are increasing with aging of population. As patients over 76 years of age had been excluded from many clinical trials until recently, relatively weaker evidences exist about the efficacy and safety of chemotherapy for AGC in this population. Purpose: The aim of the study is to elucidate the efficacy of the chemotherapy of the elderly AGC patients in our hospital. Method: Retrospective reviews of 150 AGC patients who receive chemotherapies in Osaki Citizen Hospital from October 2010 to March 2013 were undertaken. We defined ‘younger’ as those patients aged 75 years or younger, and ‘elderly’' as aged over 76 years. We retrospectively compared the treatment regimen and efficacy. Result: Among the 150 patients, the number of younger and elderly AGC patients was 94 and 56 respectively. Seven younger patients and 15 elderly patients received BSC alone. Introduction rate of chemotherapy for the elderly was lower than that for younger patients. Median TTF of the whole chemotherapy of younger and elderly patients was 213 days and 200 days, respectively, with no significant difference. Conclusion: It is often difficult to introduce chemotherapy for elderly patients, because of their organ dysfunction, comorbidities, or social backgrounds. This study suggested, if applied properly, the prolongation of survival by chemotherapy may be expected in elderly as well as in younger AGC patients.