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Background Clinical trials have reported the efficacy of tropomyosin receptor kinase (TRK) inhibitors against neurotrophic receptor tyrosine kinase (NTRK) fusion gene-positive advanced solid tumors. The accumulated evidence of tumor-agnostic agent has made since TRK inhibitors were approved and used in clinical practice. Therefore, we have revised the ‘Japan Society of Clinical Oncology (JSCO)/Japanese Society of Medical Oncology (JSMO)-led clinical recommendations on the diagnosis and use of tropomyosin receptor kinase inhibitors in adult and pediatric patients with neurotrophic receptor tyrosine kinase fusion-positive advanced solid tumors, cooperated by the Japanese Society of Pediatric Hematology/Oncology (JSPHO)’. Methods Clinical questions regarding medical care were formulated for patients with NTRK fusion-positive advanced solid tumors. Relevant publications were searched by PubMed and Cochrane Database. Critical publications and conference reports were added manually. Systematic reviews were performed for each clinical question for the purpose of developing clinical recommendations. The committee members identified by JSCO, JSMO, and JSPHO voted to determine the level of each recommendation considering the strength of evidence, expected risks and benefits to patients, and other related factors. Thereafter, a peer review by experts nominated from JSCO, JSMO, and JSPHO, and the public comments among all societies' members was done. Results The current guideline describes 3 clinical questions and 14 recommendations for whom, when, and how NTRK fusion should be tested, and what is recommended for patients with NTRK fusion-positive advanced solid tumors. Conclusion The committee proposed 14 recommendations for performing NTRK testing properly to select patients who are likely to benefit from TRK inhibitors.

Neuroendocrine carcinoma (NEC) of the head and neck is a rare type of malignancy, accounting for only 0.3% of all head and neck cancers, and its clinicopathological and genomic features have not been fully characterized. We conducted a retrospective analysis of 27 patients with poorly differentiated NEC of the head and neck seen at our institution over a period of 15 years. Patient characteristics, adopted therapies, and clinical outcomes were reviewed based on the medical records. Pathological analysis and targeted sequencing of 523 cancer-related genes were performed using evaluable biopsied/resected specimens based on the clinical data. The most common tumor locations were the paranasal sinus (33%) and the oropharynx (19%). Eighty-one percent of the patients had locally advanced disease. The 3-year overall survival rates in all patients and in the 17 patients with locally advanced disease who received multimodal curative treatments were 39% and 53%, respectively. Histologically, large cell neuroendocrine carcinoma was the predominant subtype (58% of evaluable cases), and the Ki-67 labeling index ranged from 59 to 99% (median: 85%). Next-generation sequencing in 14 patients identified pathogenic/likely pathogenic variants in TP53, RB1, PIK3CA-related genes (PREX2, PIK3CA, and PTEN), NOTCH1, and SMARCA4 in six (43%), three (21%), two (14%), two (14%), and one (7%) patients, respectively. Sequencing also detected the FGFR3-TACC3 fusion gene in one patient. The median value of the total mutational burden (TMB) was 7.1/Mb, and three patients had TMB ≥ 10. Regardless of the aggressive pathological features, our data revealed favorable clinical characteristics in the patients with locally advanced disease who received curative treatment. The lower TP53 and RB1 mutation prevalence rates compared to those described for small cell lung cancer suggests the biological heterogeneity of NEC in different parts of the body. Furthermore, the FGFR3-TACC3 fusion gene and mutations in genes encoding the components of the NOTCH and PI3K/AKT/mTOR pathways found in our study may be promising targets for NEC of the head and neck.

Naomi Hayashi,1 Yasuyoshi Sato,1 Yu Fujiwara,1,2 Naoki Fukuda,1 Xiaofei Wang,1 Kenji Nakano,1 Testuya Urasaki,1 Akihiro Ohmoto,1 Makiko Ono,1 Junichi Tomomatsu,1 Yukiko Sato,3 Hiroki Mitani,4 Takashi Toshiyasu,5 Shunji Takahashi1 1Department of Medical Oncology, The Cancer Institute Hospital of Japanese Foundation for Cancer Research, Tokyo, Japan; 2Department of Medicine, Icahn School of Medicine at Mount Sinai, Mount Sinai Beth Israel, New York City, NY, USA; 3Pathology, The Cancer Institute Hospital of Japanese Foundation for Cancer Research, Tokyo, Japan; 4Head and Neck Oncology, The Cancer Institute Hospital of Japanese Foundation for Cancer Research, Tokyo, Japan; 5Radiation Oncology, The Cancer Institute Hospital of Japanese Foundation for Cancer Research, Tokyo, JapanCorrespondence: Yasuyoshi SatoThe Cancer Institute Hospital of Japanese Foundation for Cancer Research, 3-8-31 Ariake, Koto, Tokyo, 135-8550, JapanTel +8135200111Fax +81335200141Email yasuyoshi.sato@jfcr.or.jpPurpose: There have been few reports on the evaluation of cancer cachexia based on skeletal muscle mass index (SMI) in patients with head and neck cancer.Patients and Methods: One hundred and ninety-two head and neck cancer patients were enrolled. In definitive and adjuvant chemoradiotherapy settings, clinical outcomes were compared between cachexia and non-cachexia patients.Results: Forty patients were diagnosed with cachexia (20.8%). In the definitive setting, overall survival (OS) was significantly shorter in the cachexia group (3-year OS: 50.0% vs 88.5%; p < 0.01), and multivariate analysis identified UICC stage IV, baseline albumin of < 4 and cachexia as poor prognostic factors. However, cachexia was not significant in the adjuvant setting.Conclusion: Cancer cachexia was negatively associated with prognosis in patients with HNC who received definitive chemoradiotherapy. Nutritional intervention during chemoradiotherapy may improve survival in these patients.Keywords: head and neck cancer, squamous cell carcinoma of head and neck, sarcopenia, cachexia, muscle, skeletal, chemoradiotherapy, prognosis

BACKGROUND/AIM Lenvatinib is standard therapy for radioiodine-refractory differentiated thyroid cancer (RR-DTC), although the optimal timing for starting treatment is still controversial. The aim of this study was to evaluate the prognostic impact of baseline tumour size (BTS) in patients with RR-DTC treated with lenvatinib. PATIENTS AND METHODS Fifty-one RR-DTC patients who had at least one measurable lesion and treated with lenvatinib were retrospectively analysed. BTS was defined as the sum of the longest dimensions of all measurable target lesions. RESULTS Median progression-free survival (PFS) and overall survival (OS) in the larger BTS (≥42 mm) group were shorter than those in the smaller (

Background: Large prospective studies of chemotherapy for metastatic or recurrent adenoid cystic carcinoma (ACC) of the head and neck are lacking due to the rarity of ACC. The aim of this study is to evaluate the efficacy of carboplatin plus paclitaxel toward ACC and perform an exploratory investigation of the prognostic factors to investigate the optimal strategy for metastatic or recurrent ACC.Methods: We retrospectively analyzed recurrent or metastatic ACC patients treated with carboplatin plus paclitaxel between April 2007 and September 2019 in our hospital. Objective response rate (ORR), disease control rate (DCR), progression-free survival (PFS) and overall survival (OS) were evaluated, and an exploratory analysis of the prognostic factors including tumor growth rate (TGR) was conducted.Results: A total of 26 ACC patients were enrolled. ORR and DCR were 11.5% and 76.9%; the median PFS and OS were 8.1 and 22.3 months, respectively. From the results of the multivariate analysis, higher (≥ 6%/month) TGR was associated with worse PFS (hazard ratio [HR] 7.00, 95%CI 1.34–36.53, p = 0.02) and OS (HR 29.33, 95%CI 3.38–254.80, p Conclusions: Carboplatin plus paclitaxel showed modest efficacy for recurrent or metastatic ACC patients. Watchful waiting may be optimal for ACC patients with lower TGR. Systemic chemotherapy should be considered when TGR increases during active surveillance.

Simple Summary Second-line systematic therapy options for soft-tissue sarcoma (STS) have remained unchanged for decades due to the rarity and various histological types associated with STS. Challenges with molecular-targeted treatments for STS led to the approval of pazopanib and its wide use for STS. However, predictive markers of pazopanib treatment for STS have not been identified. Baseline neutrophil-to-lymphocyte ratio (NLR) is known as a candidate biomarker for several cancers. In this retrospective study, we investigated the use of the NLR as a predictor for the efficacy and prognosis of pazopanib in patients with STS. Our findings could be useful for the development of biomarker-targeted therapies for STS. Abstract Pazopanib with trabectedin and eribulin is widely used to treat soft-tissue sarcoma (STS). We have shown that baseline neutrophil-to-lymphocyte ratio (NLR) may predict the efficacy and patient prognosis of eribulin. Changes in NLR, but not baseline NLR, can predict patient prognosis of trabectedin. However, prognostic factors of pazopanib for STS have not been identified. We present a retrospective analysis of 141 patients treated with pazopanib for recurrent or metastatic non-round cell STS. Univariate and multivariate analyses were performed to determine the predictive factors of durable clinical benefit (DCB), overall survival (OS), and progression-free survival. L-sarcoma histology (odds ratio [OR] = 0.31, 95% CI = 0.12–0.79; p = 0.014) and pre-treatment NLR < 3.0 (OR = 2.03, 95% CI = 1.02–6.67; p = 0.045) were independent predictive factors of DCB. Pre-treatment NLR < 3.0 (hazard ratio [HR] = 0.55, 95% CI = 0.36–0.84; p = 0.0057), liposarcoma histology (HR = 1.78, 95% CI = 1.09–2.91; p = 0.022), primary extremity site (HR = 0.48, 95% CI = 0.31–0.75; p = 0.0010), ECOG PS ≥ 1 (HR = 1.62, 95% CI = 1.08–2.42; p = 0.019), and CRP < 0.3 (HR = 0.52, 95% CI = 0.33–0.82; p = 0.0050) were independent predictive factors of OS. These findings indicate that baseline NLR predicts the efficacy and patient prognosis of pazopanib for STS.

Background: The clinical benefit of systemic chemotherapy for recurrent/metastatic retroperitoneal/intra-abdominal soft tissue sarcoma (STS) compared to its benefits for other primary lesions has not been known or sufficiently evaluated. Methods and Patients: We retrospectively reviewed the cases of the STS patients who consulted a department of medical oncology in Tokyo between June 2011 and March 2018, and we extracted the cases of patients with primary sites at the retroperitoneum/intra-abdomen (cohort R) or extremities/trunk (cohort E) who received systemic chemotherapy in a recurrent/metastatic setting, comparing the cohorts’ characteristics, chemotherapy details, and prognoses. Results: Of all 337 STS patients, we enrolled 49 patients in cohort R and 75 patients in cohort E. Liposarcoma was more frequently observed in cohort R (51.0%) than cohort E (22.7%). The median chemotherapy treatment line was two lines (range: 1–6) in cohort R and three lines (range: 1–9) in cohort E. The doxorubicin usage rates differed in recurrent/metastatic settings (90.0% in cohort R and 55.0% in cohort E), due mainly to the higher rate of a perioperative chemotherapy treatment history in cohort E (52.0% vs. 6.1% in cohort R). The median overall survival from the start of salvage chemotherapy was 31.9 months (cohort R; 95% CI: 20.9–42.8) and 27.1 months (cohort E; 95% CI: 21.6–32.5) (p = 0.549). Conclusion: There were differences in the distributions of pathology and antitumor drugs used in a salvage setting between retroperitoneal/intra-abdominal and extremities/trunk STS patients in recurrent/metastatic settings, but the prognoses with salvage chemotherapy were similar in the two cohorts.

Comprehensive cancer genomic profile (CGP) tests are being implemented under Japanese universal health insurance system. However, the clinical usefulness of CGP test for breast cancer patients has not been evaluated. Of the 310 patients who underwent CGP testing at our institution between November 2019 and April 2021, 35 patients with metastatic breast cancer whose treatment strategy was discussed by our molecular tumor board within the study period were investigated after exclusion of 2 cases that could not be analyzed. The turn-around time, drug accessibility, and germline identification detection were evaluated. The subtype was luminal in 20 patients (57.1%), triple-negative in 12 patients (34.3%), and luminal-HER2 in 3 patients (8.6%). Actionable gene mutations were detected in 30 patients (85.7%), and 7 patients (20.0%) were recommended for clinical trial participation, with the drug administered to 2 patients (5.7%). Three patients (8.6%) died due to disease progression before the test results were disclosed. We report the results of an initial assessment of the utility of CGP testing for patients with metastatic breast cancer under Japanese universal health insurance system. Conducting CGP tests at a more appropriate time could provide patients with greater benefit from treatments based on their specific gene mutations.

Objectives: This retrospective observational study is conducted to evaluate the association between cancer cachexia and prognosis in head and neck cancer patients treated with chemoradiotherapy using skeletal muscle mass index at the level of the third lumbar vertebra with computed tomography.Methods: Two hundred forty-two patients were enrolled and categorized into the following four groups based on cancer cachexia criteria and treatment setting: definitive chemoradiotherapy with cachexia, definitive chemoradiotherapy without cachexia, adjuvant chemoradiotherapy with cachexia, and adjuvant chemoradiotherapy without cachexia. Progression-free survival (PFS) and overall survival (OS) between cachexia and non-cachexia groups were compared by treatment setting using the long-rank test. Prognostic factors were evaluated using the Cox proportional hazards model.Results: Fifty patients were diagnosed with cancer cachexia (20.7%). In the definitive setting, both PFS and OS were significantly shorter in the cachexia group (median PFS, 15.5 months vs. not reached, p < 0.01; median OS, 48.4 months vs. not reached. p < 0.01). Conversely, there was no significant difference between the two groups in the adjuvant setting. UICC Stage IV, base of albumin of Conclusion: Cancer cachexia was negatively related with prognosis in patients with head and neck squamous cell carcinoma who received definitive chemoradiotherapy. Nutritional intervention during chemoradiotherapy may improve survival in these patients. Further research is warranted.

Background: In the absence of a current standard of care, precision oncology with next-generation sequencing provides an important therapeutic option for patients with rare malignancy. Here, we sought to establish the clinical relevancy of comprehensive genomic profiling (CGP) for patients with rare malignancy. Methods: We reviewed 341 patients who underwent CGP (FoundationOne CDx; OncoGuide NCC OncoPanel System)in our institution between 2019 and 2021. Cases were classified as common or rare malignancy based on the Rare Cancers in Europe (RARECARE) definition (incidence of Results: With the exception of 7 unclassifiable cases, rare malignancy accounted for 149 of the 334 cases (45%), with the most common being female genital cancers (32%), followed by digestive cancers (24%), sarcoma (16%), and others (28%). Many (83%) of the patients with rare malignancy harbored at least one pathogenic/likely-pathogenic variant. The commonly mutated genes were TP53 (41%), PIK3CA (20%), ARID1A (14%), and KRAS (13%). ERBB2amplification was detected in 6% of patients (median copy number, 8). Gene fusion in EWSR1 was found in 4% of patients (sarcoma) and in FGFR2 in 1% (cholangiocarcinoma and salivary duct carcinoma). TMB-high (≥10 mut/Mb) and MSI-high cases were found in 8% and 2% of cases, respectively. Druggable alterations were detected in 36 patients; this percentage was not significantly different to that of common malignancy (24% vs. 17%, P=0.10). The common druggable alterations were BRAF V600E (n=10), ERBB2 amplification (n=9), PIK3CA E542K (n=6), and BRCA1/2 variant (n=6). There was no significant difference in OS between the rare and common malignancy groups (1-year OS rate: 62% vs. 46%, P=0.24). Conclusion: In this study, the ratio of rare malignancy was higher than that typically found in previous epidemiological studies (about 20%-25%). We observed no adverse impact for OS, which might be due to the high number of patients (n=48) with intractable pancreatic cancer. Remarkably, >20% of patients harbored a potential druggable alteration. Our results suggest the clinical relevance of CGP for patients with rare malignancy, and its potential utility to provide clues for future clinical development. Citation Format: Akihiro Ohmoto, Naomi Hayashi, Ippei Fukada, Masumi Yamazaki, Mayu Yunokawa, Akiyoshi Kasuga, Eiji Shinozaki, Arisa Ueki, Akiko Tonooka, Kengo Takeuchi, Seiichi Mori, Kazuma Kiyotani, Shunji Takahashi. Druggable gene alterations in Japanese patients with rare malignancy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5735.

Cytotoxic chemotherapy, including cyclophosphamide, vincristine, and dacarbazine (CVD) therapy, is widely used to treat metastatic pheochromocytoma and paraganglioma. Because these diseases are rare, studies are needed to establish treatment strategies. This was a single-center and retrospective study to analyze the efficacy of chemotherapy for patients with metastatic pheochromocytoma and paraganglioma diagnosed in 1983-2020. Clinical characteristics, tumor volume response, biochemical response based on catecholamine level, overall survival, and progression-free survival were evaluated. Patients with a complete response or partial response in tumor volume or catecholamine level were classified as responders. Sixteen patients were administered chemotherapy for a median of 16.5 cycles (interquartile range, 10-42). The tumor volume response was classified as follows: partial response (N = 4), stable disease (N = 9), and progressive disease (N = 3) (disease control rate = 81%). The biochemical responses were as follows: complete response (N = 2), partial response (N = 5), no change (N = 3), and progressive disease (N = 1) (disease control rate = 91%). The 5-year survival rate was 50% (95% confidence interval [CI], 21-74%) and median overall survival was 4.4 years (95% CI, 2.4 years-not reached). Overall survival and progression-free survival between responders and nonresponders were not statistically different. One patient developed myelodysplastic syndrome during CVD therapy. In conclusion, chemotherapy achieved disease control among more than half of patients, although survival did not differ between responders and nonresponders. Further fundamental research and prospective trials are needed to analyze the efficacy of CVD therapy.

Background Head and neck squamous cell carcinoma (HNSCC) is a geriatric cancer. However, older adult patients are frequently underrepresented in large clinical trials. Aims The aim of this study is to assess the efficacy and safety of the EXTREME regimen (platinum + fluorouracil + cetuximab) in older and younger adult patients with HNSCC. Methods and results Patients with recurrent or metastatic HNSCC treated with the EXTREME regimen were retrospectively analyzed. We compare the efficacy and safety in older (aged ≥70 years) younger (aged

Peripheral sensory neuropathy (PSN) caused by oxaliplatin-based adjuvant chemotherapy adversely affects patients' quality of life. This study evaluated the efficacy and safety of capecitabine plus oxaliplatin (CAPOX) with intermittent oxaliplatin use compared with the standard CAPOX in adjuvant therapy for colon cancer.Patients with curative resection for stage II/III colon cancer were randomly assigned to receive either CAPOX with continuous oxaliplatin (eight cycles of CAPOX) or CAPOX with intermittent oxaliplatin (two cycles of CAPOX, four cycles of capecitabine and two cycles of CAPOX). The primary end-point was the 1-year PSN rate, and the key secondary end-point was disease-free survival (DFS).Two hundred patients were enrolled in the intent-to-treat population. After 4 patients withdrew, 196 patients were included in the safety analysis. The overall treatment completion rate was 65% for continuous vs. 89% for intermittent treatment (p 0.001). The 1-year PSN rate was 60% (95% confidence interval [CI], 50%-70%) for continuous and 16% (95% CI, 10%-25%) for intermittent treatment (p 0.001). After a median follow-up of 52 months, 40 events (20%) were observed. The 3-year DFS was 81% (95% CI, 71%-87%) for continuous and 84% (95% CI, 75%-90%) for intermittent treatment (hazard ratio [HR], 0.87; 95% CI, 0.47-1.63). Among patients with high-risk disease (T4 or N2-3), the 3-year DFS was 57% for continuous vs. 74% for intermittent treatment (HR, 0.66).CAPOX with planned intermittent oxaliplatin may be feasible as an adjuvant therapy for colon cancer and substantially reduce the duration of long-lasting PSN.UMIN000012535.

e18007 Background: Concurrent chemoradiotherapy (CCRT) with cisplatin (CDDP) is a standard treatment for locally advanced head and neck cancer (LAHNC) in the definitive setting. Three cycles of 100 mg/m2 CDDP for every three weeks (Q3W) are now recommended but compliance with CCRT is relatively low due to its severe toxicity. Therefore, the potential de-escalation strategies for LAHNC have been discussed to decrease the therapeutic toxicity. Methods: Patients with LAHNC who underwent definitive CCRT with CDDP between 2012 and 2018 at The Cancer Institute Hospital of Japanese Foundation for Cancer Research were analyzed. Patients were classified into two groups based on the planned CDDP dose: (A) 100 mg/m2 and (B) 80 mg/m2 Q3W for three times. One-to-one propensity score matching was performed to minimize bias between two groups. After patients in two groups were matched by using propensity score, the overall survival (OS), recurrence-free survival (RFS), local recurrence-free survival (LRFS), and metastatic recurrence-free survival (MRFS) were analyzed by the Kaplan-Meier method with the Cox proportional hazards model. The follow-up term was set as two years to evaluate the early survival benefit. The dose and density of CDDP and the objective adverse events were also assessed. Results: A total of 304 patients were included with the median age of 62 (Interquartile range [IQR]: 54-67) years. Among them, 249 patients (82%) were male. Patients were treated with 100 mg/m2 CDDP (n = 145) and 80 mg/m2 CDDP (n = 159) regimens. After the propensity score matching, 119 patients were included in each group, respectively. There were no significant differences in baseline characteristics between two propensity-matched cohorts. The median follow-up time was 24 months in each group. Two-year OS was 93.0% (95% confidence interval [CI]: 88.4-97.8) in group A and 94.9% (91.0-99.0) in group B. Two-year RFS was 86.5% (80.6-92.9) in group A and 83.1% (76.6-90.1) in group B, respectively. No significant difference was observed in OS (Hazard ratio [HR] = 1.42, 95% CI: 0.49-4.08, p = 0.52), RFS (HR = 0.81, 95% CI: 0.42-1.57, p = 0.54), LRFS (HR = 0.57, 95% CI: 0.24-1.36, p = 0.20), and MFS (HR = 1.32, 95% CI: 0.52-3.35, p = 0.56). The median cumulative dose of CDDP was significantly higher in group A (300 mg, interquartile range [IQR]: 240-300) than in group B (240 mg, IQR:160-240) but the frequency of hematological, hepatic, renal, electrolytic, and grade 3-5 any adverse events was not significantly different between two groups. Conclusions: Our study showed no survival difference at 2-year follow-up between 100 mg/m2 and 80 mg/m2 CDDP regimens of definitive CCRT for LAHNC. This result could support the tide of the de-escalation strategy in head and neck cancer treatment. Longer follow-up is necessary and further prospective trials comparing CDDP dosage are warranted.

Some targeted therapies alter muscle mass due to interference with pathways of muscle metabolism. The effects of mammalian target of ra pamycin (mTOR) inhibitors on muscle mass have yet to be fully elucidated. In the present study, the computerized tomography (CT) scans of patients receiving mTOR inhibitors for at least 6 months taken at baseline and post-therapy were retrospectively retrieved, and body composition analyses were performed using the software, sliceOmatic version 5.0 (TomoVision, Inc., Magog, QC, Canada). The difference in body composition parameters was evaluated for significance. The time to treatment (TTF) failure was also compared between the sarcopenic and non-sarcopenic patients at the baseline. Of the 75 patients studied, 20 matched the inclusion criteria (including 16 males). The mean duration between the CT scans was 14.4±2.0 months. A total of 12 (60%) patients were sarcopenic at the baseline, whereas three more (75% in total) became sarcopenic following treatment. The use of mTOR inhibitors significantly decreased the skeletal muscle area (P=0.011) and lean body mass (P=0.007), although it had no effect on adipose tissue (P=0.163) or body weight (P=0.262). The rate of skeletal muscle wasting was 2.6 cm2/m2, or 2.3 kg in 6 months. The TTF did not differ between sarcopenic and non-sarcopenic patients, and was not significantly associated with any other parameter. To the best of our knowledge, this is the first study to demonstrate that the long-term use of mTOR inhibitors induces a marked loss of muscle mass. Due to the predictive and prognostic role of sarcopenia in cancer patients, these findings may have important clinical implications.

Background Opioid-induced constipation (OIC) is the most common side effect of opioid therapy. Laxatives are usually used as a first-line treatment option for OIC. Treatment options for OIC are switching to other opioids associated with less frequent OIC, such as Fentanyl. Naldemedine is an orally active peripherally acting µ-opioid receptor antagonists that was approved in Japan from 2017 for management cancer-related OIC. The aim of this study is to investigate the relationship between Naldemedine administration and the maximum dose of oral Oxycodone which is the oral opioids used most at our hospital. Methods During June 2017 and December 2018, a total of 217 patients with cancer-related pain received Oxycodone at our institution. The first group of the patients concurrently received Naldemedine 0.2 mg daily (group A, n = 100) and the second group didn’t receive (group B, n = 117) for cancer-related OIC reduction. We compared the maximum Oxycodone dose between two groups by medical recode retrospectively. Results The median age of group A was 69 y.o. (range 20-87 y.o.), and the median age of group B was 67 y.o. (range 27-88y.o.). There was no significant difference in common patient background between group A and B. The median dose of maximum Oxycodone dose of group A was 40 mg/day (range 10-480 mg/day), and the median dose of maximum Oxycodone dose of group B was 20 mg/day (range 10-320 mg/day). There was a significant difference (Mann-Whitney U test, P Conclusions Naldemedine administration in patients with cancer-related OIC may increase the maximum dose of oral Oxycodone. Legal entity responsible for the study The authors. Funding Has not received any funding. Disclosure All authors have declared no conflicts of interest.

Background The aim of this study was to evaluate the efficacy and safety of CapeOX plus bevacizumab with a planned oxaliplatin stop-and-go strategy in Japanese patients with metastatic colorectal cancer (mCRC). Methods Patients with untreated mCRC were treated with 4 cycles of CapeOX plus bevacizumab therapy, followed by capecitabine plus bevacizumab maintenance therapy. Reintroduction of oxaliplatin was scheduled after 8 cycles of maintenance therapy or upon tumor progression. The primary endpoint was progression-free survival (PFS), and secondary end points included overall survival (OS), objective response rate to each treatment, reintroduction rate of oxaliplatin, frequency of peripheral sensory neuropathy (PSN), and safety. Results The 52 patients who received the protocol treatment were included in the evaluation of efficacy and safety. Median PFS and OS were 12.4 months (95% confidence interval [CI], 10.0–14.8) and 30.6 months (95% CI, 27.6–33.5), respectively. The objective response rates were 55.8% for the initial CapeOX plus bevacizumab therapy, 17.8% for capecitabine plus bevacizumab maintenance therapy, and 31.0% for reintroduced CapeOX plus bevacizumab therapy. The frequency of PSN was 63.5%, including 3.8% of patients with grade 3 PSN. No patients required treatment discontinuation because of PSN during the induction or maintenance therapy. Conclusions CapeOX plus bevacizumab therapy with a planned oxaliplatin stop-and-go strategy is a feasible first-line treatment for Japanese patients with mCRC. Trial registration This trial is registered with the University Hospital Medical Information Network in 15 March 2010 ( UMIN000006478 ).

818 Background: Opioid-induced constipation (OIC) is the most common side effect of opioid therapy. Laxatives are usually used as a first-line treatment for OIC. Treatment options for OIC are switching to other opioids associated with less frequent OIC, such as Fentanyl. Naldemedine is an orally active peripherally acting µ-opioid receptor antagonists that was approved in Japan from 2017 for management of cancer-related OIC. The aim of this study is to investigate the relationship between Naldemedine administration and the maximum dose of oral Oxycodone which is the most frequently used oral opioids at our hospital. Methods: During June 2017 and December 2018, a total of 217 patients with cancer-related pain received Oxycodone at our institution. The first group of the patients concurrently received Naldemedine 0.2 mg daily (group A, n = 101), and the second group didn’t receive it (group B, n = 116) for cancer-related OIC reduction. We compared the maximum Oxycodone dose between two groups by medical record retrospectively. Results: The median age of group A was 69 y.o. (range 20-87 y.o.), and the median age of group B was 67 y.o. (range 27-88y.o.). There was no significant difference in common patient background between group A and B. The median dose of maximum Oxycodone dose of group A was 40 mg/day (range 10-480 mg/day), and that of group B was 20 mg/day (range 10-320 mg/day). There was a significant difference in the median dose of maximum Oxycodone between group A and B (Mann-Whitney U test, P < 0.0001). In Group A, the administration was started in 31 patient Naldemedine and Oxycodone at the same time. As for 70 remaining patients, the administration was started when they had constipation after oxycodone was administrated. In those patients, the median days was 19 days from the Oxycodone administration starting date to the Naldemedine administration starting date. Conclusions: Naldemedine administration in patients with cancer-related OIC may increase the maximum dose of oral Oxycodone.

Background Patients with sensitive gene mutations could achieve better overall survival by taking targeted drugs. Many trials have shown that non-small cell lung cancer (NSCLC) patients with epidermal growth factor receptor (EFGR) mutation responded to PD-1/PD-L1 inhibitors worse than EGFR wild-type. And subgroups of trials have also reported the efficacy of PD-1/PD-L1 inhibitors in the treatment of NSCLC patients with other sensitive gene mutations. So, we conducted a complementary systematic review and meta-analysis to compare efficacy of PD-1/PD-L1 inhibitors for NSCLC patients with sensitive gene mutations. Methods PubMed, EMBASE, Web of Science and the Cochrane Central Register of Controlled Trials (Central) databases were searched for all clinical trials in NSCLC until 5th of January 2019. Eligible studies included randomized controlled trials (RCTs) comparing PD-1/PD-L1 inhibitors with chemotherapy in NSCLC patients with sensitive gene mutations. The hazard ratio (HR) and 95% confidence intervals (CIs) of overall survival (OS) or progression-free survival (PFS) were used. Results We analyzed 193 patients in this study. Among cumulative total of 210 patients, 197 were treated with PD-1 or PD-L1 inhibitors. Another 8 and 5 patients were treated with CTLA-4 inhibitor alone and combination with PD-1 inhibitor, respectively. This study included non-small cell lung cancer (n = 106; 50.5%), kidney (n = 23; 10.9%), melanoma (n = 30; 14.3%), gastric (n = 19; 9.0%), Hodgkin lymphoma (n = 11; 5.2%), urothelial carcinoma (n = 10; 4.8%) and others (n = 10; 4.8%). Any grade of irAEs occurred in 73 (34.8%) cumulative patients, and among them, 28 (13.3%) were classified as grade 3-5. The most common irAEs in any grade were skin disorders (n = 29) and endocrine disorders including thyroid dysfunction and adrenal insufficiency (n = 28). Eosinophilia occurred in 57 cumulative patients (27.1%), and 21 patients out of them had eosinophilia from baseline. Among the clinical and laboratory factors, only eosinophilia was significantly associated with the occurrence of any grade of irAEs in both univariate (p = 0.010) and multivariate (p = 0.0463) analyses. Notably, endocrine irAEs were significantly related to eosinophilia (p = 0.0287). Conclusions Eosinophilia after the initiation of treatment with ICIs predicts succeeding onset of irAEs. Legal entity responsible for the study The authors. Funding Has not received any funding. Disclosure Y. Miura: Honoraria (self): Ono; Honoraria (self): Bristol-Myers Squibb Japan; Honoraria (self): Chugai. T. Takano: Honoraria (self): Daiichi Sankyo; Honoraria (self): Kyowa Hakko Kirin; Honoraria (self): Eisai; Research grant / Funding (self): MSD; Research grant / Funding (self): Ono; Research grant / Funding (self): Merck Serono; Research grant / Funding (self): Taiho; Research grant / Funding (self): Novartis; Research grant / Funding (self): Chugai. All other authors have declared no conflicts of interest.

Background The aim of this study was to evaluate the efficacy and safety of CAPOX with planned oxaliplatin stop-and-go strategy compared to continuous use of oxaliplatin as an adjuvant setting for colon cancer. Methods Patients with curative resection of colon cancerwere randomly assigned to receive eitherCAPOX with continuous use of oxaliplatin (8 cycles of CAPOX; continuous arm) or CAPOX intermittentuse of oxaliplatin (2 cycles of CAPOX – 4 cycles of capecitabine – 2 cycles of CAPOX; intermittentarm).The primary endpoints were frequency of peripheral sensory neuropathy (PSN) at 1-year after surgery and disease-free survival rate at 3-year after surgery. The secondary end points included overall survival (OS), compliance and safety. Results A total of 200 patients were enrolled. The intent-to-treat and safety population comprised 100 and 99 patients in the continuous arm,and 100 and 98 patients in the intermittentarm. Compliance: The overall treatment completion rate and relative dose intensity of oxaliplatin were 64% and 71% in the continuous arm vs.92% and 95% in the intermittentarm(p = 0.21 and 0.12, respectively). Efficacy: The 3-year DFS was 81.6% in the continuous arm vs.82.4% in the intermittentarm(HR, 0.82; 95% CI, 0.48-1.18). Safety: The incidence of PSN (>grade 2) was 33%in the continuous arm vs.15% in the intermittentarm (p Conclusions CAPOX withplanned oxaliplatin stop-and-go strategy could be equally effectiveas an adjuvant setting for colon cancer, and substantially reduce long-term PSN and potential improve patient quality of life. Clinical trial identification 000012535 (09/December/2013). Legal entity responsible for the study Yasuhiro Kodera (Chubu Clinical Oncology Group, Japan). Funding Chubu Clinical Oncology Group. Disclosure All authors have declared no conflicts of interest.

Background According to the results of the randomized phase III study, G-SOX, the combination of S-1 and oxaliplatin (SOX) is as effective as the combination of S-1 and cisplatin for the treatment of HER2-negative advanced gastric cancer (AGC), and also has a favorable safety profile. In this trial, the dose of oxaliplatin tested was 100 mg/m2; however, the dose of 130 mg/m2 is covered by insurance in Japan, based on the results of the pivotal global study. Therefore, the efficacy and safety of the SOX regimen with oxaliplatin 130 mg/m2 (SOX130) remains to be elucidated. In this study, we conducted the final analysis of the survival outcomes in a phase II trial to assess the efficacy and safety of SOX130 in HER2-negative AGC. Methods Patients with HER2-negative AGC or recurrent gastric cancer received 80 mg/m2 S-1 per day orally on days 1-14, and 130 mg/m2 oxaliplatin intravenously, on day 1 of each 21-day cycle, until criteria for treatment withdrawal were fulfilled. The primary endpoint was the response rate (RR), and the secondary endpoints were progression-free survival (PFS) and overall survival (OS). Adverse events (AE) were recorded according to CTCAE version 4.0. Results In this study, 71 patients were enrolled from June 2015 to November 2016, but 8 patients were excluded owing to ineligibility. Therefore, the efficacy and safety analyses were finally conducted among 63 patients. The confirmed RR, assessed by an independent review committee, was 46.0% (95% confidence interval [CI]: 34.3-58.2), and the disease control rate was 77.8% (95% CI: 66.1-86.3). The median PFS and OS were 4.9 months (95% CI: 4.2-7.1) and 14.8 months (95% CI: 11.1-18.9), respectively. The incidence rates of grade 3 or 4 AE were as follows: neutropenia, 9.5%; thrombocytopenia, 11.1%; anemia, 6.3%; sensory neuropathy, 12.7%; anorexia, 19.0%; and diarrhea, 6.3%. Conclusions SOX130 showed favorable survival outcomes and an acceptable safety profile in the treatment of HER2-negative AGC.

611 Background: Adjuvant chemotherapy (ACT) has been recommended for stage III colon cancer patients in NCCN guidelines. However, the benefit of ACT is still controversial in elderly patients. Methods: We retrospectively included stage III colon cancer patients with aged over 70 that were operated between 2008 and 2015 in Tosei general hospital from Japan. We calculated 3 years recurrence rate and performed a multivariate analysis to estimate the risk of recurrence. The model was adjusted by including the following 7 confounders: Age, ECOG-PS (0-1 or ≥ 2), tumor site (right or left), T stage (T1-3 or T4 ), N stage (N1 or N2), pathological type (por-sig or other), and complete ACT (yes or no). No complete ACT was defined as discontinuation ACT and surgery alone. Results: 182 patients were identified (87 patients aged < 70 and 95 patients aged ≥ 70). ACT was performed in 58 patients (61.1%) and complete rate was 67.2% in elderly patients. The median follow up was 36.0 months. 29 patients (30.0%) had relapse. 3 years recurrence rate was 24.3% and 37.8% with complete ACT or no complete ACT (p = 0.29). In multivariate analysis, N2 was only the risk of recurrence (HR 6.95, p < 0.01). In further analysis, addition of oxaliplatin was significant risk factor of recurrence in elderly patients (HR 10.4, p < 0.01). On the other hand, in young patients, no complete ACT was only risk of recurrence (p = 0.01). 3 years survival rate was 89.1% and 81.0% with complete ACT or no complete ACT (p = 0.27). Conclusions: The multivariate analysis showed that ACT did not reduce the risk of recurrence in elderly patients. Moreover, addition of oxaliplatin suggested not only futile but harmful in those patients. These results support the previous reports (MOSAIC study and PETACC-8 trial) that microsatellite instability and RAS status may affect the effect of oxaliplatin.

Low skeletal muscle density (SMD) and low skeletal muscle index (SMI) are associated with poor overall survival (OS) in patients with various types of cancer. We retrospectively studied SMD and SMI using computed tomographic (CT) scans in patients with gastric cancer receiving chemotherapy to evaluate its prognostic significance. SMD and SMI were obtained from CT-based analysis using Slice-O-Matic® medical imaging software in patients who received S-1 plus cisplatin chemotherapy for metastatic gastric cancer. The CT images taken within 1 month before starting chemotherapy were used. The cut-off values for determining low SMD [

e21665 Background: The oral transmucosal fentanyl disintegrating tablet, Abstral, is a formulation by which fentanyl can be rapidly absorbed across the oral mucosa producing rapid onset analgesia, and which may be effective for breakthrough cancer pain. It can be administered for the patients who cannot take the oral medicine. It has been marketed since 2014 in Japan. Methods: We selected patients who were administered Abstral for breakthrough cancer pain between 2014 and 2016 at Toyama University Hospital in Japan. We retrospectively investigated administration reasons based on medical record of those patients. Results: There were 111 patients who were administered Abstral. Primary lesions of lung/Gastrointestin/others were 43/52/16, respectively. ECOG PS 0-2/3-4 were 27/84, respectively. The median age was 66 y.o. (range 35-91 y.o.). Regularly using opioid were fentanyl patch prescribed for all patients. Median dose of fentanyl patch was 25mcg/hr (range 12.5-250mcg/hr). 90 patients (81%) had difficulties in the administration of oral medicine, which was the main reason of Abstral administration. Four patients (4%) were to reduce constipation and vomiting as side effects of oxycodone. Seven patients (6%) were to start a fentanyl patch. Three patients (3%) were assessed poor effect for short-acting opioid. Only seven patients (6%) were expected of rapid onset of analgesia effect. Abstral was administered in 27 patients (24%) during aggressive treatment such as chemotherapy administration and in 84 patients (76%) after aggressive treatment. Conclusions: The oral transmucosal fentanyl was administered for the patients who cannot take the oral medicine in Japan while it is expected to be administered to those who want to relieve breakthrough pain fast. Affirming a common understanding of the efficacy of the oral transmucosal fentanyl and breakthrough cancer pain is necessary in Japan.

428 Background: The aim of this study was to evaluate the association of early tumor response to the first-line bevacizumab (BEV) combination therapy with efficacy of the subsequent therapies and survival during the BEV beyond progression (BBP) strategy for metastatic colorectal cancer (mCRC) patients. Methods: We analyzed a pooled data set from the previous phase II studies of mCRC, testing BBP strategy with the first-line mFOLFOX plus BEV (N=47) and the second-line FOLFIRI plus BEV (N=31). Patients were classified into either responders (R group, n=29) with tumor shrinkage (complete response [CR] + partial response [PR]), sub-responders (SR group, n=11) with stable disease (SD) and non-responders (NR group, n=5) with disease progression (PD) at the point of initial three months of the first-line therapy. The tumor response and PFS in the subsequent therapies and OS were evaluated. Results: In the first-line FOLFOX+BEV therapy, further tumor shrinkage was not achieved after the initial three months. PFS was 15.0 months for the R group, 8.9 months for the SR group and 2.9 months for the NR group, respectively, and there was statistical significance favoring the R group (p=0.001). In the second-line FOLFIRI+BEV, RR and DCR were 39 and 78% in the R group, 14 and 57% in the SR group, and 0 and 0% in the NR group, respectively. No additional response to the first-line therapy was observed in all groups, except for only one patient in the SR group. PFS was 8.8 months for the R group, 6.0 months for SR group and 1.4 months for NR group, respectively, and the R group was significant predictor for prolonged PFS in the second-line setting. OS were 30.8 months for the R group, 24.7 months for the SR group, and 11.1 months for the NR group, respectively. Early disease control (R+SR) was significant predictor for OS (hazard ratio [HR]: 8.48, p

631 Background: This study was designed to evaluate the influence of dose reduction and schedule modification on outcomes in patients with metastatic colorectal cancer (mCRC). Methods: Pooled datasets from two previous phase II trials of FOLFIRI (CCOG-0502; n = 36) and mFOLFOX6 (CCOG-0704; n = 30) in patients with mCRC were analyzed retrospectively. The RDIs of irinotecan and oxaliplatin were compared to response rate (RR), disease control rate (DCR), progression-free survival (PFS) and overall survival (OS). To assess the effects of dose reduction and time delay, we defined ‘dose index (DI)’ as the ratio of the actual delivered total dose to the planned total dose and ‘time index (TI)’ as the ratio of the planned duration to the actual duration of therapy. Relative dose intensity (RDI) was computed by multiplying DI by TI. DI and TI of irinotecan and oxaliplatin were compared to response rate (RR), disease control rate (DCR) and progression-free survival (PFS). Results: In patients receiving FOLFIRI therapy, the median DI and TI of irinotecan were 0.92 and 0.90, respectively. RRs were 59% vs. 12% in the higher vs. lower DI groups (p < 0.01), and 35% vs. 35% in the higher vs. lower TI groups (p = 1.00), respectively. Median PFS was 10.2 vs. 5.0 months in the higher vs. lower DI groups (p < 0.01), and 6.1 vs. 6.7 months in the higher vs. lower TI groups (p = 0.48), respectively. In mFOLFOX6 therapy, the median DI and TI of oxaliplatin were 0.97 and 0.82, respectively. RRs were 44% vs. 36% in the higher vs. lower DI groups (p = 0.65), and 44% vs. 36% in the higher vs. lower TI groups (p = 0.65), respectively. Median PFS was 7.7 vs. 6.7 months in the higher vs. lower DI groups (p = 0.13), and 8.5 vs. 5.9 months in the higher vs. lower TI groups (p = 0.02), respectively. Multivariate analyses showed that DI of irinotecan (HR 8.48; 95% CI, 2.94-24.51, p < 0.01) and TI of oxaliplatin (HR 2.74; 95% CI, 1.02-7.33, p = 0.04) were the independent prognostic factors for PFS. Conclusions: Dose reductions in irinotecan and time delays in oxaliplatin could have significant impact on PFS in patients receiving FOLFIRI and FOLFOX6, respectively.

e14614 Background: We reported that relative dose intensity (RDI) of key cytotoxic agents, irinotecan (IRI) and oxaliplatin (OX), is a significant predictor of disease control in patients with metastatic colorectal cancer (mCRC). However, in concomitant therapy with bevacizumab (BEV), the influence of adding BEV on the relation between RDI of cytotoxic agents and outcomes are unclear. In this study, we evaluate the impact of BEV on RDI of IRI and OX-based chemotherapy on the outcome of mCRC. Methods: A retrospective analysis of mCRC patients entered into three prospective clinical trials, testing FOLFIRI (CCOG-0502), mFOLFOX6 (CCOG-0704), FOLFIRI plus BEV and mFOLFOX6 plus BEV (CCOG-0801), was performed. RDI was calculated as the delivered dose intensity divided by standard dose intensity calculated for each regimen and compared to response rate (RR), disease control rate (DCR) and progression-free survival (PFS). Results: In FOLFIRI therapy, higher RDI (IRI, >median: 80%) group achieved significant better RR, DCR and PFS than lower RDI (median: 79%) group achieved better disease control than lower RDI group (RR: 47 vs. 33% [p=0.456], DCR: 100 vs. 73% [p=0.032] and PFS: 8.5 vs. 6.2 months [p=0.064]). In addition of BEV, there were no difference between higher and lower RDI (OX, median: 76%) group in any outcomes (RR: 54 vs. 74% [p=0.159], DCR: 88 vs. 91% [p=0.672] and PFS: 11.6 vs. 11.7 months [p=0.797]). Conclusions: RDI of key cytotoxic agents is a significant predictor of disease control, especially in IRI-based regimen. Nevertheless, in concomitant therapy with BEV, there were no relations between RDI of cytotoxic agents and outcomes. These results suggest that BEV could have ‘covering effect’ to reduce the influence of dose modification of cytotoxic agents in mCRC patients.

e14552 Background: XELOX plus bevacizumab (BEV) is an established first line therapy for metastatic colorectal cancer (mCRC). However, the cumulative neurotoxicity of oxaliplatin often requires therapy to be discontinued while the patient is still responding. The aim of this study was to evaluate efficacy and safety of XELOX plus BEV with oxaliplatin stop and go strategy. Methods: Fifty four patients with unresectable mCRC were enrolled as first line treatment. They were treated with four cycles of XELOX plus BEV, followed by maintenance therapy with capecitabine (Cape) plus BEV. Reintroduction of oxaliplatin was scheduled after eight cycles of Cape plus BEV or upon tumor progression. The primary endpoint was progression free survival (PFS). Results: Forty nine patients (90%) achieved to the maintenance therapy and thirty two patients (59%) were reintroduced oxaliplatin. After a median follow-up time of 24.2 months, median PFS was 13.4 months (95%CI: 11.7-15.1), median duration of disease control was 13.8 months (95%CI: 11.6-16.0) and median overall survival was 29.0 months (95%CI: 23.1-34.9). The response rate and disease control rate were 57.4% and 96.3% in the initial XELOX plus BEV therapy, 6.1% and 73.5% in Cape plus BEV maintenance therapy, and 0% and 72.4% in reintroduced XELOX plus BEV therapy. The incidence of neuropathy was 38% in initial therapy, 33% in maintenance therapy and 43% in reintroduced therapy. Conclusions: XELOX plus bevacizumab therapy with oxaliplatin stop-and-go strategy was feasible to maintain long disease control without increasing severe neurotoxicity in first-line treatment for mCRC. Clinical trial information: UMIN000006478.

508 Background: Relative dose intensity (RDI) is the ratio of delivered dose intensity of chemotherapy to standard dose intensity. There is established evidence supporting the significance of RDI in patients with various cancer, however data in patients with metastatic colorectal cancer (mCRC) are limited. In this study, we evaluate the significance of RDI of irinotecan and oxaliplatin-based chemotherapy on the outcome of mCRC. Methods: A retrospective analysis of mCRC patients entered into two prospective clinical trials, testing FOLFIRI (CCOG-0502) and mFOLFOX6 (CCOG-0704), was performed. RDI was calculated as the delivered dose intensity divided by standard dose intensity calculated for each regimen and compared to objective response rate (ORR), disease control rate (DCR) and progression-free survival (PFS). Results: The median RDI of irinotecan in FOLFIRI and oxaliplatin in mFOLFOX6 were 80% and 79%. ORRs In higher RDI (>median) group and lower RDI (

Purpose The aim of this study was to evaluate the efficacy and safety of the planned continuation of bevacizumab beyond first progression in Japanese patients with metastatic colorectal cancer (mCRC). Methods Previously untreated patients with assessable disease were treated with mFOLFOX6 plus bevacizumab until tumor progression, followed by FOLFIRI plus bevacizumab. The primary endpoint of the study was the second progression-free survival (2nd PFS), defined as duration from enrollment until progression after second-line therapy. Secondary endpoints of the study were overall survival (OS), survival beyond first progression (SBP), progression free survival (PFS), response rate (RR), disease control rate (DCR) and safety. Results In the first-line setting, 47 patients treated with mFOLFOX6 plus bevacizumab achieved RR of 61.7%, DCR of 89.4% and median PFS of 13.1 months (95% CI, 8.7 to 17.5 months). Thirty one patients went on to receive second-line therapy with FOLFIRI plus bevacizumab and achieved RR of 27.6%, DCR of 62.1% and median PFS of 7.5 months (95% CI, 5.5 to 9.5 months). Median 2nd PFS, the primary endpoint, was 18.0 months (95% CI, 13.7 to 22.3 months). The median OS was 30.8 months (95% CI, 27.7 to 33.9 months), and median SBP was 19.6 months (95% CI, 14.3 to 24.9 months), after median follow up period of 35.9 months. No critical events associated with bevacizumab were observed during the second-line therapy. Concluson The planned continuation of bevacizumab during second-line treatment is feasible for Japanese mCRC patients. A prospective randomized control study to confirm efficacy is warranted. Disclosure All authors have declared no conflicts of interest.