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Objective To evaluate the effect of a pretreatment geriatric assessment on the clinical outcomes in older patients with unresectable or recurrent pancreatic ductal adenocarcinoma (PDAC) scheduled to receive gemcitabine (GEM)/GEM+nab-paclitaxel (GnP). Patients Older patients with unresectable PDAC scheduled to receive GEM/GnP who visited Kyorin University Hospital and cooperating institutions were enrolled and followed from April 2015 to March 2020. The maximum observation period was two years. All patients underwent a cancer-specific geriatric assessment (CSGA) and optional geriatric assessment (GA) before treatment initiation and two months after the start of treatment. The patients' background characteristics, tumor progression, tumor site, and regimen (GEM/GnP) were examined in a Cox proportional hazards model. The relationship between the overall survival (OS) and GA score was also determined. Eligible patients (age ≥70 years old with histopathologically confirmed unresectable or recurrent PDAC) were scheduled to receive first-line chemotherapy. Results The performance status (PS) and activities of daily living (ADL)/instrumental ADL (IADL) scores at baseline correlated with the OS. Furthermore, even in cases with normal baseline values, lower Frontal Assessment Battery scores and higher Geriatric Depression Scale-Short Form scores after treatment initiation were significantly correlated with OS. Conclusion The baseline PS, ADL, and IADL may be prognostic factors in older PDAC patients. In addition, a normal frontal lobe function and depression scores prior to treatment initiation that rapidly worsened during treatment were independently associated with a reduced OS. Selecting appropriate interventions and improving the therapeutic environment may prolong the OS in such patients.

Pancreatic cancer has the poorest prognosis among digestive cancers. During the 1990s, the 5-year survival rate of surgical patients with pancreatic cancer was 14% in Japan. However, survival rates have increased to 40% in the 2020s due to the refinement of surgical procedures and the introduction of perioperative chemotherapy. Several pivotal randomized controlled trials have played an indispensable role to establish each standard treatment strategy. Resectability of pancreatic cancer can be classified into resectable, borderline resectable, and unresectable based on the anatomic configuration, and multidisciplinary treatment strategies for each classification have been revised rapidly. Investigation of superior perioperative adjuvant treatments for resectable and borderline resectable pancreatic cancer and the establishment of optimal conversion surgery for unresectable pancreatic cancer are the progressive subjects.

PURPOSE Genomic profiling programs have been implemented to apply next-generation sequencing (NGS) for facilitating trial enrollment. SCRUM-Japan GI-SCREEN is a large-scale genomic profiling program in advanced gastrointestinal cancers using a validated genomic assay with the goal of facilitating enrollment in targeted clinical trials, generating real-world data, and performing clinicogenomic analysis for biomarker discovery. PATIENTS AND METHODS Genotyping of tumor tissue samples from 5,743 patients with advanced gastrointestinal cancers enrolled in GI-SCREEN was centrally performed with NGS. Patients were enrolled in matched trials of targeted agents affiliated with GI-SCREEN on the basis of genotyping results. RESULTS A total of 11 gastrointestinal cancers were included, with colorectal cancer being the most common. The median age ranged from 59 to 70.5 years across cancer types. Patients enrolled after initiation of first-line treatment had significantly longer overall survival (OS) than that before treatment initiation with a median survival time difference of 8.9 months and a hazard ratio (HR) ranging from 0.25 to 0.73 across cancer types, demonstrating an immortal time bias. One hundred and forty-nine patients received matched therapies in clinical trials on the basis of their identified alterations. Among patients with colorectal cancer harboring actionable alterations, the median OS was significantly longer in patients who received matched therapies in trials than in those who did not (HR, 0.52; 95% CI, 0.26 to 1.01; P = .049). Cancer-specific pathway alterations were significantly associated with shorter survival and related to primary resistance to matched trial therapies. CONCLUSION Our genomic profiling program led to patient enrollment in targeted clinical trials and improved survival of patients with colorectal cancer who received matched therapies in clinical trials. To avoid immortal time bias, precautions are needed when using data from patients who have undergone NGS testing after initiation of the evaluated treatment line.

In Japan, the population aged 65 years and above accounts for 29% of the total population. Furthermore, the number of cancer patients among the elderly is increasing. Geriatric oncology is a discipline that deals with appropriate care for elderly cancer patients based on their characteristics. The International Society of Geriatric Oncology considers education, treatment, research, and partnership building areas of significance and priority for policy goals. In Japan, the Third Term of the Basic Plan to Promote Cancer Control is an initiative to improve the infrastructure and health services involved in cancer care. Content related to “cancer in the elderly” was added to establish guidelines for treating cancer in the elderly. Thus far, “Clinical Practice Guidelines of Cancer Drug Therapies for the Elderly” have been published. With the increasing age of the population, social security expenditures will increase substantially after the fiscal year 2022. Reforms to social security systems, such as pensions, medical care, and nursing care, are underway. It is important to enhance cooperation between oncology and geriatrics and to support cooperative systems among families and medical professionals to promote geriatric oncology. Since the working-age population and the total population have begun to decline, Japan is facing many challenges. As a leader of a super-aging society, Japan has the potential to share its experience on a global scale and address potential long-term outcomes.

Background Safe and effective treatments for advanced esophageal cancer are an unmet need in Japan. We report results of a subgroup analysis of Japanese patients enrolled in KEYNOTE-181, a randomized, open-label, phase 3 study of pembrolizumab versus chemotherapy as second-line therapy for patients with advanced or metastatic esophageal cancer whose disease progressed after standard first-line therapy. Methods Patients were randomly assigned 1:1 to receive pembrolizumab 200 mg every 3 weeks or investigator’s choice of paclitaxel, docetaxel, or irinotecan. Efficacy was evaluated in all Japanese patients and in those with programmed death ligand 1 combined positive score ≥ 10. Results Of the 152 Japanese patients enrolled (pembrolizumab, n = 77; chemotherapy, n = 75), 150 (98.7%) had squamous cell carcinoma and 79 (52.0%) had combined positive score ≥ 10. At the final analysis, median overall survival was improved among all patients (12.4 vs 8.2 months with pembrolizumab and chemotherapy, respectively; hazard ratio, 0.68; 95% CI 0.48–0.97) and patients with combined positive score ≥ 10 (12.6 vs 8.4 months; hazard ratio, 0.68; 95% CI 0.42–1.10). Fewer patients had any-grade (74.0% vs 95.9%) or grade 3–5 (16.9 vs 50.0%) treatment-related adverse events with pembrolizumab than with chemotherapy. Conclusion Consistent with the global trial results, second-line pembrolizumab therapy showed a survival benefit and a favorable safety profile compared with chemotherapy in Japanese patients with advanced esophageal cancer.

The SCRUM-Japan GI-SCREEN was a comprehensive genomic profiling project of GI cancer tissues using Oncomine Cancer Research Panel and Oncomine Comprehensive Assay. From 885 patients with AGC who successfully underwent gene profiling, 74 with

PURPOSE ERBB2 copy number (CN), measured using next-generation sequencing, is a predictive biomarker for trastuzumab efficacy in human epidermal growth factor receptor 2 (HER2)–positive advanced esophagogastric and gastric cancer (AGC). We aimed to investigate the association of ERBB2 amplification and gene coalterations with response and resistance to trastuzumab-combined chemotherapy. METHODS The SCRUM-Japan GI-SCREEN was a comprehensive genomic profiling project of GI cancer tissues using Oncomine Cancer Research Panel and Oncomine Comprehensive Assay. From 885 patients with AGC who successfully underwent gene profiling, 74 with ERBB2 amplification (CN ≥ 4.0) and who received first-line trastuzumab-combined chemotherapy were selected, and ERBB2 CN and gene coalterations were assessed. RESULTS ERBB2 CN did not differ in tumor response to trastuzumab-combined chemotherapy (one-way analysis of variance test, P = .37). Multivariate analysis using the Cox proportional hazard model revealed that ERBB2 CN (continuous log2-converted CN, hazard ratio, 0.76; 95% CI, 0.62 to 0.93; P < .01) and receptor/oncogene amplifications in the HER2 signaling pathway (hazard ratio, 2.5; 95% CI, 1.2 to 5.3; P = .01) were significant predictors for progression-free survival (PFS). ERBB2 variants coexisted in five patients (7%) and were missense mutations. Two patients with low variant allele frequencies (VAFs; 8%, 12%) showed high ERBB2 CN (55, 80) and durable response (≥ 20 months), whereas three patients with high VAFs (66%–90%) showed low ERBB2 CN (8-11) and no response with short PFS (1-10 months). CONCLUSION ERBB2 CN and gene coamplification in the HER2 signaling pathway were positive and negative predictors of PFS in trastuzumab-treated HER2-positive AGC patients, respectively. HER2-positive AGC patients with a high VAF of ERBB2 showed poor outcomes and may need HER2 tyrosine kinase inhibitors and trastuzumab deruxtecan.

Objectives Neoadjuvant therapy followed by radical resection improves the borderline-resectable pancreatic cancer (BRPC) prognosis; however, the optimal therapeutic regimen remains unclear. Gemcitabine plus nab-paclitaxel (GnP) showed a high anti-tumor effect in primary lesions in a prospective study for metastatic disease. However, evidence concerning its feasibility is still lacking in patients with BRPC. We therefore evaluated the tolerability of neoadjuvant GnP (NAC-GnP) for BRPC. Patients and Methods This single-center prospective study evaluated 10 patients with BRPC who were treated with two cycles of NAC-GnP. The primary endpoint was feasibility for NAC-GnP. Treatment feasibility was defined as a successful outcome in at least eight patients. Results Ten patients who had BRPC in contact with the celiac artery (n = 5), superior mesenteric artery (n = 3), or hepatic artery (n = 2) were enrolled. The median age was 75 (range, 40-82) years old. Grade 3 anorexia and grade 2 pneumonia occurred in one patient each, so treatment was feasible in eight patients. The median primary tumor reduction and response rates were 33% (range, 0%-68%) and 60%, respectively. Six of eight patients who had abnormal CA19-9 levels at the time of enrolment showed a decrease in CA19-9 levels, with a median decrease of 72%. Five patients underwent radical resection, including R0 resection in four. Postoperative grade IIIa Clavien-Dindo complications occurred in one patient (upper gastrointestinal bleeding and pancreatic fistula). Conclusion Two-cycle NAC-GnP is a feasible treatment for patients with BRPC. Further studies on NAC-GnP in patients with BRPC are warranted.

Irinotecan (CPT-11) is metabolized to an active metabolite 7-ethyl-10-hydroxycamptothecin (SN-38) by carboxylesterase (CES). SN-38 is then converted to the inactive metabolite SN-38 glucuronide (SN-38G) by glucuronosyltransferase 1A1 (UGT1A1). Genetic polymorphisms in UGT1A1 have been associated with altered SN-38 pharmacokinetics, which increase the risk of toxicity in patients. CPT-11 is also converted to 7-ethyl-10-[4-N-(5-aminopentanoic acid)-1-piperidino]carbonyloxycamptothecin (APC) and 7-ethyl-10-(4-amino-1-piperidino) carbonyloxycamptothecin (NPC) by cytochrome P450 3A (CYP3A), and this route also affects the plasma concentration of SN-38. We evaluated the activities of UGT1A1, CYP3A, and CES and the factors affecting the pharmacokinetics of plasma SN-38 in patients with UGT1A1 gene polymorphisms. Three male patients aged 56, 65, and 49 years were recruited for the analysis. All patients had pancreatic cancer, received FOLFIRINOX, and had UGT1A1*6/*6 (patients 1 and 3) or *6/*28 (patient 2) genetic polymorphisms. The rate constants for evaluating the enzyme activity were determined from the measured plasma concentration of CPT-11 and its metabolites using a two-compartment model by WinNonlin. The area under the plasma concentration–time curve (AUC) of SN-38 was patient 1 > patient 2 > patient 3. The rate constants obtained from the model analysis indicated the respective enzyme activities of UGT1A1 (k57), CYP3A (k13 + k19), and CES (k15). The order of values for UGT1A1 activity was patient 2 > patient 3 > patient 1. Since UGT1A1 activity was low in patient 1 with a high AUC of SN-38, it can be said that the increase in plasma concentration was due to a decrease in UGT1A1 activity. Conversely, the order of values for CYP3A and CES activities was patient 3 > patient 1 > patient 2 and patient 2 > patient 1 > patient 3, respectively. Patient 3 had the lowest AUC of SN-38, caused by a lower level of CES activity and increased CYP3A activity. In this study, we indicated that the plasma AUC of SN-38 and AUC ratio of SN-38G/SN-38 may depend on changes in the activities of CYP3A, CES, and UGT1A1. Using pharmacokinetic analysis, it is possible to directly evaluate enzyme activity and consider what kind of enzyme variation causes the increase in the AUC of SN-38.

348 Background: CapeOX is a standard regimen for treating advanced gastric cancer (AGC). However, limited data are available for its use in the elderly patients. Geriatric assessment (GA) assessment is also considered important other than the age. Therefore, we conducted a multicenter, single-arm, phase II study to evaluate the efficacy and safety of CapeOX as a first-line therapy for AGC in elderly patients. We performed GA assessments using the G8, and the MINI-COG. Methods: The inclusion criteria were: HER2-negative or unknown status, age 70 years or older, PS 0 or 1, no history of chemotherapy or radiotherapy, and an evaluable lesion based on the RECIST v1.1 guidelines. The initial treatment plan consisted of capecitabine (1,000 mg/m2, b.i.d., on days 1–14), and oxaliplatin (130 mg/m2, on day 1) every three weeks. After the initial feasibility assessment, the treatment plan was modified and consisted of capecitabine (750 mg/m2, b.i.d., on days 1–14) and oxaliplatin (100 mg/m2, on day 1) every three weeks. The primary endpoint was overall survival (OS). G8 assessments were performed before the beginning of the treatment, every three months after the start of the treatment, and at the end of the treatment. MINI-COG assessments were performed before the beginning of the treatment, and at the end of the treatment. Results: Between November 2016 and June 2020, 108 patients were enrolled, out of which 104 were evaluated. Thirty-nine patients received the initial treatment whereas sixty-five patients received the modified treatment. The primary endpoint was met. The median OS, progression-free survival (PFS), and time-to-treatment failure (TTF) were 12.9 (95% CI: 11.7–14.8), 5.8 (95% CI: 5.1–7.1), and 4.3 (95% CI: 3.9–5.7) months, respectively, for all patients. The median OS, PFS, and TTF for the initial treatment plan were 13.4 (95% CI: 9.6–16.0), 5.8 (95% CI: 4.1–7.9), and 5.3 (95% CI: 3.5–7.3) months, respectively, and for the modified treatment plan were 12.8 (95% CI: 11.3–15.3), 5.7 (95% CI: 4.4–7.0), and 4.2 (95% CI: 3.7–5.7) months, respectively. The most common grade 3/4 toxicities in the initial treatment plan patients were neutropenia (17.9%), anemia (12.8%), thrombocytopenia (12.8%), anorexia (10.3%), and nausea (10.3%) and in the modified treatment plan patients were (13.8%) and anorexia (12.3%). Mean G8 score was 11.4 before the treatment, 13.4 during the treatment and 11.6 at the end of the treatment. Mean MINI-COG score was 4.0 before the treatment, and 4.1 at the end of the treatment and the positive screen for dementia was 13.5% before the treatment and 11.4% at the end of the treatment. Conclusions: Our results show that the modified treatment plan is favorable for the elderly patients with gastric cancer based on the OS and the toxicities. Clinical trial information: 000022450 .

In July 2019, in accordance with the Medical Information Distribution Service Manual for Guideline Development 2014, which was based on the Grading of Recommendations Assessment, Development and Evaluation approach, the Japanese Society of Medical Oncology (JSMO) and the Japan Society of Clinical Oncology (JSCO) published clinical practice guidelines (CPGs) on chemotherapy and other drug therapies for older patients with cancer (JSMO-JSCO CPGs). In September 2020, at one year after the publication of these guidelines, a survey was conducted to determine the extent to which they had been disseminated to JSMO and JSCO members and implemented in daily practice.This nationwide, cross-sectional, web-based survey was conducted with JSMO and JSCO members. We surveyed the participants' overall awareness of the JSMO-JSCO CPGs, and their knowledge about, attitudes toward, and perceived barriers to adherence to each recommendation using validated questionnaires based on theoretical frameworks used in previous studies (Awareness to Adherence Model, Clinicians' Assessments of Practice Guidelines in Oncology questionnaires, and Knowledge-Attitudes-Behavior Framework).Among JSMO and JSCO members who had been informed of the survey, 1230 responded (response rate: 8.6% and 4.8%, respectively). From these respondents, 107 were excluded because they did not practice anticancer drug therapy at the time of the survey. Of the remaining 1123 eligible participants, 674 (60.0%) were aware of the JSMO-JSCO CPGs before the survey, 492 (73.0%) of whom had read all or part of the guidelines (publications 57.1%, JSMO website 34.8%, and JSCO website 14.0%). Knowledge about, attitudes toward, and barriers to adherence to each recommendation differed widely according to the clinical questions. The most commonly cited barriers were lack of awareness, lack of agreement, lack of evidence, lack of outcome expectancy, patient values and preferences, and patient factors.This survey identified different barriers to guideline adherence, including providers' knowledge, attitudes, and external factors, depending on each recommendation. Effective strategies to overcome these barriers can be expected to improve the implementation of the guideline recommendations. Based on the results of this survey, efforts should be made to promote further the use of the clinical guidelines in daily practice.

BackgroundBiliary tract cancer (BTC) has a poor prognosis and lacks a standardized second-line therapy. Vascular endothelial growth factor (VEGF), fibroblast growth factor receptor (FGFR) 4, and platelet-derived growth factor receptor (PDGFR) are highly expressed in BTC. Therefore, lenvatinib (a known inhibitor of VEGF receptors 1–3, FGFRs 1–4, and PDGFR-α) was evaluated for second-line treatment of BTC.MethodsIn this single-arm, multicenter, open-label, phase 2 study, patients with BTC received lenvatinib 24 mg orally once daily in 28-day cycles. The primary endpoint was objective response rate (ORR). Secondary endpoints included overall survival (OS), progression-free survival (PFS), PFS rate at 12 weeks, disease control rate, clinical benefit rate, safety and pharmacokinetic profiles.ResultsTwenty-six Japanese patients were enrolled and treated; 3 had a confirmed partial response per investigator assessment and per independent imaging review (IIR); ORR was 11.5% (90% confidence interval [CI]: 3.2–27.2). Median PFS was 3.19 months (95% CI: 2.79–7.23) per investigator assessment and 1.64 months (95% CI: 1.41–3.19) per IIR. Median OS was 7.35 months (95% CI: 4.50–11.27). Grade ≥ 3 treatment-emergent adverse events (TEAEs) occurred in 21 patients (80.8%) and included hypertension (n = 10 [38.5%]), proteinuria (n = 3 [11.5%]), palmar-plantar erythrodysesthesia (n = 3 [11.5%]), decreased appetite (n = 3 [11.5%]), and anemia (n = 3 [11.5%]). Two deaths occurred due to TEAEs between treatment initiation and 30 days after last dose, but neither were considered treatment related.ConclusionsLenvatinib demonstrated antitumor activity in BTC, with a tolerable safety profile, and should be further evaluated as potential second-line therapy for this difficult to treat population.Trial registrationClinicalTrials.govNCT02579616. Date of registration: October 19, 2015.

Safety of combination chemotherapy using platinum and fluorouracil has not been evaluated adequately for advanced gastric cancer (AGC) in elderly patients.We initiated a phase II study to evaluate the efficacy and safety of capecitabine plus oxaliplatin (CapeOX) as first-line therapy for patients with AGC aged ≥70 years. Planned assessment of toxicity was made upon recruitment of the first 20 patients.In five out of 20 patients, unacceptable toxicity was observed, including three patients who were unable to complete the initial two courses due to adverse events. Among the other 15 patients, dose reduction due to toxicity were needed in 10 and treatment delay for adverse events also occurred in 12 patients during the first two courses.Early analyses of safety suggest that the CapeOX regimen was not tolerated without dose reduction for elderly patients with AGC in this study.

This phase 1b trial evaluated the toxicity and efficacy of S-1, irinotecan, and oxaliplatin combination therapy (S-IROX) as first-line chemotherapy in patients with advanced pancreatic cancer (APC).Patients aged 20-75 years with APC and an Eastern Cooperative Oncology Group performance status of 0 or 1 were eligible to receive escalating doses of S-1 (60 or 80 mg msup2/sup·day) on days 1-7, fixed doses of oxaliplatin (85 mg/msup2/sup) biweekly, and escalating doses of irinotecan (150, 165, or 180 mg/msup2/sup) once every 2 weeks. In the dose-escalation cohort, a 3 + 3 design was used to determine the maximum-tolerated dose (MTD) and explore the recommended dose (RD). A dose-expansion cohort was added to further evaluate the safety and efficacy of the combination. This trial was registered at UMIN-CTR (UMIN000012054).Approximately 47 patients were enrolled, of whom 45 were eligible for the analysis. The MTD was not determined, but the RD was determined to be dose level 1 based on a review of data from each level. Among the 45 patients, the ORR was 51.1% [95% confidence interval (CI), 35.8-66.3%]. The median progression-free survival and median overall survival was 6.9 months (95% CI, 5.1-8.8 months) and 15.8 months (95% CI, 9.8-20.8 months), respectively. Common adverse events included neutropenia, elevated liver enzyme levels, diarrhoea, and nausea.The S-IROX regimen showed promising efficacy with manageable toxicities in Japanese patients with APC. A randomised phase 2/3 trial comparing S-IROX, mFOLFIRINOX, and gemcitabine plus nab-paclitaxel is currently ongoing (jRCTs031190009).

In Japan, the population aged 65 and over accounts for 29% of the total population, and the number of elderly cancer patients is increasing. Geriatric oncology is an academic area that considers the characteristics of the elderly and provides appropriate cancer care. The International Society of Geriatric Oncology considers education, medical care, research, and partnership formation as priority areas and has set them as policy goals. In Japan, the content related to"cancer in the elderly"has been added to the 3rd-term Basic Plan to Promote Cancer Control Programs, aiming to formulate cancer treatment guidelines for the elderly. So far, the"Guidelines for Cancer Chemotherapy for the Elderly"have been published. With the aging of the population, social security costs will increase significantly after 2022, when the baby boomer generation will be 75 years old. Currently, reforms of social security systems such as pensions, medical care, and long-term care are underway. In order to promote geriatric oncology, it is important to enhance cooperation between oncology and geriatrics and to support the cooperation system between families and medical staff. In Japan, where the working-age population and the total population have begun to decline, we are facing many challenges. The experience of Japan, a top runner in a super- aged society, has the potential to be shared on a global scale and should be addressed from a long-term perspective.

This open-label first-in-human study evaluated JPH203, which is a novel selective L-type amino acid transporter 1 inhibitor. We also evaluated the association between the N-acetyltransferase 2 phenotype and outcomes. Japanese patients with advanced solid tumors received daily intravenous JPH203 treatment for 7 days, followed by a 21-day rest period, at escalating doses of 12–85 mg/m2. Dose-limiting toxicities were evaluated during the first cycle using a 3 + 3 design. The study enrolled 17 patients, although grade 3 liver dysfunction was detected in one of six patients receiving 60 mg/m2 and in the first patient to receive 85 mg/m2. Further enrollment was terminated and the maximum tolerated dose was defined as 60 mg/m2. The AUC∞ increased between 12 mg/m2 and 25 mg/m2, although no differences were observed at 25–40 mg/m2. Partial response was observed for one patient with biliary tract cancer (BTC) at the 12 mg/m2 dose, and disease control was achieved by 3 of 6 patients at the 12 mg/m2 and 25 mg/m2 dose levels. Based on these results, we recommend a phase II dose of 25 mg/m2. The disease control rate for BTC was 60%. Two patients with grade 3 liver dysfunction had the rapid N-acetyltransferase 2 phenotype, and disease control was more common for the non-rapid phenotype (50% vs. 12.5%). It appears that JPH203 was well-tolerated and provided promising activity against BTC. The N-acetyltransferase 2 phenotype might help predict the safety and efficacy of JPH203. Clinical trial registration: UMIN000016546.

Background The development of novel antitumor agents and accompanying biomarkers has improved survival across several tumor types. Previously, we published provisional clinical opinion for the diagnosis and use of immunotherapy in patients with deficient DNA mismatch repair tumors. Recently, efficacy of tropomyosin receptor kinase inhibitors against neurotrophic receptor tyrosine kinase (NTRK) fusion gene-positive advanced solid tumors have been established as the second tumor-agnostic treatment, making it necessary to develop the guideline prioritized for these patients. Methods Clinical questions regarding medical care were formulated for patients with NTRK-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 Japan Society of Clinical Oncology (JSCO) and Japanese Society of Medical Oncology (JSMO) 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 Japanese Society of Pediatric Hematology/Oncology, and the public comments among all Societies’ members was done. Results The current guideline describes 3 clinical questions and 15 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 In the NTRK guideline, the committee proposed 15 recommendations for performing NTRK testing properly to select patients who are likely to benefit from tropomyosin receptor kinase inhibitors.

Background/aim Amino acids are among the most important nutrients for supplying energy and building protein blocks in cancers. L-type amino acid transporter (LAT) 1 is known to play a critical role in cancer growth. We have completed the first-in-human phase I study using the LAT1-specific inhibitor JPH203. Patients and methods We evaluated plasma free amino acids (PFAAs), body mass index (BMI), and efficacy of JPH203 in patients enrolled in the phase I study. Results LAT1-substrate PFAAs and branched chain amino acids (BCAAs) were higher in patients with biliary tract cancer (BTC) than in those with other cancers. High inhibition of uptake of LAT1-substrate PFAAs was associated with survival. BMI of more than the median was associated with disease control and survival. BCAAs tended to be associated with BMI. Conclusion BCAAs and BMI are useful predictors of the efficacy of JPH203, which shows promising activity against BTC.

Gemcitabine plus nab-paclitaxel is the current standard chemotherapy for patients with metastatic pancreatic cancer. We conducted a phase I/II study in Japan, in which high response rates and manageable toxicity were observed. In this study, two patients were reported as experiencing pancreatitis due to chemotherapy. In general, pancreatitis is sometimes observed when the tumor involves the pancreatic duct, and the onset is observed before the diagnosis or at the initial stage. The onset of pancreatitis in these cases was unique and observed after the start of chemotherapy. Pancreatitis may be induced by the alleviation of stenosis of the pancreatic duct associated with tumor shrinkage.

Aflibercept plus 5‐fluorouracil/levofolinate/irinotecan (FOLFIRI) is a second‐line treatment for metastatic colorectal cancer. This ancillary exploratory analysis of data in Japanese people was aimed at exploring the relationship between a set of potential prognostic biomarkers and efficacy endpoints following aflibercept plus FOLFIRI therapy. Sixty‐two patients with metastatic colorectal cancer received aflibercept (4 mg/kg) plus FOLFIRI every 2 weeks. Seventy‐eight potential protein biomarkers were chosen for analysis based on their roles in angiogenesis, tumor progression, and tumor‐stroma interaction. Plasma levels of biomarkers at baseline and at pre‐dose 3 (day 1 of treatment cycle 3) were measured in all patients by ELISA. Relationships between these levels and efficacy endpoints were assessed. Ten potential biomarkers had a ±30% change from baseline to pre‐dose 3 (adjusted P

IntroductionElderly cancer patients often have ageing-related physical and psychosocial problems that should be fully shared with their oncologists. Geriatric assessment (GA) can assess these ageing-related problems and guide management. Communication support might also facilitate implementation of GA-guided management. We will conduct a multicentre, randomised controlled trial to examine the efficacy of a programme that combines a GA summary, management recommendations and communication support to facilitate ageing-related communications between elderly Japanese patients with cancer and their oncologists, and thus to implement programme-guided management.Methods and analysisWe plan to recruit a total of 210 patients aged ≥70 years, diagnosed with incurable cancers of gastrointestinal origin, and referred for first-line or second-line chemotherapy. In the intervention arm, a summary of management recommendations based on a GA and question prompt list (QPL) will be provided to patients and shared with their oncologists at the first outpatient visit after randomisation by trained intervention providers. For 5 months after the initial intervention, implementation of GA-guided management recommendations will be reviewed monthly with the patients and their oncologists to implement management as needed. The GA and QPL will be re-evaluated at 3 months, with a summary provided to patients and their oncologists. Those participants allocated to the usual care arm will receive usual oncology care. The primary endpoint is the number of conversations about ageing-related concerns at the first outpatient visit after randomisation.Ethics and disseminationThis study was approved by the institutional review board of the National Cancer Center Japan on 15 April 2021 (ID: 2020–592). Study findings will be disseminated through peer-reviewed journals and conference presentations.Trial registration numberUMIN000045428.

Recently there are many humanoid robot research projects for motion generation and control, planning, vision processing, sound analysis, voice recognition and others. There are many useful results for these elementary technologies by the effort of researchers. The humanoid robot HOAP (Fig.1, Fujitsu Automation) contributed these researchers and I also received a benefit from this robot for motion generation and control investigation. And in parallel, several researchers are working on formulation as a system based on these elementary technologies. The researchers in this area think how to integrate the system using many technologies and how to realize a suitable system for a certain purpose.

The Japan Clinical Oncology Group established a policy for geriatric oncology research suggesting several solutions for various issues which commonly occur in geriatric research., Due to the rapid aging of Japan’s population, clinical research focusing on older patients with cancer is urgently needed. The Japan Clinical Oncology Group (JCOG) has conducted several such clinical trials, but there has been no formal policy for geriatric research. We have therefore established a JCOG policy for geriatric cancer research. We defined the patient selection policy based on treatment tolerance and chronological age. Older patients are categorized into three conceptual groups: ‘fit patients’ who can undergo the same standard treatment given to younger patients, ‘frail patients’ for whom best supportive or palliative care is indicated and ‘vulnerable patients’ who fall between the fit and frail categories. Unmet needs often exist for vulnerable patients. The policy recommends that study endpoints include not only survival but also other endpoints such as physical and cognitive function because the objective of therapy in older patients is not only extended life expectancy but also maintenance of the patient’s general condition. In this viewpoint, co-primary or composite endpoints that incorporate geriatric assessment in the study design are often applicable. Study design will differ depending on the study population, clinical question, and treatment. Even for older patients, a randomized clinical trial is still the gold standard when the clinical question asks which treatment is better. An observational study of a broader population is applicable for investigating actual conditions of older patients. This JCOG Geriatric Research Policy includes several practical solutions for various issues in geriatric research. We plan to revise this policy periodically to guide future geriatric research.

The impact of age on survival after hepatic resection for hepatocellular carcinoma (HCC) has not been thoroughly examined. We reviewed the data of a nationwide follow-up survey to determine the outcomes of hepatectomy for HCC in elderly patients.Management of malignant diseases in elderly patients has become a global clinical issue because of the increased life expectancy worldwide. Advancements in surgical techniques and perioperative management have reduced age-related contraindications for liver surgery.In all, 12,587 patients with HCC who underwent curative hepatic resection were included in this cohort study and classified according to age group [40-59 years (n = 2991), 60-74 years (n = 7576,), and ≥75 years (n = 2020)]. Clinicopathological features, long-term survival, and cumulative incidences of death after hepatic resection were compared among the groups. The cause-specific subdistribution hazard ratios for 3 types of death depending on age were also estimated.Preoperative liver function tests showed that the prothrombin activity and platelet count were higher in the ≥75-year age group than in the other age groups. The overall survival was significantly lower in the elderly than younger patients. However, recurrence-free survival was almost identical among the 3 groups. The cumulative incidence of HCC-related or liver-related death was almost identical among the 3 groups; however, the cumulative incidence of other causes of death was significantly different. The 60-year subdistribution hazard ratio for other causes of death increased remarkably with increasing age.Elderly patients in this nationwide survey had significantly worse overall survival after hepatectomy than middle-aged and young patients. The cumulative incidence of other causes of death in elderly patients was significantly different from that of HCC-related or liver-related death among the 3 groups.

Aflibercept targets vascular endothelial growth factor. The present study involved assessing the efficacy, safety and pharmacokinetics of aflibercept plus 5-fluorouracil/levofolinate/irinotecan (FOLFIRI) as a second-line treatment for metastatic colorectal cancer (mCRC) in Japanese patients. Aflibercept (4 mg/kg) plus FOLFIRI was administered every 2 weeks in 62 patients with mCRC until disease progression, unacceptable toxicity or patient withdrawal. Tumors were imaged every 6 weeks. The primary endpoint was objective response rate (ORR); secondary endpoints were progression-free survival, overall survival, safety, and pharmacokinetics of aflibercept, irinotecan and 5-fluorouracil. A total of 60 patients were evaluated for ORR; 50 had received prior bevacizumab. The ORR was 8.3% (95% confidence interval [CI]: 1.3%-15.3%), and the disease control rate (DCR) was 80.0% (69.9%-90.1%). The median progression-free survival was 5.42 months (4.14-6.70 months) and the median overall survival was 15.59 months (11.20-19.81 months). No treatment-related deaths were observed, and no significant drug-drug interactions were found. The most common treatment-emergent adverse events were neutropenia and decreased appetite. Free aflibercept had a mean maximum concentration (coefficient of variation) of 73.2 μg/mL (15%), clearance of 0.805 L/d (22%) and volume of distribution of 6.2 L (18%); aflibercept bound with vascular endothelial growth factor had a clearance of 0.162 L/d (9%) (N = 62). Aflibercept did not significantly affect the pharmacokinetics of irinotecan or 5-fluorouracil: The clearance was 11.1 L/h/m2 (28%) for irinotecan and, at steady state, 72.6 L/h/m2 (56%) for 5-fluorouracil (N = 10). Adding aflibercept to FOLFIRI was shown to be beneficial and well-tolerated in Japanese patients with mCRC. ClinicalTrials.gov Identifier: NCT01882868.

The risk of cancer increases with age, and the need of cancer treatments are dramatically increasing in the super-aged society. Comprehensive Geriatric Assessment is an approach that provides comprehensive medical care by evaluating in detail the physical, mental, and social functions of patients. It is also important to make an intervention plan and follow-up over the long term. The NCCN guidelines for older adults indicate an approach to decision-making based on life expectancy, the ability of decision-making, and patients’ goals. As pancreatic cancer increases with age, we should consider the process of decision-making for vulnerable and elderly patients.

Background In Japan, approximately half of all lung cancer patients are aged > 75 years, and the proportion of older patients is increasing. In older patients, it is necessary to consider comorbidities and concomitant drug use to ensure optimal cancer treatment; however, geriatric assessment (GA) is not widely performed. We plan to conduct a study (ENSURE-GA) of GA in older lung cancer patients to determine whether GA with intervention improves patient satisfaction with their treatment. Methods The study will be a phase III comparative clinical trial with a cluster-randomized design, and it will be conducted at 81 sites distributed throughout Japan. Approximately 1000 lung cancer patients aged ≥ 75 years will be enrolled in the study. All participants will undergo a standardized GA before starting treatment (using an iPad). At the intervention sites, the GA results and intervention method recommended on the basis of the GA results will be returned as an instant report to guide the physician’s choice of intervention. At the control sites, the physician will decide on interventions based on standard practice. All participants will complete a patient satisfaction survey before treatment initiation (after the GA) and 3 months later. Discussion The purpose of the ENSURE-GA study is to evaluate whether GA with interventions improves patient satisfaction with treatment outcomes. The study may lead to the increased use of GA and improved treatment of cancer in older adults. The results will also be used to prepare guidelines for treating older cancer patients and will provide a foundation for the development of a standardized geriatric oncology system. Trial registration The study has been registered in the University Hospital Medical Information Network database (no. UMIN000037590). The registration date is August 4, 2019, and the protocol version is 2.0. (https://upload.umin.ac.jp/cgi-open-bin/ctr/ctr_view.cgi?recptno=R000042853.)

Purpose Patients with RAS-positive tumors respond poorly to chemotherapies and have a few treatment options. Salirasib is an oral RAS inhibitor that competitively blocks the membrane association of RAS proteins. The aim of this phase I multiple-ascending-dose clinical trial was to investigate the safety and pharmacokinetics of Salirasib in Japanese patients with relapsed/refractory solid tumors and to explore its efficacy. Methods Salirasib was started at a dose of 100-mg twice-daily and escalated to a maximum of 1000-mg twice-daily from days 1 to 21 of a 28-day regimen. The pharmacokinetics was evaluated on days 1 and 21. Dose-limiting toxicity (DLT) and adverse events (AEs) were monitored throughout the trial. Patients with stable disease or better repeated the dosing regimen. Results A total of 21 patients received Salirasib. Among 14 patients tested, 4 had KRAS mutations. Cmax and AUCinf were maximal at 800 mg. No maximum tolerable dose was discerned, as no DLT was observed in any dosing group. The most frequently observed AEs were gastrointestinal disturbances, including diarrhea, abdominal pain, and nausea. No AEs led to discontinuation. All patients completed the first regimen and 11 patients repeated the regimen (median: 2 cycles; range: 1–13). Patients with KRAS mutations showed median progression-free survival of 227 days (range: 79–373). Conclusion Salirasib was safe and well tolerated in Japanese patients, and 800-mg twice-daily is recommended for phase II trials. Although the number of participants with KRAS mutations was limited, the remarkably long progression-free period warrants further investigation. Clinical trial registration JAPIC Clinical Trials Information; JapicCTI-121751. Electronic supplementary material The online version of this article (10.1007/s00280-018-3618-4) contains supplementary material, which is available to authorized users.

Ramucirumab, a monoclonal antibody vascular endothelial growth factor receptor-2 antagonist, given as monotherapy improved survival in a global phase 3 study (REGARD) of patients with gastric cancer. However, REGARD did not include Japanese patients. This study evaluated the efficacy and safety of ramucirumab monotherapy in Japanese patients with advanced gastric cancer. This multicenter, open-label, nonrandomized phase 2 study (Clinicaltrials.gov: NCT01983878) was performed at 16 Japanese sites. Patients with advanced gastric or gastroesophageal junction cancer after disease progression following first-line chemotherapy received intravenous ramucirumab 8 mg/kg every 2 weeks. Primary efficacy outcome: 12-week progression-free survival rate (PFS). Thirty-six patients were enrolled. The 12-week PFS rate was 23.8% [90% confidence interval (CI) 12.4–37.2); the primary outcome was not met as the lower limit of the CI was outside the threshold of 16%. Median PFS was 6.6 weeks (90% CI 6.1–7.1). No patients achieved an objective response, and 11 (31%) patients achieved disease control. Median overall survival was 8.6 months (90% CI 5.7–10.7). The most frequent treatment-emergent adverse events (TEAEs) were diarrhea (9/36; 25%) and decreased appetite (8/36; 22%). Three patients reported Grade ≥ 3 ileus; all other Grade ≥ 3 TEAEs were reported by ≤ 2 patients. The most frequent adverse events of special interest (AESIs) were hypertension (10/36; 28%), bleeding/hemorrhage (7/36; 19%), and proteinuria (7/36; 19%). All Grade ≥ 3 AESIs were reported by ≤ 2 patients. These findings suggest that ramucirumab monotherapy has clinical activity and a manageable safety profile in Japanese patients with gastric cancer after disease progression following first-line chemotherapy.

Objective The feasibility of continuous geriatric assessments (GAs) has not been evaluated fully in elderly patients with cancer. We prospectively investigated this issue by administering a recommended-GA set (r-GA) repeatedly to patients undergoing chemotherapy for gastrointestinal cancer on an outpatient basis. Methods We administered the r-GA before chemotherapy and every two months thereafter. Continuous GAs was defined as the completion of at least two assessments, including the pre-treatment evaluation. The r-GA included the Barthel Index [Basic Activities of Daily Living (BADL)], Mini-Mental State Examination-Japanese (MMSE-J), Instrumental Activities of Daily Living (IADL) scale, Vitality Index (VI), and Geriatric Depression Scale-15. We also used the Vulnerable Elders Survey (VES)-13 to screen overall vulnerability. We analyzed the correlations between each baseline GA score and the overall survival (OS) and the association between the OS and changes in each patient's GA scores over time. Patients Patients ≥65 years of age who presented to our department for initial consultation were enrolled and followed between December 2012 and January 2017. Results Twenty-one elderly patients (median age, 76 years old) were enrolled. GAs were completed within 20 minutes. In an age- and performance status (PS)-adjusted Cox proportional hazards analysis, the baseline BADL, MMSE-J, and VI scores correlated significantly with the OS (p=0.012, p=0.032, and p=0.012, respectively). During the clinical course, decreases in the MMSE-J and VES-13 scores were correlated with the OS (p=0.022 and p=0.019, respectively). Conclusion Outpatient GA administration is feasible. Low baseline BADL, MMSE-J, and VI scores and decreased MMSE-J and VES-13 scores over time may prognosticate the OS.

Lessons Learned Axitinib exhibited marginal activity against gemcitabine-refractory unselected biliary tract cancer. Pretreated soluble vascular endothelial growth factor receptor-2 may be a useful biomarker for axitinib treatment outcome. Ascites should be carefully monitored in patients receiving anti–vascular endothelial growth factor receptor therapy including axitinib in advanced biliary tract cancer. Background There are no clear options for second-line treatment in patients with gemcitabine (GEM)-refractory biliary tract cancer (BTC). We conducted a multicenter, single-arm, phase II trial to confirm the efficacy and safety of axitinib, a potent selective inhibitor of vascular endothelial growth factor receptor (VEGFR)-1/2/3, in patients with GEM-refractory BTC. Methods Patients refractory or intolerant to GEM-based chemotherapy were enrolled. Axitinib was administered orally at an initial dose of 5 mg twice daily. The primary endpoint was progression-free survival (PFS), and the threshold and expected values were set at 2 and 3 months, respectively. The target sample size was 32 patients. Results Nineteen patients were enrolled. The trial was interrupted for a total of 13 months for the evaluation of adverse events. Thirteen patients were previously treated with ≥2 regimens. The median PFS was 2.8 months (95% confidence interval [CI]: 2.1–4.1). The median overall survival was 5.8 months (95% CI: 3.3–9.7). The response rate was 5.3% (95% CI: 0.0–15.3). Grade 3 ascites occurred in two patients. Baseline soluble VEGFR-2 levels were significantly associated with PFS. Conclusion Axitinib exhibited marginal activity against GEM-refractory BTC. Ascites should be carefully monitored in axitinib-treated patients with advanced BTC.

We evaluated the safety and efficacy of ramucirumab plus paclitaxel versus placebo plus paclitaxel in patients previously treated for advanced gastric or gastroesophageal junction adenocarcinoma in Japanese and Western subgroups from the RAINBOW trial.Patients received ramucirumab at 8 mg/kg or placebo (days 1 and 15) plus paclitaxel at 80 mg/m(2) (days 1, 8, and 15 of a 28-day cycle). End points were compared between treatment arms within Japanese (N = 140) and Western (N = 398) populations.The incidence of adverse events of grade 3 or higher was higher for ramucirumab plus paclitaxel in both populations (Japanese population, 83.8 % vs 52.1 %; Western population, 79.1 % vs 61.9 %). Neutropenia was the commonest adverse event of grade 3 or higher, with a higher incidence for ramucirumab plus paclitaxel (Japanese population, 66.2 % vs 25.4 %; Western population, 32.1 % vs 14.7 %). The incidence of febrile neutropenia was low and was similar between treatment arms in both populations. The overall survival hazard ratio was 0.88 (95 % confidence interval, 0.60-1.28) in the Japanese population and 0.73 (95 % confidence interval, 0.58-0.91) in the Western population. The progression-free survival hazard ratio was 0.50 (95 % confidence interval, 0.35-0.73) in the Japanese population and 0.63 (95 % confidence interval, 0.51-0.79) in the Western population. The objective response rate was higher for ramucirumab plus paclitaxel in both populations (Japanese population, 41.2 % vs 19.4 %; Western population, 26.8 % vs 13.0 %), as was the 6-month survival rate (Japanese population, 94.1 % vs 71.4 %; Western population, 66.0 % vs 49.0 %).Safety profiles of the ramucirumab plus paclitaxel arm were similar between populations, though there was a higher incidence of neutropenia in Japanese patients. Progression-free survival and objective response rate improvements were observed for ramucirumab plus paclitaxel in both populations. CLINICALTRIALS.NCT01170663.