A Retrospective Study of Gemcitabine Plus Nab-Paclitaxel for Advanced Pancreatic Cancer Refractory to Gemcitabine Monotherapy.

BACKGROUND/AIM: This study aimed to investigate the efficacy and safety of gemcitabine (GEM) plus nab-paclitaxel (nab-PTX), termed GnP, which is limited, in patients with advanced pancreatic cancer (PC) who show good tolerance to GEM monotherapy prior to being refractory to it. PATIENTS AND METHODS: We retrospectively analyzed the data of patients with locally advanced or metastatic PC who received GEM followed by GnP between December 2014 and March 2019, regardless of the treatment line. RESULTS: A total of 14 patients who received GnP after becoming refractory to GEM were included in this study. Eight patients were included in the nab-PTX-naïve group, seven of whom were treated with GEM monotherapy as first-line chemotherapy, and one was refractory to GEM monotherapy after modified FOLFIRINOX treatment. The other six patients were included in the nab-PTX reintroduction group. In this group, all patients received GnP followed by GEM maintenance therapy to prevent adverse events, such as peripheral neuropathy and fatigue. Two patients in the nab-PTX-naïve group showed partial response and none in the reintroduction group; median progression-free survival was 7.6 and 1.4 months and median overall survival was 9.4 and 6.2 months, respectively. In the safety analysis, grade 3 anemia and peripheral neuropathy were observed in one patient in the nab-PTX reintroduction group, while the remaining adverse events were of grade 1 or 2. CONCLUSION: GnP is safe and effective even in patients with GEM-refractory PC, and GEM treatment followed by GnP can be an effective treatment option for patients with nab-PTX-naïve PC.

Multicenter phase II study of capecitabine plus oxaliplatin in older patients with advanced gastric cancer: the Tokyo Cooperative Oncology Group (TCOG) GI-1601 study.

BACKGROUND: Capecitabine plus oxaliplatin (CapeOX) is a standard treatment option for advanced gastric cancer (AGC). We conducted a prospective multicenter phase II study to evaluate the efficacy and safety of CapeOX as a first-line therapy for AGC in older patients. METHODS: Chemotherapy-naive patients aged ≥ 70 years with AGC were eligible. Initial treatment comprised capecitabine (2000 mg/m2 on days 1-14) and oxaliplatin (130 mg/m2 on day 1) every 3 weeks. After the initial feasibility assessment, the dose was reduced considering toxicity (capecitabine, 1500 mg/m2 on days 1-14; and oxaliplatin, 100 mg/m2 on day 1 every 3 weeks). The primary endpoint was overall survival (OS). RESULTS: In total, 108 patients were enrolled, of whom 104 were evaluated. Thirty-nine patients received the original-dose treatment, whereas 65 received the reduced-dose treatment. The median OS, progression-free survival (PFS), and time to treatment failure (TTF) were 12.9 (95% CI 11.6-14.8), 5.7 (95% CI 5.0-7.0), and 4.3 (95% CI 3.9-5.7) months, respectively, for all patients; 13.4 (95% CI 9.5-16.0), 5.8 (95% CI 4.1-7.8), and 5.3 (95% CI 3.5-7.2) months in the original-dose group; and 12.8 (95% CI 11.3-15.3), 5.7 (95% CI 4.4-7.0), and 4.1 (95% CI 3.7-5.7) months in the reduced-dose group. The most common grade 3/4 toxicities were neutropenia (17.9%), anemia (12.8%), and thrombocytopenia (12.8%) in the original-dose group and neutropenia (13.8%) and anorexia (12.3%) in the reduced-dose group. CONCLUSIONS: These findings demonstrate CapeOX's efficacy and safety in older AGC patients.

Efficacy of Targeted Trials and Signaling Pathway Landscape in Advanced Gastrointestinal Cancers From SCRUM-Japan GI-SCREEN: A Nationwide Genomic Profiling Program.

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.

A Prospective Study of Neoadjuvant Gemcitabine Plus Nab-paclitaxel in Patients with Borderline-resectable Pancreatic Cancer.

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. 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.

The Prognostic Utility of a Geriatric Assessment for Patients with Pancreatic Cancer Receiving Gemcitabine-based Chemotherapy: A Prospective Observational Study.

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.

A nationwide, cross-sectional, web-based survey on healthcare providers' knowledge about, attitudes toward, and perceived barriers to adherence to clinical practice guidelines for anticancer drug therapy for older patients with cancer in Japan.

INTRODUCTION: 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. MATERIALS AND METHODS: 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). RESULTS: 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. DISCUSSION: 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.

Geriatric assessment and management with question prompt list using a web-based application for elderly patients with cancer (MAPLE) to communicate ageing-related concerns: J-SUPPORT 2101 study protocol for a multicentre, parallel group, randomised controlled trial.

INTRODUCTION: Elderly 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 ANALYSIS: We 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 DISSEMINATION: This 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 NUMBER: UMIN000045428.

Safety and efficacy of S-IROX (S-1, irinotecan and oxaliplatin combination therapy) in patients with advanced pancreatic cancer: A multicenter phase 1b dose-escalation and dose-expansion clinical trial.

BACKGROUND: 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). METHODS: 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 m2·day) on days 1-7, fixed doses of oxaliplatin (85 mg/m2) biweekly, and escalating doses of irinotecan (150, 165, or 180 mg/m2) 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). RESULTS: 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. CONCLUSIONS: 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).

Association of ERBB2 Copy Number and Gene Coalterations With Trastuzumab Efficacy and Resistance in Human Epidermal Growth Factor Receptor 2-Positive Esophagogastric and Gastric Cancer.

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.

Trends in the surgical treatment for pancreatic cancer in the last 30 years.

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.

Initial Safety Analysis of CapeOx for Elderly Patients With Advanced Gastric Cancer Patients: A Phase II Trial.

BACKGROUND: Safety of combination chemotherapy using platinum and fluorouracil has not been evaluated adequately for advanced gastric cancer (AGC) in elderly patients. PATIENTS AND METHODS: 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. RESULTS: 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. CONCLUSION: Early analyses of safety suggest that the CapeOX regimen was not tolerated without dose reduction for elderly patients with AGC in this study.

Treatments for elderly cancer patients and reforms to social security systems in Japan.

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.

[Oncology in Super-Aged Society].

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.

Second-line pembrolizumab versus chemotherapy in Japanese patients with advanced esophageal cancer: subgroup analysis from KEYNOTE-181.

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.

Effect of UGT1A1, CYP3A and CES Activities on the Pharmacokinetics of Irinotecan and its Metabolites in Patients with UGT1A1 Gene Polymorphisms.

BACKGROUND AND OBJECTIVES: 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. METHODS: 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. RESULTS: 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. CONCLUSION: 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.

Protocol for a multi-site, cluster-randomized, phase III, comparative clinical trial of geriatric assessment of older patients with non-small-cell lung cancer: the ENSURE-GA study.

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 .).

Multicenter Phase II Trial of Axitinib Monotherapy for Gemcitabine-Based Chemotherapy Refractory Advanced Biliary Tract Cancer (AX-BC Study).

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.

Phase 2 study of lenvatinib monotherapy as second-line treatment in unresectable biliary tract cancer: primary analysis results.

BACKGROUND: Biliary 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. METHODS: In 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. RESULTS: Twenty-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. CONCLUSIONS: Lenvatinib 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 REGISTRATION: ClinicalTrials.gov NCT02579616 . Date of registration: October 19, 2015.