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Limited information is available regarding the impact of body weight loss (BWL) in patients with advanced gastric cancer (AGC) who receive second-line chemotherapy. We retrospectively reviewed data for consecutive AGC patients who received second-line treatment with taxane-based chemotherapy at our institution between January 2014 and September 2018. We calculated variables, including percent BWL per month during chemotherapy (%BWL/m), and analyzed the correlations between BWL and other clinicopathological parameters with survival. Forty-four AGC patients were registered (median age, 67.5 years; females, n = 16 [36.3%]; severe ascites, n = 12 [27.3%]). The median overall survival was significantly shorter among patients with a %BWL/m of 1% or more, compared with patients with less weight loss (6.3 mo, vs. 12.3 mo, P = 0.038). The %BWL/m (≥1% vs. <1%) was significantly correlated with survival in a univariate analysis (HR = 2.11, P = 0.04), and the survival period was shorter for patients with severe ascites (HR = 1.92; 95% CI, 0.90–3.90) and if their %BWL/m was 1% or more (HR = 2.01; 95% CI, 0.98–4.10) in a multivariate analysis. In conclusion, BWL during second-line chemotherapy was associated with a poor prognosis among patients with AGC. [ABSTRACT FROM AUTHOR]

The epidermal growth factor receptor (EGFR) and RAS/RAF signaling pathway plays pivotal roles in tumor progression via proliferation, survival, invasion, and immune evasion. Two anti-EGFR monoclonal antibodies, cetuximab and panitumumab, have become essential components in the treatment of patients with metastatic colorectal cancer (mCRC). Treatment with these anti-EGFR antibodies has shown definite benefits when administered in all treatment lines and is strongly recommended as the preferred regimen to prolong survival, especially when administered in the first- and third-lines. Recent efforts have revealed not only mechanisms responsible for resistance to anti-EGFR antibodies, including expanded RAS mutations as a negative predictive biomarker, but also the possibility of continuing anti-EGFR antibody treatment in combination with chemotherapy. Furthermore, the challenges associated with the pharmaceutical development of treatments for patients with mutant-type BRAF mCRC are ongoing. In this review, we provide an overview of the EGFR and RAS/RAF signaling pathway and antitumor activity, focusing on practical aspects such as established treatments including patient selection, treatment strategies, and future perspectives for drug development targeting the EGFR and RAS/RAF signaling pathway. [ABSTRACT FROM AUTHOR]

Background: Long‐term anti‐EGFR antibody treatment increases the risk of severe dermatologic toxicities. This single‐arm, phase II trial aimed to investigate the strategy of switching from cetuximab to bevacizumab in combination with FOLFIRI based on early tumor shrinkage (ETS) in patients with RAS wild‐type metastatic colorectal cancer (mCRC). Methods: Radiologic assessment was performed to evaluate ETS, defined as ≥20% reduction in the sum of the largest diameters of target lesions 8 weeks after the introduction of FOLFIRI plus cetuximab. ETS‐negative patients switched to FOLFIRI plus bevacizumab, whereas ETS‐positive patients continued FOLFIRI plus cetuximab for eight more weeks, with a switch to FOLFIRI plus bevacizumab thereafter. The primary endpoint was progression‐free survival. Results: This trial was prematurely terminated due to poor accrual after a total enrollment of 30 patients. In 29 eligible patients, 7 were ETS‐negative and 22 were ETS‐positive. Two ETS‐negative patients and 17 ETS‐positive patients switched to FOLFIRI plus bevacizumab 8 weeks and 16 weeks after initial FOLFIRI plus cetuximab, respectively. Median progression‐free and overall survival durations were 13.4 and 34.7 months, respectively. Six (20%) patients experienced grade ≥3 paronychia, which improved to grade ≤2 by 18 weeks. Grade ≥3 acneiform rash, dry skin, and pruritus were not observed in any patients. Conclusions: Our novel treatment strategy delivered acceptable survival outcomes and reduced severe dermatologic toxicities. [ABSTRACT FROM AUTHOR]

Chronic kidney disease (CKD) is one of the most disabling disorders with significant comorbidity and mortality. Incidence and prevalence of CKD in cancer survivors are remarkably high in both adults and pediatric patients. The reasons for this high incidence/prevalence are multifold but kidney damage by cancer itself and cancer treatment (pharmacotherapy/surgery/radiation) are the main reasons. Since cancer survivors commonly have significant comorbidities, risk of cancer recurrence, limited physical function or life expectancy, special attentions should be paid when considering the treatment of CKD and its complications. Especially, shared decision-making should be considered when selecting the renal replacement therapies with as much information/facts/evidence as possible. [ABSTRACT FROM AUTHOR]

Background: Chemotherapies have limited efficacy in pancreatic cancer (PC) and biliary tract cancer (BTC), underscoring the need for new regimens. Recently, tumor-agnostic approaches have been developed for some targeted therapies in advanced solid tumors; however, the frequency of alterations by clinical and genomic background is unclear in PC and BTC.Methods: To assess the frequencies of druggable gene alterations and investigate new potential therapeutic targetable genomic alterations, advanced PC and BTC patients were tested with comprehensive genomic profiling at Foundation Medicine during the course of clinical care.Results: A total of 16 913 PC patients and 3031 BTC patients were available for analyses, and frequencies of genomic alterations were stratified by age (≥40 years or <40 years), microsatellite instability status, tumor mutational burden status (high ≥10 or low <10 Muts/Mb), and select genomic alterations. Alterations in BRCA2, BRAF, ERBB2, CDK12, PIK3CA, FGFR2, EGFR, and other potential targets were seen across cohorts, with enrichment observed within particular subsets such as in PC patients lacking a KRAS mutation. In BTC patients, the rate of ERBB2 amplification was statistically significantly higher in the tumor mutational burden-high population (23.3% vs 13.7%). Interestingly, CDK12 rearrangement was observed in BTC patients with ERBB2 amplification tumors. In patients younger than 40 years, FGFR2 rearrangement (4%) was observed in PC: GATA6 amplification (11.1%) and rearrangement of BRAF (2.8%)FGFR2 (5.6%) was observed in BTC patients.Conclusions: We identified an appreciable frequency of immunotherapy biomarkers and targetable gene alterations in both PC and BTC, with notable frequencies in PC samples lacking KRAS mutations and children or adolescent and young adult populations, that should encourage comprehensive genomic profiling testing. [ABSTRACT FROM AUTHOR]

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. ERBB2 CN and gene coamplification on the HER2 pathway in gastric cancer are predictors for trastuzumab response. [ABSTRACT FROM AUTHOR]

Background: Cancer cachexia is a syndrome characterized by anorexia and decreased body weight. This study evaluated the efficacy and safety of anamorelin, an orally active, selective ghrelin receptor agonist, in patients with cancer cachexia and a low body mass index (BMI). Methods: This multicenter, open‐label, single‐arm study enrolled Japanese patients with non–small cell lung cancer or gastrointestinal cancer with cancer cachexia (BMI < 20 kg/m2, involuntary weight loss > 2% in the last 6 months, and anorexia). Patients were administered 100 mg of anamorelin once daily for up to 24 weeks. The primary end point was a composite clinical response (CCR) at 9 weeks, which was defined as an increase in body weight of ≥5% from the baseline, an increase of ≥2 points in the score of the 5‐item Anorexia Symptom Scale of the Functional Assessment of Anorexia/Cachexia Therapy, and being alive. Results: One hundred two patients were eligible and enrolled. The means and standard deviations for age and BMI were 71.0 ± 8.2 years and 17.47 ± 1.48 kg/m2, respectively. The CCR rate at 9 weeks was 25.9% (95% confidence interval [CI], 18.3%‐35.3%), which met the primary end point with a lower 95% CI exceeding the prespecified minimum of 8%. Improvements in body weight and anorexia were durable and were accompanied by improvements in patients' global impression of change for appetite/eating‐related symptoms and overall condition. Adverse drug reactions occurred in 37 of 101 treated patients (36.6%), with the most common being glycosylated hemoglobin increases, constipation, and peripheral edema. Conclusions: Anamorelin improved body weight and anorexia‐related symptoms in patients with cancer cachexia and a low BMI with durable efficacy and favorable safety and tolerability. Lay Summary: Anamorelin is a drug that stimulates appetite and promotes weight gain.This clinical trial was aimed at determining its efficacy and safety in Japanese cancer patients with a low body mass index and cachexia, a syndrome associated with anorexia and weight loss.Anamorelin was found to improve body weight and anorexia‐related symptoms in these patients, and these effects were durable for up to 24 weeks. Moreover, anamorelin was generally well tolerated.These findings suggest that anamorelin is a valuable treatment option for patients with cancer cachexia and a low body mass index. This single‐arm trial is aimed at investigating the efficacy and safety of anamorelin in Japanese patients with cancer cachexia and a low body mass index. Anamorelin improves body weight and anorexia‐related symptoms with durable efficacy and favorable safety and tolerability. [ABSTRACT FROM AUTHOR]

Background: Monitoring proteinuria is important for the management of patients with cancer treated with anti-vascular endothelial growth factor (VEGF) or anti-VEGF receptor (VEGFR) inhibitors (VEGF/Ri). Here we investigated the difference between the urine protein/creatinine ratio (UPCR) and a qualitative value test (QV) on the decision making of treatment continuation and the usefulness of UPCR testing in patients with gastrointestinal cancer treated with anti-VEGF/Ri.Methods: From January 2017 to December 2018, a survey was conducted based on the medical records of patients with gastrointestinal cancer with a QV of ≥2+ during the use of anti-VEGF/Ri at seven Japanese institutions participating in the Onco-nephrology Consortium. The primary endpoint was the ratio of the worst UPCR < 2.0 (low UPCR) in cases with a QV2+ at the point of the first proteinuria onset. The secondary endpoints were a comparison of low UPCR and worst UPCR ≥2.0 (high UPCR), the concordance rate between UPCR and QV in the Common Terminology Criteria for Adverse Events (CTCAE) grading, and the differences in the decision making for anti-VEGF/Ri continuation.Results: Among the 71 patients enrolled, the proportion of low UPCR in onset QV2+ (n = 53) was 66% (n = 35). In a comparison between low (n = 36) and high UPCR cases (n = 24), body weight (P = 0.036), onset QV status (P = 0.0134), and worst QV status (P < 0.0001) were significantly associated with UPCR levels. The concordance rate for CTCAE Grade 2 of both the QV and UPCR was 83%. Regarding the judgment of anti-VEGF/Ri continuation, treatment was continued in 42.4% of cases when the QV became 3+, whereas only 25% continued treatment when the UPCR value became high.Conclusion: Urine dipstick test results may overestimate proteinuria, and the UPCR result tended to be more critical than the QV when deciding the treatment policy.Trial Registration: This study is a multiple institutional retrospectively registered observational trial.Clinical Trial Number: University Hospital Medical Information Network (UMIN) Clinical Trials Registry (protocol ID UMIN000042545 ). [ABSTRACT FROM AUTHOR]

Objectives: This study aimed to evaluate whether a decrease of computed tomography (CT) value for tumors serves as a predictive marker in patients with advanced gastric cancer (aGC) who have undergone chemotherapy with vascular epithelial growth factor receptor 2 inhibitor (ramucirumab). Method: We retrospectively analyzed 44 patients with aGC who received taxane alone (TAX arm; n = 33), ramucirumab alone, or ramucirumab in combination with taxane (RAM arm; n = 11) as second-line or later chemotherapy between July 2010 and October 2016. In all patients, tumor size and tumor CT value were evaluated at two timepoints: pretreatment and first evaluation. We calculated the change of the tumors' CT value. The associations of these factors with tumor response, progression-free survival (PFS), and overall survival were investigated. Results: Ten (90.9%) of 11 patients in the RAM arm and 18 (54.5%) of 33 patients in the TAX arm showed decreased CT values. The rate of CT value change in the RAM arm (median −32.80%, range −53.63 to 6.84%) was higher than that in the TAX arm (median −0.44%, range −37.47 to 40.64%; p = 0.0005). When using the median value of CT value change as a cut-off, PFS was significantly longer in patients with a high rate of CT value change (decrease ≥32.80%) than in those with a low rate (decrease <32.80%) in the RAM arm (median 292 and 112 days; p = 0.045), while no significant difference of this kind was found in the TAX arm (median 91 and 125 days; p = 0.45). Conclusions: Patients with aGC treated with ramucirumab experienced a significant decrease of CT value of tumors and had an association between the rate of CT value change and PFS. Our study suggests that CT value changes of tumors may be a predictor for the efficacy of ramucirumab in aGC. [ABSTRACT FROM AUTHOR]

Background: Most advanced elderly cancer patients experience fatigue, anorexia, and declining physical function due to cancer cachexia, for which effective interventions have not been established. We performed a phase I study of a new nonpharmacological multimodal intervention called the nutritional and exercise treatment for advanced cancer (NEXTAC) program and reported the excellent feasibility of and compliance with this program in elderly patients with advanced cancer who were at risk for cancer cachexia. We report here the background, hypothesis, and design of the next-step multicenter, randomized phase II study to evaluate the efficacy of the program, the NEXTAC-TWO study.Methods: Patients with chemo-naïve advanced non-small cell lung cancer or pancreatic cancer, age ≥ 70 years, performance status ≤2, with adequate organ function and without disability according to the modified Katz index will be eligible. In total, 130 participants will be recruited from 15 Japanese institutions and will be randomized into either the intervention group or a control group. Computer-generated random numbers are allocated to each participant. Stratification factors include performance status (0 to 1 vs. 2), site of primary cancer (lung vs. pancreas), stage (III vs. IV), and type of chemotherapy (cytotoxic vs. others). Interventions and assessment will be performed 4 times every 4 ± 2 weeks from the date of randomization. Interventions will consist of nutritional counseling, nutritional supplements (rich in branched-chain amino acids), and a home-based exercise program. The exercise program will include low-intensity daily muscle training and lifestyle education to promote physical activity. The primary endpoint is disability-free survival. It is defined as the period from the date of randomization to the date of developing disability or death due to any cause. This trial also plans to evaluate the improvements in nutritional status, physical condition, quality of life, activities of daily living, overall survival, and safety as secondary endpoints. Enrollment began in August 2017. The study results will demonstrate the efficacy of multimodal interventions for elderly cancer patients and their application for the maintenance of physical and nutritional conditions in patients with cancer cachexia. This work is supported by a grant-in-aid from the Japan Agency for Medical Research and Development.Discussion: This is the first randomized trial to evaluate the efficacy and safety of a multimodal intervention specific for elderly patients with advanced cancer.Trial Registration: Registered at August 23, 2017. Registry number: UMIN000028801 . [ABSTRACT FROM AUTHOR]

Background: S-1 is an oral anticancer drug, containing tegafur (a prodrug of 5-fluorouracil, 5-FU), 5-chloro-2,4-dihydroxypyridine, and potassium oxonate. As renal dysfunction is known to increase exposure of 5-FU following S-1 administration, the incidence of severe adverse reactions is increased in patients with impaired renal function. However, no reliable information on its dose modification for patients with renal dysfunction has been provided. Methods: We conducted a prospective pharmacokinetic study to develop an S-1 dosage formula based on renal function. Sixteen cancer patients with various degrees of renal function received a single dose of S-1 at 40 mg/m. A series of blood samples were collected at predefined times within 24 h to assess the plasma concentration profiles of 5-FU, 5-chloro-2,4-dihydroxypyridine, and tegafur. A mathematical model for the relationship between renal function and exposure of 5-FU was constructed by a population pharmacokinetic analysis. Results: The clearance of 5-FU following S-1 administration was related to body surface area and creatinine clearance in the range 15.9-108.8 mL/min as estimated by the Cockcroft-Gault equation. The S-1 dosage formula was derived as follows:where AUC is the area under the concentration-time curve, CLcr is creatinine clearance, and BSA is body surface area. The recommended daily doses of S-1 in Asia and Europe were also proposed as nomograms according to exposure matching to the previously reported area under the concentration-time curve of 5-FU, which confirmed the efficacy and toxicity in pivotal registration studies. Conclusions: We have developed a novel formula for determining the S-1 dosage on the basis of renal function. Further validation is needed to confirm the formula for practical application. [ABSTRACT FROM AUTHOR]

Background: Although colorectal mucinous adenocarcinomas (MCs) are conventionally regarded as exhibiting high-grade differentiation, they can be divided by differentiation into 2 groups according to the glandular appearance: low-grade mucinous adenocarcinoma (low-MC) and high-grade mucinous adenocarcinoma (high-MC). Methods: Patients with colorectal cancer (CRC) who underwent surgical resection between 2000 and 2012 were enrolled in this study. Among the cases with MC, the clinicopathological and genetic differences between low-MC and high-MC were investigated with next-generation sequencing. Results: A total of 1373 patients with CRC were analyzed. Forty patients (2.9%) had MC, and 13 patients had high-MC. Patients with MC had significantly shorter disease-free survival (DFS) and overall survival (OS) periods than those with nonmucinous carcinoma. When low-MC patients and high-MC patients were compared, those with high-MC had significantly shorter DFS and OS periods than those with low-MC. Multivariate analyses revealed that high-MC was significantly associated with both shorter DFS and shorter OS, but low-MC was not. A genome analysis revealed that low-MC had a considerably larger number of mutations than high-MC, and Kirsten rat sarcoma viral oncogene homolog (KRAS) mutations and adenomatous polyposis coli mutations were particularly frequently found in low-MC. In contrast, SMAD family member 4 (SMAD4) mutations were frequently found in high-MC. Conclusions: High-MC is an independent prognostic factor in CRC (but low-MC is not), and it is genetically different from other CRCs, including low-MC. Both the clinicopathological differences and the genetic differences suggest that low-MC and high-MC should be distinguished in clinical settings. [ABSTRACT FROM AUTHOR]

Background Recent studies have shown that proton pump inhibitor (PPI) negatively impacts on the clinical benefit from ICIs. Gut microbiome modulated by PPI may contribute to decreased efficacy. It has been also reported that H2 blocker (H2B) or gastrectomy affected gut microbiome. We assessed in this study the association of GAS including PPI, H2B and gastrectomy with clinical outcome from ICI. Methods We retrospectively investigated advanced cancers pts treated with ICIs as the 1st- to the 3rd-line treatment at our institution between July 2014 and September 2018. GAS was defined as using PPI or H2B within 30 days before start of ICI, or having past history of gastrectomy. Response to ICIs was assessed by RECIST v1.1. Performance status (PS), body mass index, antibiotics, steroid, LDH level, albumin level, CPR and neutrophil-lymphocyte ratio (NLR) were compared between the GAS and non-GAS arms. Associations of nominal variables with the response were evaluated. Results Total of 115 pts (lung 69.9%, skin 11.3%, head and neck 7.8%, renal cell 6.9%, stomach 4.2%, and urothelium 2.5%) were evaluated. The types of ICIs were nivolumab of 72.2%, pembrolizumab of 22.6%, and atezolizumab of 5.2%. Sixty of 115 pts recieved GAS (PPI 83.3%, H2B 11.6%, and gastorectomy 5%) before start of ICI. Patients' characteristics between the GAS and non-GAS arms was almost well balanced. However, pts with lower PS (>2) or high NLR were more frequently observed in the GAS arm (20% vs. 0%, 40% vs. 16%, respectively). The response rate (RR) was almost significantly lower in the GAS arm than the non-GAS arm (12% vs. 25%, P = 0.055). GAS did not remain statistically significant in a multivariate analysis (P = 0.091), while LDH was significant in both uni- and multivariate analyses. Conclusion Pts with GAS and pts without GAS have different patients' background such as PS and NLR, and the RR in pts with GAS was numerically lower compared to that without GAS in advanced cancer treated with ICI. [ABSTRACT FROM AUTHOR]

Recent studies have shown that proton pump inhibitor (PPI) negatively impacts on the clinical benefit from ICIs. Gut microbiome modulated by PPI may contribute to decreased efficacy. It has been also reported that H2 blocker (H2B) or gastrectomy affected gut microbiome. We assessed in this study the association of GAS including PPI, H2B and gastrectomy with clinical outcome from ICI. We retrospectively investigated advanced cancers pts treated with ICIs as the 1st- to the 3rd-line treatment at our institution between July 2014 and September 2018. GAS was defined as using PPI or H2B within 30 days before start of ICI, or having past history of gastrectomy. Response to ICIs was assessed by RECIST v1.1. Performance status (PS), body mass index, antibiotics, steroid, LDH level, albumin level, CPR and neutrophil-lymphocyte ratio (NLR) were compared between the GAS and non-GAS arms. Associations of nominal variables with the response were evaluated. Total of 115 pts (lung 69.9%, skin 11.3%, head and neck 7.8%, renal cell 6.9%, stomach 4.2%, and urothelium 2.5%) were evaluated. The types of ICIs were nivolumab of 72.2%, pembrolizumab of 22.6%, and atezolizumab of 5.2%. Sixty of 115 pts recieved GAS (PPI 83.3%, H2B 11.6%, and gastorectomy 5%) before start of ICI. Patients' characteristics between the GAS and non-GAS arms was almost well balanced. However, pts with lower PS (>2) or high NLR were more frequently observed in the GAS arm (20% vs. 0%, 40% vs. 16%, respectively). The response rate (RR) was almost significantly lower in the GAS arm than the non-GAS arm (12% vs. 25%, P = 0.055). GAS did not remain statistically significant in a multivariate analysis (P = 0.091), while LDH was significant in both uni- and multivariate analyses. Pts with GAS and pts without GAS have different patients' background such as PS and NLR, and the RR in pts with GAS was numerically lower compared to that without GAS in advanced cancer treated with ICI. [ABSTRACT FROM AUTHOR]