Chemotherapy For Gastrointestinal Cancer Research Articles

Could Sarcopenia Be Related to Chemotherapy in Gastrointestinal Cancer? A Cross-Sectional Study Including Comprehensive Geriatric Assessment

Background: Sarcopenia, which is characterized by the progressive loss of skeletal muscle mass, strength, and functionality, adversely affects cancer outcomes. This study aims to evaluate the development and progression of sarcopenia in patients with gastrointestinal cancer undergoing chemotherapy and its impact on comprehensive geriatric assessment outcomes in older participants. Methods: This cross-sectional study included 351 gastrointestinal cancer patients from October 2018 to December 2019. Pre- and post-chemotherapy measurements were taken for 243 participants. Sarcopenia was assessed using EWGSOP-2 criteria, including muscle mass, strength, and performance evaluations. A comprehensive geriatric assessment was conducted for patients aged 65 years and older. Results: The median age of participants was 57.84 years, with 31.7% being female and 29.2% being aged 65 years or older. A significant increase in the prevalence of sarcopenia post-chemotherapy was observed. The factors significantly associated with sarcopenia included low hand grip strength (−0.264; p < 0.001) and slow gait speed (0.222; p = 0.007). The muscle mass and albumin levels of older patients declined significantly post-treatment. Conclusions: This study highlights a strong association between chemotherapy and sarcopenia in gastrointestinal cancer patients, emphasizing the need for early detection and tailored interventions. Comprehensive geriatric assessments can provide critical insights that improve patient outcomes during chemotherapy.

Self-reported cancer-related cognitive impairment is associated with perturbed neurotransmission pathways.

Cancer-related cognitive impairment (CRCI) is reported by 45% of patients with cancer. Significant gaps in knowledge remain regarding the mechanisms that underlie CRCI. Using a data-driven approach, the study purpose was to evaluate for perturbed pathways associated with membership in the High versus the Low CRCI profiles. Patients completed the Attentional Function Index six times over two cycles of chemotherapy. Using findings from a previous latent profile analysis, subgroups of patients with high versus low levels of CRCI were evaluated (i.e., High versus Low CRCI profiles). Gene expression was quantified using either ribonucleic (RNA)-sequencing or microarray analyses and pathway impact analyses were performed. Signaling pathways were defined using the Kyoto Encyclopedia of Genes and Genomes database. A total of 508 patients had data available for analysis. Of the 261 patients in the RNA-sequencing sample, 48.7% were in the High class and 51.3% were in the Low class. Of the 247 patients the microarray sample, 46.6% were in the High class and 53.4% were in the Low class. Pathway impact analyses identified seven perturbed pathways related to neurotransmission (i.e., glutamatergic synapse, GABAergic synapse, dopaminergic synapse, serotonergic synapse, long-term depression, cholinergic synapse, retrograde endocannabinoid signaling). This study is the first to describe associations between self-reported CRCI in patients receiving chemotherapy for breast, gastrointestinal, gynecological, or lung cancer and seven neurotransmission pathways. These findings provide new insights into potential targets for mechanistically based interventions.

Trajectories of Depressive Symptoms Among Patients Undergoing Chemotherapy for Breast, Gastrointestinal, Gynecological, or Lung Cancer.

Individuals who undergo chemotherapy for cancer are at elevated risk of developing depressive symptoms, yet substantial interindividual variation exists in trajectories of these symptoms. To examine interindividual variations in trajectories of depressive symptoms during 2 cycles of chemotherapy and to evaluate associations between demographic and clinical characteristics, symptom severity scores, psychological adjustment characteristics (eg, stress and coping), and initial levels and trajectories of depressive symptoms. Patients (n = 1323) diagnosed with breast, gynecologic, lung, or gastrointestinal cancer completed the Center for Epidemiological Studies-Depression Scale 6 times, over 2 cycles of chemotherapy. At enrollment, patients provided demographic information and completed a broad range of symptom, stress, and coping measures. Hierarchical linear modeling was used to identify characteristics associated with initial levels and trajectories of depressive symptoms. Interindividual differences in initial levels of depressive symptoms were associated with marital status, functional status, level of comorbidity, chemotherapy toxicity, sleep disturbance, morning fatigue, cognitive function, global and cancer-related stress, and coping characteristics (ie, sense of coherence, venting, behavioral disengagement, and self-blame). Interindividual differences in depression trajectories were associated with education, cancer type, chemotherapy toxicity, sleep disturbance, evening energy, evening fatigue, cognitive function, global and cancer-related stress, and self-blame. We present new findings concerning the trajectories and predictors of depressive symptoms during chemotherapy. Modifiable risk factors (eg, stress and coping) are important targets for intervening to address depressive symptoms in oncology patients.

Symptom experiences and influencing factors in patients undergoing chemotherapy for gastrointestinal cancers: a qualitative study.

To explore the symptom experiences and influencing factors of gastrointestinal (GI) cancer patients on chemotherapy (CTX) in China. Semi-structured interviews were conducted with 13 GI cancer patients undergoing CTX. Following the Colaizzi 7-step analysis method, the interview data were read carefully, meaningful statements related to the research questions were extracted, coded, collected, and described in detail, and the authenticity of the theme was verified. Nine themes were grouped into two main areas including the characteristics of symptom experiences and influences on symptom experiences. The symptom experiences of patients undergoing CTX for GI cancer is poor and influenced by multiple factors. Nurses need to pay attention to the assessment and monitoring of CTX-related symptoms, improve symptom recognition, enhance doctor-patient communication and social support, explore intelligent management methods, and increase the efficiency of healthcare services to improve patients' symptom experience.

Effectiveness and tolerability of programmed cell death protein-1 inhibitor + chemotherapy compared to chemotherapy for upper gastrointestinal tract cancers.

The combination of programmed cell death protein-1 (PD-1) inhibitor and chemotherapy is approved as a standard first- or second-line treatment in patients with advanced oesophageal or gastric cancer. However, it is unclear whether this combination is superior to chemotherapy alone. To assess the comparative effectiveness and tolerability of combining PD-1 inhibitors with chemotherapy vs chemotherapy alone in patients with advanced gastric cancer, gastroesophageal junction (GEJ) cancer, or oesophageal carcinoma. We searched the PubMed and Embase databases for studies that compared the efficacy and tolerance of PD-1 inhibitors in combination with chemotherapy vs chemotherapy alone in patients with advanced oesophageal or gastric cancer. We employed either random or fixed models to analyze the outcomes of each clinical trial, encompassing data on overall survival (OS), progression-free survival (PFS), objective response rate, and adverse events (AEs). Nine phase 3 clinical trials (7016 advanced oesophageal and gastric cancer patients) met the inclusion criteria. Our meta-analysis demonstrated that the pooled PD-1 inhibitor + chemotherapy group had a significantly longer OS than the chemotherapy-alone group [hazard ratio (HR) = 0.76, 95% confidence interval (CI): 0.71-0.81]; the pooled PFS result was consistent with that of OS (HR = 0.67, 95%CI: 0.61-0.74). The count of patients achieving an objective response in the PD-1 inhibitor + chemotherapy group surpassed that of the chemotherapy-alone group [odds ratio (OR) = 1.86, 95%CI: 1.59-2.18]. AE incidence was also higher in the combination-therapy group than in the chemotherapy-alone group, regardless of whether ≥ grade 3 only (OR = 1.30, 95%CI: 1.07-1.57) or all AE grades (OR = 1.88, 95%CI: 1.39-2.54) were examined. We performed a subgroup analysis based on the programmed death-ligand 1 (PD-L1) combined positive score (CPS) and noted extended OS and PFS durations within the CPS ≥ 1, CPS ≥ 5, and CPS ≥ 10 subgroups of the PD-1 inhibitor + chemotherapy group. In contrast to chemotherapy alone, the combination of PD-1 inhibitor and chemotherapy appears to present a more favorable option for initial or subsequent treatment in patients with gastric cancer, GEJ tumor, or oesophageal cancer. This holds true particularly for individuals with PD-L1 CPS scores of ≥ 5 and ≥ 10.

Are measures and related symptoms of cachexia recorded as outcomes in gastrointestinal cancer chemotherapy clinical trials?

Cachexia is prevalent in gastrointestinal cancers and worsens patient outcomes and chemotherapy compliance. We examined to what extent registered gastrointestinal cancer chemotherapy clinical trials record measures and related symptoms of cachexia as outcomes, and whether these were associated with trial characteristics. Four public trial registries (2012-2022) were accessed for Phase II and/or III randomized controlled pancreatic, gastric, and colorectal cancer chemotherapy trial protocols. Trial outcome measures of overall survival and toxicity/side effects, and those related to cachexia [physical activity, weight/body mass index (BMI), dietary limitations, caloric intake, lean muscle mass] and symptoms (appetite loss, diarrhoea, pain, fatigue/insomnia, constipation, nausea, vomiting, and oral mucositis) were extracted, along with the number and types of performance status and patient-reported outcomes (PROs) tools. Data were summarized descriptively. Chi-square tests examined associations between outcomes and trial characteristics (cancer type, trial location, funding source, PROs tools, and commencement year). Statistical significance was set at P<0.05. We included 540 trial protocols (pancreatic (35.2%), colorectal (33.3%) and gastric (31.5%)), with most trials from Europe (44.1%). Trial lead investigator was from academia (28.3%), industry (27.6%) and government (26.3%). Allied health professional involvement (26.9%) occurred at eligibility. Adjuvant therapy in trials was mainly treatment-related (68.1%). Additional medication included anti-nausea (2.2%) and analgesia (0.9%). Trial protocols mostly recorded overall survival (90.4%) and toxicity (78.9%), and the symptoms appetite loss (26.1%) and diarrhoea (19.1%), with the other symptoms recorded in <10% of the trials. Reporting of physical activity (P=0.001), dietary limitations (P=0.002), lean muscle mass (P=0.027), appetite loss (P<0.001), pain (P=0.001), nausea (P=0.012), and oral mucositis (P=0.049) varied depending cancer type. Toxicity/side effects (P=0.022), physical activity (P<0.001), appetite loss, nausea, and vomiting (all P<0.001), diarrhoea (P=0.010), pain (P=0.001), fatigue/insomnia (P=0.001) varied depending on the trial location. Trial funding was predominantly from private/industry (34.3%) and influenced the reporting of overall survival (P=0.049), weight/BMI (P=0.005), caloric intake (P=0.015), and pain (P=0.031). Performance status and PROs tools were mentioned in 91.2% and 46.3% of the trials, respectively. Trials that incorporated PROs tools were more likely to report cachexia related outcomes, except for overall survival, lean muscle mass, and oral mucositis. The proportion of trials measuring weight/BMI increased with trial commencement year (P=0.04). Cachexia-related outcomes were under-recorded in gastrointestinal cancer chemotherapy trials. As trial patients experience a high symptom burden, cachexia-relevant measures and symptoms should be assessed throughout the trial, and integrated with primary endpoints to support their progress.

Study of prevalence and risk factors of chemotherapy-induced mucositis in gastrointestinal cancer using machine learning models.

Chemotherapy-induced mucositis (CIM) significantly impacts clinical outcomes and diminishes the quality of life in patients with gastrointestinal cancer. This study aims to prospectively determine the incidence, severity, and underlying risk factors associated with CIM in this patient population. To achieve this objective, we introduce a novel Machine Learning-based Toxicity Prediction Model (ML-TPM) designed to analyze the risk factors contributing to CIM development in gastrointestinal cancer patients. Within the winter season spanning from December 15th, 2018 to January 14th, 2019, we conducted in-person interviews with patients undergoing chemotherapy for gastrointestinal cancer. These interviews encompassed comprehensive questionnaires pertaining to patient demographics, CIM incidence, severity, and any supplementary prophylactic measures employed. The study encompassed a cohort of 447 participating patients who provided complete questionnaire responses (100%). Of these, 328 patients (73.4%) reported experiencing CIM during the course of their treatment. Notably, CIM-induced complications led to treatment discontinuation in 14 patients (3%). The most frequently encountered CIM symptoms were diarrhea (41.6%), followed by nausea (37.8%), vomiting (25.1%), abdominal pain (21%), gastritis (10.5%), and oral pain (10.3%). Supplementary prophylaxis was administered to approximately 62% of the patients. The analysis revealed significant correlations between the overall incidence of CIM and gender (p=0.015), number of chemotherapy cycles exceeding one (p=0.039), utilization of platinum-based regimens (p=0.039), and administration of irinotecan (p=0.003). Specifically, the incidence of diarrhea exhibited positive correlations with prior surgical history (p=0.037), irinotecan treatment (p=0.021), and probiotics usage (p=0.035). Conversely, diarrhea incidence demonstrated an adverse correlation with platinum-based treatment (p=0.026). In conclusion, this study demonstrates the successful implementation of the ML-TPM model for automating toxicity prediction with accuracy comparable to conventional physical analyses. Our findings provide valuable insights into the identification of CIM risk factors among gastrointestinal cancer patients undergoing chemotherapy. Furthermore, the results underscore the potential of machine learning in enhancing our understanding of chemotherapy-induced mucositis and advancing personalized patient care strategies.

Evaluation of clinical effects of a multidisciplinary-collaborated cancer support team for gastrointestinal cancer chemotherapy: prospective observational study protocol of M-CAST study

BackgroundAlthough the multidisciplinary-collaborated team approach in cancer treatment has recently become popular, prospectively evaluated evidence is limited. We started a multidisciplinary-collaborated cancer support team (MCST) to facilitate cooperation across multidisciplinary medical staff in our hospital and established clinical evidence of supportive care. This study aimed to prospectively evaluate the clinical activity and effect of MCST in patients with gastrointestinal cancer receiving chemotherapy.MethodsThis is a single-center, single-arm, observational study. Patients with gastrointestinal cancer scheduled to receive chemotherapy are enrolled and supported by the MCST. The primary endpoints are the number of interventions by medical staff and the number of patients who showed improvement in side effects. The secondary endpoints are the severity of side effects, medical expenses, number of consultations, the acceptance rate of prescription recommendations, adjuvant chemotherapy completion rates, dose intensity, and time required for co-medical intervention. In addition, medical staff and attending physicians evaluate all adverse events.DiscussionThis study is expected to contribute to establishing new cancer-supportive care teams for patients with gastrointestinal cancer receiving chemotherapy and those with cancer receiving chemotherapy.Trial registrationThis trial was registered in the Japan Registry of Clinical Trials (jRCT) as jRCT1030220495.The date of first registration, 29/11/2022, https://jrct.niph.go.jp/search

CT-determined sarcopenia is associated with neutropenia in patients undergoing hyperthermic intraperitoneal chemotherapy for gastrointestinal cancer

BackgroundWith better patient selection and the increasing experience in patients undergoing hyperthermic intraperitoneal chemotherapy (HIPEC) combined surgery, the rate of severe postoperative complications and mortality decreased significantly. However, leukopenia and neutropenia were still a particular concern, and their relation to sarcopenia was not clarified.MethodsData of consecutive patients who underwent HIPEC for gastrointestinal cancer were collected and analyzed retrospectively between September 2020 and August 2022. Sarcopenia was assessed using psoas muscle index (PMI) at the L3 level on preoperative computed tomography (CT).ResultsAmong 103 patients enrolled, 37 (35.9%) were classified as sarcopenic. Most leukopenia and neutropenia occurred during the hospital leaving period after HIPEC and surgery. Before the first time of postoperative chemotherapy, the blood tests revealed 11 (29.73%) and 6 (9.09%) patients were diagnosed with neutropenia in sarcopenia and no sarcopenia groups, respectively. Logistic regression analysis revealed sarcopenia was independently associated with the increased risk of neutropenia (OR 5.58, 95% CI 1.70–18.29, p = 0.005). An incremental albumin level was protective against the occurrence of leukopenia and neutropenia.ConclusionsSarcopenia and low albumin level were significantly associated with an increased rate of delayed neutropenia after HIPEC in that disease setting and could be the preoperative risk predictors.

Preventing adverse events of chemotherapy for gastrointestinal cancer by educating patients about the nocebo effect: a randomized-controlled trial

BackgroundAdverse events of chemotherapy may be caused by pharmacodynamics or psychological factors such as negative expectations, which constitute nocebo effects. In a randomized controlled trial, we examined whether educating patients about the nocebo effect is efficacious in reducing the intensity of self-reported adverse events.MethodsIn this proof-of-concept study, N = 100 outpatients (mean age: 60.2 years, 65% male, 54% UICC tumour stage IV) starting first-line, de novo chemotherapy for gastrointestinal cancers were randomized 1:1 to a nocebo education (n = 49) or an attention control group (n = 51). Our primary outcome was patient-rated intensity of four chemotherapy-specific and three non-specific adverse events (rated on 11-point Likert scales) at 10-days and 12-weeks after the first course of chemotherapy. Secondary outcomes included perceived control of adverse events and tendency to misattribute symptoms.ResultsGeneral linear models indicated that intensity of adverse events differed at 12-weeks after the first course of chemotherapy (mean difference: 4.04, 95% CI [0.72, 7.36], p = .02, d = 0.48), with lower levels in the nocebo education group. This was attributable to less non-specific adverse events (mean difference: 0.39, 95% CI [0.04, 0.73], p = .03, d = 0.44) and a trend towards less specific adverse events in the nocebo education group (mean difference: 0.36, 95% CI [− 0.02, 0.74], p = .07, d = 0.37). We found no difference in adverse events at 10-days follow-up, perceived control of adverse events, or tendency to misattribute non-specific symptoms to the chemotherapy.ConclusionsThis study provides first proof-of-concept evidence for the efficacy of a brief information session in preventing adverse events of chemotherapy. However, results regarding patient-reported outcomes cannot rule out response biases. Informing patients about the nocebo effect may be an innovative and clinically feasible intervention for reducing the burden of adverse events.Trial registrationRetrospectively registered on March 27, 2018 to the German Clinical Trial Register (ID: DRKS00009501).

440TiP TRESBIEN (OGSG 2101): Encorafenib, binimetinib and cetuximab for early relapse stage II/III BRAF V600E-mutated CRC

The BRAF V600E mutation accounts for approximately 5% of colorectal cancer (CRC) cases and is an extremely poor prognostic factor. There are no clear recommendations for patients with early recurrent BRAF V600E-mutated CRC, during or after adjuvant chemotherapy. Recently, triplet therapy of encorafenib, binimetinib, and cetuximab, resulted in significantly longer overall survival and a higher response rate than standard chemotherapy in patients with previously treated metastatic CRC with the BRAF V600E mutation (Kopetz S, N Engl J Med. 2019.). Furthermore, in first-line treatment for BRAF V600E-mutated CRC, triplet therapy showed a promising response rate and disease control rate (Cutsem EV, Ann Oncol. 2021). These results suggest that triplet therapy may be effective even in early recurrent BRAF V600E-mutated CRC during or after adjuvant chemotherapy. The TRESBIEN study is an open-label, multicenter, single-arm phase II study designed to evaluate whether encorafenib, binimetinib, and cetuximab are effective for patients with early recurrent BRAF V600E-mutated CRC during or after adjuvant chemotherapy (jRCTs051210152). The main inclusion criteria were BRAF V600E- mutated stage II/III colorectal adenocarcinoma after radical resection, recurrence during or within six months of adjuvant chemotherapy with measurable lesions, no prior treatment with encorafenib, binimetinib, or cetuximab, age ≥ 20 years, ECOG PS 0 to 2, with adequate organ function. Patients will receive encorafenib, binimetinib, and cetuximab. The primary endpoint was objective response rate. To achieve 90% power to show a significant response benefit with a one-sided alpha level of 0.05, assuming a threshold objective response rate of 6.0% and an expected value of at least 26.0%, we estimated that 25 patients were required. The secondary endpoints included overall survival, progression-free survival, disease control rate, duration of response, time to treatment failure, and safety. This is the first study to investigate whether triplet therapy combined with encorafenib, binimetinib, and cetuximab is effective for the treatment of early recurrent BRAF V600E-mutated CRC. The first patient was enrolled in January 2022. jRCTs051210152. Osaka Gastrointestinal cancer chemotherapy Study Group (OGSG).

DOWNREGULATION OF SLC-16 CAN INCREASE APOPTOSIS LEVEL IN GASTROINTESTINAL CANCER

Background: Gastrointestinal cancers constitute 35% of all cancer-related deaths and chemotherapy resistance is a major challenge for the treatment of these cancers. The SLC gene family encodes various group of membrane transmitters that play critical roles in establishing cellular homeostasis by transporting ions and different molecular groups. To date, studies have revealed the active roles of some of SLC members in chemotherapy resistance in various malignancies. However, there is no study to investigate the roles of SLC-16 gene in tumor biology. Therefore, we aimed to consider the effects of downregulation of SLC-16 in cell lines related to gastrointestinal cancers. Methods: SCL-16 expression was downregulated in SW-480, KATO-3and PANC-1 cell lines using sh-RNA transfection. RT-PCR and western blot were performed to prove downregulation of SCL-16 knockdown levels in these cell lines. Then, Oxaliplatin was treated to all cells and the effects of this drug were evaluated by cell cycle, apoptosis, and cell migration assays in downregulated SRC cells. Results: SLC-16 was found to be down-regulated after sh-RNA transfection at the mRNA and protein levels. In the downregulated group of SCL-16, it was detected that Oxaliplatin increased apoptosis and cell numbers in the G-1 of the cell cycle but had no effect on the cells’ ability to metastasize. Conclusion: SLC-16, one of the SLC families, plays critical roles in the stabilization of cancer cells, and targeting applications of this gene may be a potential way to enhance the effects of chemotherapy in gastrointestinal cancer.

Hyperlipidemia as a risk factor for Trousseau syndrome-related cerebral infarction in patients with advanced gastrointestinal cancer.

Trousseau syndrome-related cerebral infarction rarely occurs during chemotherapy in patients with gastrointestinal (GI) cancer, and its clinical features remain unclear. The present study aimed to examine the clinical features of Trousseau syndrome-related cerebral infarction developed during chemotherapy for GI cancer. The present retrospective cohort study consecutively enrolled 878 patients with unresectable GI cancer who received chemotherapy at the Multidisciplinary Treatment Cancer Center, Kurume University Hospital (Kurume, Japan) between April 2014 and March 2020. Patients with colorectal cancer (n=308) were the most common, followed by those with pancreatic (n=242), gastric (n=222) and biliary tract (n=59) cancer, neuroendocrine tumors (n=34) and duodenal cancer (n=11). Among the 878 patients, Trousseau syndrome-related cerebral infarction occurred in 8 (0.9%) patients with a median age of 70.5 years (range, 58–75 years), and 50% of the patients were male (4/8). In total, 3 patients had gastric cancer, 3 had pancreatic cancer and 2 had biliary tract cancer. A greater percentage of patients with Trousseau syndrome-related cerebral infarction had hyperlipidemia (38.0%) than those without (8.2%; P=0.005). Hyperlipidemia was a risk factor for occurrence of Trousseau syndrome-related cerebral infarction with an odds ratio of 7.009 (95% confidence interval, 1.785-27.513). Trousseau syndrome-related cerebral infarction developed during GI chemotherapy was rare and hyperlipidemia may predict its onset.

Phase I trial of CA-4948, an IRAK4 inhibitor, in combination with FOLFOX/PD-1 inhibitor +/- trastuzumab for untreated unresectable gastric and esophageal cancer.

TPS4168 Background: Activated NFκB has been linked to aggressive phenotype, poor survival outcomes and resistance to chemotherapy in multiple gastrointestinal cancers including gastroesophageal cancer (GEC). Preclinical studies established that: 1) Genotoxic stress incurred by chemotherapy induces TLR9, which signals through IRAK4 to drive pro-survival NFκB signaling; 2) The survival mechanism through IRAK4 is independent of cancer types and mutational profiles based on colorectal and pancreatic cancer models; and 3) IRAK4 inhibition reduces tumor desmoplasia and revitalizes intratumoral T cells, setting the stage for successful combination with immune checkpoint inhibitors in a highly aggressive autochthonous pancreatic cancer mouse model. These data combined provide a strong rationale to add CA-4948 to systemic therapy for multiple advanced gastrointestinal malignancies, where resistance to chemotherapy is inevitable and benefit of PD-1 inhibitors is limited to small population. CA-4948 is a novel, first-in-class reversible inhibitor of IRAK4. In a phase I trial, patients with relapsed/refractory hematologic malignancies tolerated CA-4948 monotherapy well with mild fatigue, neutropenia, and nausea as most common adverse events. Recommended phase 2 dose (RP2D) was determined as 300 mg orally twice daily. CA-4948 has not been tested in combination with cytotoxic chemotherapy or immune checkpoint inhibitors for solid tumors in clinic. We hypothesize that inhibition of IRAK4 with CA-4948 will potentiate the effect of immune checkpoint inhibitor while deepening the efficacy of cytotoxic chemotherapy in GEC. Methods: This is a phase I trial of CA-4948 in combination with FOLFOX/PD-1 inhibitor with or without trastuzumab for unresectable GEC. During Dose Escalation, we will investigate CA-4948 in combination with FOLFOX/nivolumab by BOIN algorithm evaluating 4 different dose levels. Starting dose of CA-4948 for Part A will be 200 mg twice daily. Once RP2D is determined, the study will proceed to Dose Expansion, including Cohorts A and B. Cohort A will enroll up to 12 patients with HER2 negative disease at the RP2D of CA-4948 determined at the Dose Escalation phase. Cohort B will investigate CA-4948 in combination with FOLFOX/pembrolizumab and trastuzumab. The initial 6 patients in Cohort B will be considered safety lead-in to confirm the safety and tolerability at the RP2D, followed by additional patients, up to 12 patients treated at the RP2D. The primary objective is to determine the safety and RP2D of CA-4948 in combination with FOLFOX/PD-1 inhibitor with or without trastuzumab. Secondary objectives are to determine the preliminary efficacy of the combination. Correlative studies to evaluate pharmacodynamic effects and to identify biomarkers associated with disease response are planned. Clinical trial information: NCT05187182.

A high stress profile is associated with severe pain in oncology patients receiving chemotherapy.

Oncology patients receiving chemotherapy can experience both cancer and non-cancer pain. In addition, oncology patients face numerous stressors and their responses are highly variable. Stress and pain are intricately linked. The purpose of this study was to evaluate for differences in pain characteristics and mood disturbance among oncology patients with distinct stress profiles. From a sample of 957 patients with and without pain, latent profile analysis identified three groups of patients with distinct stress profiles (i.e., Stressed, Normative, Resilient). In the subset of 671 patients with pain, receiving chemotherapy for breast, lung, gastrointestinal, or gynecologic cancer, we evaluated for differences among the stress profiles in terms of pain characteristics (e.g., intensity, qualities, interference) and mood disturbance (anxiety, depressive symptoms). Compared to Normative patients (n=333; 49.6%), Stressed patients (n=305; 45.5%) reported higher levels of pain intensity, pain interference, anxiety, and depressive symptoms and more commonly described pain as throbbing, shooting, burning, exhausting, tiring, penetrating, nagging, miserable, and unbearable. Compared to Resilient patients (n=33; 4.9%), Stressed patients reported significantly higher mood-related pain interference scores and more severe anxiety and depressive symptoms. A high stress profile is common (45.5%) and is associated with more severe pain and associated symptoms. Efforts to identify and target this group for interventions may improve patient outcomes.

Development of a physiologically based pharmacokinetic model to predict irinotecan disposition during inflammation

Irinotecan, a first-line chemotherapy for gastrointestinal (GI) cancers has been causing fatal toxicities like bloody diarrhea and steatohepatitis for years. Irinotecan goes through multiple-step drug metabolism after injection and one of its intermediates 7-ethyl-10-hydroxy-camptothecin (SN-38) is responsible for irinotecan side effect. However, it is unclear what is the disposition kinetics of SN-38 in the organs subjected to toxicity. No studies ever quantified the effect of each enzyme or transporter on SN-38 distribution. In current study, we established a new physiologically based pharmacokinetic (PBPK) model to predict the disposition kinetics of irinotecan. The PBPK model was calibrated with in-house mouse pharmacokinetic data and evaluated with external datasets from the literature. We separated the contribution of each parameters in irinotecan pharmacokinetics by calculating the normalized sensitivity coefficient (NSC). The model gave robust prediction of SN-38 distribution in GI tract, the site of injury. We identified that bile excretion and UDP-glucuronosyltransferases (UGT) played more important roles than fecal excretion and renal clearance in SN-38 pharmacokinetics. Our NSC showed that the impact of enzyme and transporter on irinotecan and SN-38 pharmacokinetics evolved when time continued. Additionally, we mapped out the effect of inflammation on irinotecan metabolic pathways with PBPK modelling. We discovered that inflammation significantly increased the blood and liver exposure of irinotecan and SN-38 in the mice receiving bacterial endotoxin. Inflammation suppressed UGT, microbial metabolism but increased fecal excretion. The present PBPK model can serve as an efficacious and versatile tool to quantitively assess the risk of irinotecan toxicity.

Impact of the Cancer and Aging Research Group score and treatment intensity on survival and toxicity outcomes in older adults with advanced noncolorectal gastrointestinal cancers.

Little is known regarding the predictive value of the Cancer and Aging Research Group (CARG) score, a validated chemotherapy toxicity prediction tool for older adults with cancer, for survival outcomes. This was a prospective observational study of patients ≥65 years old receiving first-line chemotherapy for advanced noncolorectal gastrointestinal cancer for which combination chemotherapy is the standard of care. Overall survival (OS), time to treatment failure (TTF), which was defined as the time from the start of first-line chemotherapy to the discontinuation of first-line chemotherapy for any reason, and toxicity were compared in 4 groups of patients: 1) non-high-risk (nHR) CARG score (<10) and standard-intensity therapy (ST), 2) nHR score and reduced-intensity therapy (RT), 3) high-risk (HR) CARG score (≥10) and ST, and 4) HR score and RT. Fifty patients (median age, 71 years) were enrolled. The median OS in months was 19.7 in nHR/ST (n = 19) group, 12.7 in nHR/RT (n = 9) group, 4.5 in HR/ST (n = 12) group, and 3.9 in HR/RT (n = 10) group (log-rank test, P = .005). The median TTF in months was 9.1 in nHR/ST group, 2.5 in nHR/RT group, 2.3 in HR/ST group, and 3.0 in HR/RT group (log-rank test, P = .04). The CARG-score category was prognostic of OS (HR, 3.04; 95% confidence interval [CI], 1.59-5.83, P = .001) and TTF (HR, 2.60; 95% CI, 1.31-5.20, P = .007). The incidence of grade 3-5 toxicity was 68% in nHR/ST group, 33% in nHR/RT group, 92% in HR/ST group, and 70% in HR/RT group (Fisher exact test, P = .048). Risk-adapted chemotherapy based on the CARG-score may improve treatment outcomes.

HGCSG1902: Multicenter, prospective, observational study for patients with dysgeusia caused by chemotherapy for gastrointestinal cancer.

649 Background: Dysgeusia is the one of important adverse events in patients treated with chemotherapy because it could reduce daily oral intake and worsen patient’s nutritional status. It is said that the lack of zinc is often observed in patients with chemotherapy because taste buds cells injured by chemotherapy require large amounts of zinc for their regeneration and cytotoxic agents have the possibility of working as a chelator for zinc. Some retrospective studies showed that zinc administration may improve dysgeusia in patients treated with chemotherapy, however, there is no prospective study. Therefore, we planned this study to clarify the effect of zinc therapy on dysgeusia in patients with gastrointestinal cancer. Methods: This was a multicenter, prospective observational study. From February 2020 to June 2021, patients with dysgeusia during chemotherapy for gastrointestinal cancer were enrolled from 17 institutes in Japan. The investigator selected one of the following treatment: no intervention (N), polaprezinc administration (P: contains 34.1mg of zinc par daily normal dose), or zinc acetate hydrate administration (Z: contains 50-100mg of zinc par daily normal dose). Serum zinc levels were measured at baseline, after 6 and 12 weeks, respectively. Dysgeusia was assessed by questionnaires according to four criteria, CTCAE v5.0, Subjective Total Taste Acuity (STTA), Visual Analogue Scale (VAS), and Chemotherapy-induced Taste Alteration Scale (CiTAS) at the time of enrollment and after 12 weeks. Results: A total of 180 patients, 60 in each group, were enrolled in the study. The mean serum zinc levels in each group at baseline were similar (67.3, 66.6, and 67.5μg/dl in N, P, Z group, respectively) and lower than lower limit of normal. The mean alterations of serum zinc level from baseline to after 12 weeks were -3.8, +14.3, and +46.6μg/dl in N, P, Z group, respectively. The STTA score was significantly improved in the P group compared to the N group at 12 weeks (p = 0.045), whereas it was not improved in the Z group (p = 0.945). The association between the alteration values of serum zinc level and improvement of dysgeusia was not observed. Conclusions: In this study, administration of polarezinc or zinc acetate hydrate increased serum zinc levels, but there was no significant correlation between the degree of serum zinc elevation and the improvement of dysgeusia. The STTA score was improved only in P group, thus our results suggest there are any factors for improvement of dysgeusia by polaprezinc administration other than serum zinc levels. Clinical trial information: UMIN000039653.

Incidence, severity, and onset of oral mucositis in 5-FU based chemotherapy for gastrointestinal cancer.

77 Background: 5-fluorouracil has been used in treatment of gastrointestinal cancers for more than 40 years. Numerous toxicities of 5-FU are known. Little is known about the occurrence, natural course and causes of oral mucositis (OM) of 5-FU in GI tumors. There is little data on the additional toxicity of VEGF and EGFR antibodies together with 5-FU. We followed the occurrence, severity and localization of OM of 5-FU in consecutive patients as part of their cancer treatment. The primary aim of the study was to determine the severity, course and risk factors of OM up to the first six cycles of ctx. OM was evaluated by repeated inspections of the oral cavity and patient questionnaires. Methods: Pts who received 5-FU for the first time or who had not received ctx for at least 12 months. 64 consecutive pts were included in the observational study from March 2018 to March 2019. Out of 64 pts a total of 41 (28 m/13f) had complete documentations (inspections of the oral cavity and questionnaires) and were available for the evaluation. Results: Mean age 65 ys (range 42-83), 60% were treated for CRC, 22% esophageal/gastric cancer, and 18% other GI-cancers. 13 were non-smokers, 25 former smokers; 7 pts had daily alcohol consumption while 7 pts never consumed alcohol. 10/41 pts wore a dental prosthesis. The mean BMI was 26.5 (range 18.8-41.5). Initial very good/ good oral hygiene was given in 3/20 patients. 80% of the pts developed xerostomia after the first cycle, almost every patient needed support for symptoms due to oral problems during ctx. Of 41 pts, an OM could be documented in 38 pts. A total of 93% of the patients developed a mild course of the mucositis with grade 1-2. OM developed between the 2nd and 3rd cyle in the majority of pts. At the third cyle, only 8 pts had OM of grade 0, while 23 pts had grade 1 and 9 pts were grade 2. It was of note here that of these 9 pts with grade 2, 6 had grade 0 in the 2nd cycle. During cycle 5 and 6 only seven pts had a CTC score of 0, but no pat developed a CTC 3 or 4 OM. We could not document a connection between the occurrence of oral mucositis and the oral hygiene measures used, as no severe course of OM CTC Grad 3 or 4 could be detected. We could not find any relation to the type of 5-FU therapy (doublet, triplet +/- monoclonal antibodies). Conclusions: The incidence of oral mucositis with CTC score of 1 and 2 was 93%, but serious grade 3 and 4 mucositis rates were not observed. Xerostomia was observed in 80% after the first course of treatment. Symptomatic mucositis occurs early within 4 weeks after starting chemotherapy. Local measures appear suitable for symptom control of OM.

Chemotherapy in older adults with gastrointestinal cancer:Current practices and future directions in Japan.

Chemotherapy for cancer has significantly improved owing to the increasing number of effective chemotherapeutic agents and supportive care. Recently, the number of older cancer patients has rapidly increased owing to the aging of the global population. However, in most cases, it is difficult to treat those using similar dosages or schedules as that of younger patients because older patients generally have unfavorable factors, such as decreased performance status and physical and cognitive conditions, thus increasing the incidence of complications and side effects. Chemotherapy for gastrointestinal cancers has made significant progress in recent years with the introduction of molecular-targeted agents and immunotherapy. However, clinical trials showed limited evidence regarding the efficacy of chemotherapy in older cancer patients, accounting for half of all patients, making it difficult to develop a well-established treatment strategy. This review aimed to evaluate the current state of chemotherapy for gastrointestinal cancer in older adults. Furthermore, the limitations and future perspectives were discussed. J. Med. Invest. 69 : 25-30, February, 2022.