The performance of metabolomics-based prediction scores for mortality in older patients with solid tumors.

Prognostic information is needed to balance benefits and risks of cancer treatment in older patients. Metabolomics-based scores were previously developed to predict 5- and 10-year mortality (MetaboHealth) and biological age (MetaboAge). This study aims to investigate the association of MetaboHealth and MetaboAge with 1-year mortality in older patients with solid tumors, and to study their predictive value for mortality in addition to established clinical predictors. This prospective cohort study included patients aged ≥ 70 years with a solid malignant tumor, who underwent blood sampling and a geriatric assessment before treatment initiation. The outcome was all-cause 1-year mortality. Of the 192 patients, the median age was 77 years. With each SD increase of MetaboHealth, patients had a 2.32 times increased risk of mortality (HR 2.32, 95% CI 1.59-3.39). With each year increase in MetaboAge, there was a 4% increased risk of mortality (HR 1.04, 1.01-1.07). MetaboHealth and MetaboAge showed an AUC of 0.66 (0.56-0.75) and 0.60 (0.51-0.68) for mortality prediction accuracy, respectively. The AUC of a predictive model containing age, primary tumor site, distant metastasis, comorbidity, and malnutrition was 0.76 (0.68-0.83). Addition of MetaboHealth increased AUC to 0.80 (0.74-0.87) (p = 0.09) and AUC did not change with MetaboAge (0.76 (0.69-0.83) (p = 0.89)). Higher MetaboHealth and MetaboAge scores were associated with 1-year mortality. The addition of MetaboHealth to established clinical predictors only marginally improved mortality prediction in this cohort with various types of tumors. MetaboHealth may potentially improve identification of older patients vulnerable for adverse events, but numbers were too small for definitive conclusions. The TENT study is retrospectively registered at the Netherlands Trial Register (NTR), trial number NL8107. Date of registration: 22-10-2019.

Toxicity in Older Patients with Cancer Receiving Immunotherapy: An Observational Study.

BACKGROUND: Checkpoint inhibition has emerged as an effective treatment strategy for a variety of cancers, including in older adults. However, older patients with cancer represent a heterogenous group as they can vary widely in frailty, cognition, and physical status. OBJECTIVE: This study aims to investigate the association between clinical frailty and immune-related treatment toxicity, hospitalization, and treatment discontinuation due to immune-related treatment toxicity in older patients treated with checkpoint inhibitors. METHODS: Patients aged 70 years and older treated with checkpoint inhibitors were selected from the TENT study, IMAGINE study, and "Tolerability and safety of immunotherapy study". Clinical frailty was assessed by the Geriatric-8 test score and World Health Organization (WHO) status. Outcomes were grades 3-5 toxicity, hospitalization, and treatment discontinuation due to toxicity during treatment. RESULTS: Of 99 patients included, 22% had comorbidities. While 33% of the patients were considered frail based on an abnormal Geriatric-8 test score of < 15, physical impairments were considered absent in 51% (WHO score of 0) and mild in 40% (WHO score of 1). Despite the limited sample size of the cohort, consistent trends were observed with patients with an abnormal Geriatric-8 test score of < 15 or a higher WHO score of 1 for having higher odds of toxicity [odds ratio (OR) 2.32 (95% CI 0.41-13.02); OR 1.33 (95% CI 0.45-4.17)], treatment discontinuation due to immune-related treatment toxicity [OR 2.25 (95% CI 0.61-8.31); OR 2.18 (95% CI 0.7-6.73)], and hospitalization due to immune-related treatment toxicity [OR 3.72 (95% CI 0.39-35.4); OR 1.31 (95% CI 0.35-4.9)]. Moreover, in a sub-analysis, we observed that the treatment discontinuation due to immune-related treatment toxicity occurred often in patients with grade 1-2 toxicity as well. CONCLUSIONS: Although not statistically significant, in older patients treated with immunotherapy in a real-life population with cancer, we observed consistent trends towards increased toxicity, hospitalization, and treatment discontinuation with increasing frailty. Larger studies are needed to confirm these exploratory results. Moreover, older patients with a lower toxicity grade 1-2 experienced early treatment discontinuation frequently, suggesting a lower tolerance of toxicity.

Chemotherapy-Related Toxic Effects and Quality of Life and Physical Functioning in Older Patients.

Importance: Although older patients are at increased risk of developing grade 3 or higher chemotherapy-related toxic effects, no studies, to our knowledge, have focused on the association between toxic effects and quality of life (QOL) and physical functioning. Objective: To investigate the association between grade 3 or higher chemotherapy-related toxic effects and QOL and physical functioning over time in older patients. Design, Setting, and Participants: In this prospective, multicenter cohort study, patients aged 70 years or older who were scheduled to receive chemotherapy with curative or palliative intent and a geriatric assessment were included. Patients were treated with chemotherapy between December 2015 and December 2021. Quality of life and physical functioning were analyzed at baseline and after 6 months and 12 months. Exposures: Common Terminology Criteria for Adverse Events grade 3 or higher chemotherapy-related toxic effects. Main Outcomes and Measures: The main outcome was a composite end point, defined as a decline in QOL and/or physical functioning or mortality at 6 months and 12 months after chemotherapy initiation. Associations between toxic effects and the composite end point were analyzed with multivariable logistic regression models. Results: Of the 276 patients, the median age was 74 years (IQR, 72-77 years), 177 (64%) were male, 196 (71%) received chemotherapy with curative intent, and 157 (57%) had gastrointestinal cancers. Among the total patients, 145 (53%) had deficits in 2 or more of the 4 domains of the geriatric assessment and were classified as frail. Grade 3 or higher toxic effects were observed in 94 patients (65%) with frailty and 66 (50%) of those without frailty (P = .01). Decline in QOL and/or physical functioning or death was observed in 76% of patients with frailty and in 64% to 68% of those without frailty. Among patients with frailty, grade 3 or higher toxic effects were associated with the composite end point at 6 months (odds ratio [OR], 2.62; 95% CI, 1.14-6.05) but not at 12 months (OR, 1.09; 95% CI, 0.45-2.64) and were associated with mortality at 12 months (OR, 3.54; 95% CI, 1.50-8.33). Toxic effects were not associated with the composite end point in patients without frailty (6 months: OR, 0.76; 95% CI, 0.36-1.64; 12 months: OR, 1.06; 95% CI, 0.46-2.43). Conclusions and Relevance: In this prospective cohort study of 276 patients aged 70 or older who were treated with chemotherapy, patients with frailty had more grade 3 or higher toxic effects than those without frailty, and the occurrence of toxic effects was associated with a decline in QOL and/or physical functioning or mortality after 1 year. Toxic effects were not associated with poor outcomes in patients without frailty. Pretreatment frailty screening and individualized treatment adaptions could prevent a treatment-related decline of remaining health.

Design and rationale of a routine clinical care pathway and prospective cohort study in older patients needing intensive treatment.

BACKGROUND: Treatment decisions concerning older patients can be very challenging and individualised treatment plans are often required in this very heterogeneous group. In 2015 we have implemented a routine clinical care pathway for older patients in need of intensive treatment, including a comprehensive geriatric assessment (CGA) that was used to support clinical decision making. An ongoing prospective cohort study, the Triaging Elderly Needing Treatment (TENT) study, has also been initiated in 2016 for participants in this clinical care pathway, to study associations between geriatric characteristics and outcomes of treatment that are relevant to older patients. The aim of this paper is to describe the implementation and rationale of the routine clinical care pathway and design of the TENT study. METHODS: A routine clinical care pathway has been designed and implemented in multiple hospitals in the Netherlands. Patients aged ≥70 years who are candidates for intensive treatments, such as chemotherapy, (chemo-)radiation therapy or major surgery, undergo frailty screening based on the Geriatric 8 (G-8) questionnaire and the Six-Item Cognitive Impairment Test (6CIT). If screening reveals potential frailty, a CGA is performed. All patients are invited to participate in the TENT study. Clinical data and blood samples for biomarker studies are collected at baseline. During follow-up, information about treatment complications, hospitalisations, functional decline, quality of life and mortality is collected. The primary outcome is the composite endpoint of functional decline or mortality at 1 year. DISCUSSION: Implementation of a routine clinical care pathway for older patients in need of intensive treatment provides the opportunity to study associations between determinants of frailty and outcomes of treatment. Results of the TENT study will support individualised treatment for future patients. TRIAL REGISTRATION: The study is retrospectively registered at the Netherlands Trial Register (NTR), trial number NL8107 . Date of registration: 22-10-2019.