Longitudinal Geriatric Vulnerability, Chemotherapy Toxicity, and Functional Outcomes in Older Adults With Gastrointestinal Cancer

The association between geriatric vulnerability and sarcopenia-related functional impairment will be assessed using G8, VES-13, and the Strength, Assistance with Walking, Rise from a Chair, Climb Stairs, and Falls (SARC-F) questionnaire. SARC-F evaluates five domains of physical function, each scored from 0 to 2, yielding a total score ranging from 0 to 10. Higher scores indicate greater difficulty with physical activities and greater sarcopenia-related vulnerability; a score ≥4 is considered a positive screening result. G8 scores range from 0 to 17, with lower scores indicating greater vulnerability, while VES-13 scores range from 0 to 10, with higher scores indicating greater vulnerability. Associations between the scores will be summarized using correlation coefficients at baseline, month 3, and month 6.

The relationship between geriatric vulnerability and nutritional status will be evaluated using G8, VES-13, and the Mini Nutritional Assessment-Short Form (MNA-SF). The MNA-SF is a six-item nutritional screening instrument with a total score ranging from 0 to 14. Scores of 12-14 indicate normal nutritional status, 8-11 indicate risk of malnutrition, and 0-7 indicate malnutrition. Lower MNA-SF scores represent poorer nutritional status. G8 scores range from 0 to 17 and decrease with increasing vulnerability, whereas VES-13 scores range from 0 to 10 and increase with increasing vulnerability. The associations between nutritional status and the two geriatric screening scores will be evaluated using correlation coefficients at each scheduled assessment.

The association between geriatric vulnerability and independence in basic daily activities will be assessed using G8, VES-13, and the Katz Index of Activities of Daily Living (ADL). Katz ADL evaluates six basic functional domains: bathing, dressing, toileting, transferring, continence, and feeding. Each domain is scored according to independence or dependence, yielding a total score ranging from 0 to 6. Higher scores indicate greater functional independence; a score of 6 represents independence in all six activities, while lower scores indicate increasing dependence. G8 and VES-13 scores will be examined in relation to Katz ADL scores at baseline, month 3, and month 6. Associations will be reported using correlation coefficients calculated from available paired assessments.

The association between geriatric vulnerability and independence in instrumental daily activities will be evaluated using the G8 and VES-13 screening tools and the Lawton-Brody Instrumental Activities of Daily Living (IADL) scale. The study uses the eight-domain IADL scoring version, assessing activities such as using the telephone, shopping, food preparation, housekeeping, laundry, transportation, medication management, and financial management. Total scores range from 0 to 8, with higher scores indicating greater independence and lower scores indicating greater assistance requirements. G8 scores decrease and VES-13 scores increase with worsening vulnerability. Relationships between the geriatric screening instruments and IADL scores will be quantified using correlation coefficients at the scheduled assessments.

The association between geriatric vulnerability and clinical performance status will be assessed using G8, VES-13, and the Eastern Cooperative Oncology Group (ECOG) performance status scale. ECOG performance status ranges from 0 to 5, where 0 indicates full activity without restriction, 1 indicates restriction in strenuous activity, 2 indicates ambulatory status with preserved self-care but inability to work, 3 indicates limited self-care and confinement to bed or chair for more than half of waking hours, 4 indicates complete disability, and 5 indicates death. Performance status correlations will be assessed among living participants using available scores. Higher ECOG scores reflect worse performance status, whereas lower G8 scores and higher VES-13 scores indicate greater geriatric vulnerability. Associations will be summarized using correlation coefficients.

Overall survival (OS) will be defined as the time from initiation of systemic chemotherapy to death from any cause, regardless of disease status or treatment attribution. Survival time will be measured in months. Participants who remain alive will be censored on the most recent date they are documented to be alive, or at the administrative data cutoff if earlier. The primary summary will be the Kaplan-Meier estimated probability of remaining alive at 12 months, expressed as a percentage with a corresponding 95% confidence interval. The number of deaths, available follow-up duration, and number of participants remaining at risk at 12 months will also be reported. Participants with less than 12 months of follow-up will contribute their observed time and will not automatically be classified as survivors at 12 months.

Progression-free survival (PFS) will be defined as the time from initiation of systemic chemotherapy to the first documented disease progression, recurrence after curative-intent treatment, or death from any cause, whichever occurs first. Disease progression or recurrence will be identified from available clinical and radiological assessments. Survival time will be measured in months. Participants without a qualifying event will be censored at the date of their last adequate disease assessment, subject to the administrative data cutoff. The outcome will be summarized using the Kaplan-Meier estimated probability of remaining free from progression, recurrence, or death at 12 months, with a corresponding 95% confidence interval. Event counts and the number of participants at risk at 12 months will be reported.

The incidence of severe chemotherapy-related toxicity will be assessed as the proportion of participants experiencing at least one adverse event classified as grade 3 or higher according to the Common Terminology Criteria for Adverse Events (CTCAE), version 5.0, during the first 180 days after chemotherapy initiation. Grade 3 events indicate severe or medically significant toxicity, grade 4 events indicate life-threatening consequences, and grade 5 events indicate death related to an adverse event. For this binary endpoint, each participant will be counted once if at least one qualifying event occurs, regardless of the number of adverse-event episodes. The highest recorded CTCAE severity grade per participant and the distribution of hematological and nonhematological events may also be summarized descriptively.

The discriminative performance of four baseline risk assessment instruments will be evaluated for predicting CTCAE grade ≥3 chemotherapy-related toxicity within 180 days. G8 ranges from 0 to 17, with lower scores indicating greater vulnerability; VES-13 ranges from 0 to 10, with higher scores indicating greater vulnerability. The Cancer and Aging Research Group (CARG) chemotherapy toxicity score ranges from 0 to 19, while the combined Chemotherapy Risk Assessment Scale for High-Age Patients (CRASH) score ranges from 0 to 12, with higher scores indicating greater estimated toxicity risk. Performance will be quantified using the area under the receiver operating characteristic curve (AUC; range 0-1) for each score, with 95% confidence intervals. Comparative analyses will examine differences in discrimination between instruments.

Longitudinal geriatric vulnerability will be evaluated using repeated measurements of the Geriatric 8 (G8) and Vulnerable Elders Survey-13 (VES-13) scores at baseline, month 3, and month 6. G8 scores range from 0 to 17, with lower values indicating greater vulnerability; scores ≤14 indicate an impaired geriatric screening result. VES-13 scores range from 0 to 10, with higher scores indicating greater vulnerability; scores ≥3 indicate a positive vulnerability screen. Change will be calculated separately for each instrument as the follow-up score minus the baseline score. A negative change in G8 or a positive change in VES-13 indicates worsening vulnerability. Results will be expressed in score points, with adjusted mean changes and 95% confidence intervals where appropriate.

Functional deterioration will be defined as a reduction of at least 1 point in the Katz Index of Activities of Daily Living (ADL) score between baseline and month 6. The Katz ADL scale assesses independence in bathing, dressing, toileting, transferring, continence, and feeding. Total scores range from 0 to 6, where 6 indicates independence in all six activities and lower scores indicate increasing dependence. The endpoint will be reported as the number and proportion of participants with a documented decline of at least 1 point among those with evaluable baseline and month-6 assessments. Participants who die before month 6 will not be assigned an unobserved functional score. Missing assessments among surviving participants will be documented separately.

Longitudinal changes in nutritional status and sarcopenia-related vulnerability will be evaluated separately using the Mini Nutritional Assessment-Short Form (MNA-SF) and SARC-F questionnaire. MNA-SF scores range from 0 to 14, with 12-14 indicating normal nutrition, 8-11 indicating risk of malnutrition, and 0-7 indicating malnutrition. Lower scores indicate poorer nutritional status. SARC-F scores range from 0 to 10 and assess difficulties with strength, walking assistance, rising from a chair, climbing stairs, and falls. Higher SARC-F scores indicate greater sarcopenia-related vulnerability, with ≥4 considered a positive screening result. Changes will be calculated as follow-up minus baseline score for each instrument and reported separately in score points, with corresponding confidence intervals.

Quality of life will be assessed longitudinally using the Older People's Quality of Life Brief Questionnaire (OPQOL-Brief), a 13-item measure addressing aspects of well-being and quality of life relevant to older adults. Each item is scored using a five-point response scale, resulting in a total score ranging from 13 to 65. Higher scores indicate better perceived quality of life, whereas lower scores indicate poorer perceived quality of life. Assessments will be performed before chemotherapy initiation and approximately 3 and 6 months later. Changes will be calculated as the follow-up score minus the baseline score. Results will be reported as mean score changes, with 95% confidence intervals, accounting for repeated observations where appropriate. Missing assessments after death will not be imputed.

Disease-free survival (DFS) will be evaluated among participants receiving adjuvant chemotherapy following curative-intent surgery, provided that absence of residual or recurrent disease is documented at the start of adjuvant treatment. DFS will be defined as the interval from adjuvant chemotherapy initiation to the first documented cancer recurrence or death from any cause, whichever occurs first. Participants without a qualifying event will be censored at the last adequate disease assessment, subject to the administrative cutoff. The Kaplan-Meier estimated probability of remaining alive and disease-free at 12 months will be reported as a percentage with a corresponding 95% confidence interval. Participants receiving neoadjuvant treatment will not be included in this postoperative disease-free analysis.

A composite outcome will be used to characterize survival and functional independence over the 180-day observation period. The composite endpoint will be defined as either death from any cause during follow-up or a decline of at least 1 point in Katz Activities of Daily Living (ADL) score from baseline to month 6. Katz ADL scores range from 0 to 6, with higher scores indicating greater independence. A participant experiencing either component will be classified as having a composite event and will be counted once. Death will be considered an event regardless of whether a subsequent functional assessment is available. Surviving participants without a month-6 Katz ADL assessment will have an indeterminate composite outcome unless addressed using an explicitly defined missing-data sensitivity analysis.