Predicting Chemotherapy Toxicity Using FRAIL and FIND in Older Adults With Gastrointestinal Cancers

This prospective observational study evaluated the relationship between frailty and chemotherapy-related toxicity in older adults with gastrointestinal cancers. Frailty was assessed using two validated screening tools: the FRAIL scale and the FiND questionnaire. Both tools are short, patient-reported screening instruments designed to identify vulnerability, reduced physiological reserve, and early mobility limitations in older adults. Both frailty instruments (FRAIL and FiND) have validated Turkish-language versions, ensuring cultural and linguistic appropriateness for use in older adults in Turkey.

Frailty Assessment Instruments

• FRAIL Scale (Score Range: 0-5)

The FRAIL scale includes five items (Fatigue, Resistance, Ambulation, Illness, and Loss of weight).

Each item scores 1 point for "Yes" and 0 points for "No":

Fatigue: Feeling tired most or all of the time

Resistance: Difficulty climbing 10 steps

Ambulation: Difficulty walking one block

Illness: Having ≥5 chronic illnesses

Loss of Weight: Unintentional weight loss ≥5% in the past 6 months

Interpretation:

0 points: Robust

1-2 points: Pre-frail

3-5 points: Frail

• FiND Questionnaire (Score Range: 0-5)

The FiND tool distinguishes frailty from mobility disability and includes five dichotomous questions:

Mobility Items:

Inability to walk 400 meters

Inability to climb one flight of stairs

Frailty Items:

Unintentional weight loss

Persistent fatigue

Reduction in physical activity

Interpretation:

0: Normal

1-2: Mild frailty or early disability

3-5: Frailty or mobility disability

Frailty assessments were conducted at baseline, mid-treatment (~3 months), and end of treatment (~6 months). Nutritional status was assessed with the Mini Nutritional Assessment-Short Form (MNA-SF), performance status with ECOG, and comorbidity burden with the modified Charlson Comorbidity Index (mCCI).

CTCAE v5.0 Toxicity Assessment

Chemotherapy-related adverse events were systematically recorded at each treatment cycle according to the Common Terminology Criteria for Adverse Events (CTCAE) version 5.0, focusing on clinically relevant toxicities frequently observed during fluoropyrimidine-based adjuvant chemotherapy.

Hematologic Toxicities

Neutropenia

Febrile neutropenia

Anemia

Thrombocytopenia

Gastrointestinal Toxicities

Nausea / vomiting

Diarrhea

Constipation

Mucositis / stomatitis

Neurologic Toxicities

Peripheral sensory neuropathy (oxaliplatin-related)

Constitutional Toxicities

Fatigue

Weight loss

Decreased appetite

Dermatologic Toxicities

Hand-foot syndrome (capecitabine-related)

Rash

Laboratory Abnormalities

Elevated liver enzymes

Renal function changes

Toxicity Grading

Toxicities were graded on a 5-point scale:

Grade 1-2: Mild to moderate

Grade 3: Severe, medically significant

Grade 4: Life-threatening

Grade 5: Treatment-related death

The primary endpoint was the incidence of Grade ≥3 toxicity. Secondary analyses explored dose delays, treatment reductions, early discontinuation, and associations between frailty dynamics and toxicity patterns.

Study Objective and Rationale

The study aimed to determine whether short, rapid frailty screens can help predict chemotherapy tolerance in older adults. Identifying patients at higher risk of toxicity may allow clinicians to personalize treatment intensity, optimize supportive care, and avoid unnecessary harm.

This research contributes real-world evidence supporting the integration of frailty screening into routine oncology practice.

Inclusion criteria

• Age ≥65 years
• Histologically confirmed gastrointestinal (GI) malignancy, including: Colorectal adenocarcinoma (colon or rectum), Gastric adenocarcinoma, Pancreatic adenocarcinoma, Biliary tract cancer (cholangiocarcinoma, gallbladder cancer) Small intestine adenocarcinoma, Esophageal cancer (adenocarcinoma or squamous cell carcinoma)
• Completion of curative-intent surgery with a postoperative plan for adjuvant chemotherapy.
• Receipt of standard adjuvant chemotherapy, including (but not limited to): FOLFOX, CAPOX (XELOX), Capecitabine monotherapy, FOLFIRINOX (selected fit older adults only), Gemcitabine ± capecitabine
• Initiation of adjuvant chemotherapy within the study period.
• Baseline frailty assessment (FRAIL Scale and FiND questionnaire) completed before the first chemotherapy cycle.
• Ability to provide informed consent and comply with frailty and toxicity follow-up assessments.

Exclusion criteria

• Age <65 years.
• Metastatic, recurrent, or unresectable disease at the time of adjuvant treatment.
• Receiving neoadjuvant-only treatment without subsequent adjuvant chemotherapy.
• Non-adenocarcinoma GI malignancies treated with protocols outside standard adjuvant chemotherapy (e.g., GIST receiving adjuvant imatinib; neuroendocrine tumors).
• Prior chemotherapy within 12 months for another malignancy.
• Missing baseline frailty assessment (FRAIL or FiND).
• Missing toxicity follow-up after chemotherapy initiation.
• Severe cognitive impairment, advanced dementia, or psychiatric illness preventing reliable questionnaire completion.
• Concurrent participation in another interventional clinical trial that may alter chemotherapy toxicity or functional outcomes.