Geriatric Oncology multidomain intervention study to prevent Cognitive impairment among older Indian patients with cancer receiving chemotherapy: a multicentric randomised controlled trial (GOCog)

Abstract

Background

Chemotherapy-related cognitive dysfunction is a common adverse effect in older adults receiving cancer-directed therapy, impairing independence, treatment adherence, and quality of life. Evidence from India is limited, and culturally adapted interventions are lacking. We aim to assess (i) the effectiveness of a multidomain intervention (exercise and cognitive training) on cognition, function, and quality of life; (ii) the feasibility and compliance to the intervention; and (iii) exploratory imaging and biomarker correlates.

Methods

We will conduct a multicentric randomised controlled trial with two parallel arms among patients ≥ 60 years planned for systemic chemotherapy at Tata Memorial Centre (Mumbai) and Medical Trust Hospital (Kochi). A total of 364 participants will be randomised 1:1 to the intervention group (exercise + cognitive training) or control group (usual care). The intervention will consist of a 3-month program combining supervised and home-based aerobic, resistance exercises and structured cognitive training activities. The primary endpoint will be the difference in the mean change in cognition from baseline to end of study between the two arms, as measured by FACT-Cog. Secondary endpoints will include objective cognition, depression, function, fatigue, quality of life, progression-free survival, and overall survival. Tertiary endpoints will include FDG-PET imaging and biomarker analysis. Outcomes will be assessed at baseline and 3 months. Compliance will be monitored via patients’ diaries and step counts, as recorded by wearables (when feasible).

Discussion

This study will provide the first randomised evidence from India on the efficacy and feasibility of a multidomain intervention for chemotherapy-related cognitive dysfunction in older patients with cancer. Findings will help improve the tolerability of chemotherapy in older patients with cancer, inform survivorship care models particularly in low- and middle-income countries and contribute to international guidelines.

Trial registration

Clinical Trials Registry-India (CTRI/2023/12/060849). Registered prospectively on 27 December 2023.

Supplementary Information

The online version contains supplementary material available at 10.1186/s12877-026-07513-8.

Background

Advances in cancer screening, early diagnosis, and improved systemic therapies have led to a growing population of cancer survivors worldwide. Alongside these successes, concerns about the late effects of treatment have become increasingly prominent. One of the most common and distressing sequelae is cancer-related cognitive decline (CRCD), often referred to as “chemo-brain.” CRCD manifests as subtle but clinically significant impairments in short-term memory, attention, and executive function, rather than frank dementia, and can compromise independence, treatment adherence, decision-making capacity, and quality of life in older adults with cancer [1–6].

The interaction between cancer, ageing, and anticancer treatments is believed to accelerate the trajectory of cognitive decline [7–10]. A review by Janelsins et al. reported that nearly 30% of patients exhibit cognitive decline prior to treatment, 75% have measurable cognitive impairment during chemotherapy, and 35% develop it in the months to years after treatment completion [11]. Cognitive changes may also be tumour-related, with impairments specific to lesion location, such as occipital tumours leading to visual deficits [12]. CRCD significantly extends disease-related disability, limiting activities of daily living, impeding workplace performance, and complicating adherence to treatment regimens.

Multiple risk factors contribute to CRCD, including demographic, medical, and biological characteristics. Age is frequently cited, but both younger and older patients are affected [13, 14]. Poor cognitive reserve prior to chemotherapy is a strong predictor of post-treatment decline in processing speed [15]. Other factors such as race, ethnicity, socioeconomic status, disease stage, and diet may also influence cognitive outcomes, though these remain under-investigated [16, 17].

Animal model research has validated CRCD as a legitimate medical condition. Rodent studies confirm that commonly used anticancer drugs produce moderately severe and often long-lasting cognitive deficits [18–21]. Mechanistic insights include hippocampal and frontal lobe dysfunction, mitochondrial impairment, and cytokine dysregulation [22, 23].

Defining CRCD remains challenging due to variability across cognitive domains and individual differences. The International Cognition and Cancer Task Force (ICCTF) recommends standardised criteria, such as > 2 test scores < − 1.5 standard deviations (SD) from the normative mean or one test score < − 2.0 SD [24, 25]. However, tools validated in Western populations (e.g., Hopkins Verbal Learning Test-Revised, Trail Making Test) may not be culturally appropriate in India.

The Functional Assessment of Cancer Therapy-Cognition (FACT-Cog) is widely used to assess cognitive difficulties in cancer survivors. It includes four subscales: perceived cognitive impairment, comments from others, perceived cognitive abilities, and impact of cognitive impairments on quality of life. Prior studies report mean declines of 15.9 points between pre- and post-chemotherapy [26], with a minimal clinically important difference of ~ 10 points [27].

18-Fluorodeoxyglucose Positron Emission Tomography (18 F-FDG PET) scans can be valuable in evaluating for the presence of cognitive impairment and predicting the risk of progression to more severe cognitive dysfunction or dementia. Reduced glucose metabolism, which is measured by the 18 F-FDG PET radiotracer, in specific areas of the brain regions can indicate neuronal dysfunction and can serve as a biomarker for neurodegenerative diseases [28–31]0.18 F-FDG PET can identify patterns of reduced brain metabolism, particularly in regions vulnerable to Alzheimer’s disease, which can be indicative of progression to dementia [32–36]. Thus, 18 F-FDG PET can help identify patients who are at higher risk of progressing from mild cognitive impairment to dementia [37, 38]. Studies have shown that reduced glucose metabolism in areas like the posterior cingulate cortex, hippocampus, and temporoparietal regions, as seen on 18 F-FDG PET, or generalised reduction in whole brain cortical glycolysis can be predictive of progression from mild cognitive impairment to either Alzheimer’s disease or other forms of severe neurocognitive dysfunction, including chemotherapy-induced cognitive dysfunction [39–41]. Thus, 18 F-FDG PET can be a useful adjunct to clinical assessment in the evaluation of cognitive impairment [42–45]. An important limitation for the use of 18 F-FDG PET in the evaluation of cognitive impairment is the potential for variation in the patterns of hypometabolism seen in patients with mild cognitive impairment; additionally, some individuals with mild cognitive impairment may not show significant abnormalities on 18 F-FDG PET. Alternatives to 18 F-FDG PET scans include arterial spin labelled perfusion magnetic resonance imaging (ASL-MRI) which can provide similar information about brain perfusion, but, this is not as easily available in our setup.

Cognitive impairment in patients with cancer likely arises from oxidative stress, systemic and neuro‑inflammation, disrupted neurotransmission, and direct neuronal injury, and integrating biochemical biomarkers with neuropsychological testing may improve early diagnosis, monitoring, and targeted interventions; key biomarker classes described in the literature include neuroinflammatory cytokines (notably IL‑6) that activate microglia and disrupt synaptic plasticity [46, 47], oxidative‑stress markers such as malondialdehyde (MDA) and 8-hydroxy-2’-deoxyguanosine (8-OHdG) which are end-products of lipid peroxidation and DNA oxidation [48–50], neurotrophic factors (reduced levels of brain-derived neurotrophic factor [BDNF]) linked to impaired neurogenesis and cognition [51], neuronal‑injury markers including Neurofilament light chain (NfL), tau, and S100 calcium-binding protein B (S100B) that indicate axonal/astrocytic damage and blood-brain barrier disruption [52, 53], cholinergic markers (elevated acetylcholinesterase [AChE] activity) that accelerate acetylcholine breakdown and worsen memory/attention [54–56], and metabolic/vitamin and endocrine markers (folate, B12, T3/T4/TSH) with variable associations with cognitive outcomes in cancer populations [57–60].

Management of CRCD is an unmet need. A survey of 1,600 survivors found that 75% self-reported cognitive symptoms related to cancer treatments, and most expressed interest in receiving support, particularly cognitive training [61]. Non-pharmacological approaches such as exercise and cognitive training have shown meaningful benefits in preventing cognitive decline [62, 63]. The Physical Activity Guidelines for Americans highlight improved cognition across the lifespan with exercise [64]. The FINGER trial (Finnish Geriatric Intervention Study to Prevent Cognitive Impairment and Disability) demonstrated that multidomain interventions (diet, exercise, cognitive training, vascular risk monitoring) can improve or maintain cognition in at-risk older adults [65]. In oncology, prospective studies have shown that physical activity before and during chemotherapy is associated with better cognitive outcomes [66].

Cognitive training is a behavioural method that improves or restores cognitive functions, enhancing brain connectivity, cortical thickness, and neurotransmitter function. Impairments in executive function can have downstream effects on language, social cognition, and memory. International guidelines (American Society of Clinical Oncology [ASCO], International Society of Geriatric Oncology [SIOG], National Comprehensive Cancer Network [NCCN]) recommend routine cognitive assessment as part of the multidisciplinary geriatric assessment [67, 68].

Indian data highlight the urgency of this issue. In the Tata Memorial Hospital geriatric oncology clinic, 18% of patients had cognitive impairment prior to chemotherapy based on the Mini-Mental Status Examination (MMSE) [69]. More detailed assessment using Addenbrooke’s Cognitive Examination III (ACE-III) in 124 patients revealed that 19.4% had mild cognitive impairment and 9.7% had major neurocognitive disorders, indicating a baseline prevalence of ~ 29% (unpublished data). The prevalence of CRCD following chemotherapy in Indian patients is unknown, and the benefits of multidomain interventions remain untested.

In routine practice, neither exercise nor cognitive training is incorporated into the supportive care regimen for older patients with cancer who are receiving systemic chemotherapy. The GOCog trial was designed to address this gap by evaluating the efficacy of a structured multidomain intervention (exercise and cognitive training) in preventing CRCD among older Indian patients with cancer receiving chemotherapy.

Methods/design

Study hypothesis

A 3-month multidomain intervention (including cognitive training and exercise) can decrease the chemotherapy-related cognitive decline in older Indian patients with cancer receiving chemotherapy, compared to usual care.

Aims and objectives

Primary objective

• To investigate the effect of a 3-month multidomain intervention (cognitive training, physical exercise) on cognition as assessed by FACT-Cog, in older patients with cancer receiving chemotherapy

Secondary objectives

• To investigate the effects of 3-month multidomain intervention on:

  • ◦ Objective cognition using ACE-III
  • ◦ Depressive symptoms using Geriatric Depression Scale-Short Form
  • ◦ Function using Katz and Lawton’s Activities of Daily Living
  • ◦ Fatigue on Likert scale ranging from 0 to 10
  • ◦ Quality of life using European Organisation for Research and Treatment of Cancer QLQ-C30, v 3.0, and EORTC QLQ-ELD14
  • ◦ Factors that affect chemotherapy-related cognitive dysfunction
  • ◦ Factors that affect the efficacy of the multidomain intervention on cognitive dysfunction
  • ◦ Progression-free survival
  • ◦ Overall survival
  • ◦ Change in vulnerabilities in the geriatric assessment

Tertiary objectives

• To assess imaging to evaluate cognitive impairment

• To assess changes in biomarkers

Study design and setting

The GOCog study consists of a multicentric, phase III, randomised controlled trial with two parallel arms, conducted to evaluate the efficacy of a multidomain intervention in preventing CRCD among older adults with cancer. The study is being conducted in the Departments of Medical Oncology, Physiotherapy and Psycho-oncology at Tata Memorial Centre, Mumbai, Maharashtra, and Medical Trust Hospital, Kochi, Kerala. The study protocol was planned in accordance with the Standard Protocol Items: Recommendations for Interventional Trials (SPIRIT) 2025 statement (Supplementary Table 1).

The study was prospectively registered with the Clinical Trials Registry of India (CTRI/2023/12/060849), following ethics committee approvals at each participating site. Recruitment of the study participants began in August 2024, and as of December 2025, 156 participants have been recruited. Active recruitment is ongoing at Tata Memorial Centre, Mumbai, and Medical Trust Hospital, Kochi, with additional collaborating centres to be included to ensure timely accrual of the target sample size. The multicentric nature of the trial enhances generalisability across diverse patient populations and healthcare settings in India, while the pragmatic design ensures feasibility and integration into routine oncology practice.

Eligibility criteria

The inclusion and exclusion criteria are detailed in Table 1.

Table 1.

Eligibility criteria for the GOCog trial: Geriatric Oncology multidomain intervention study to prevent Cognitive impairment among older Indian patients with cancer receiving chemotherapy: A multicentric randomised controlled trial

INCLUSION CRITERIA	EXCLUSION CRITERIA
• Patient with a diagnosis of malignancy, aged 60 years and above • Patient is planned to receive systemic chemotherapy • Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) 0 to 2	• Pre-existing severe cognitive impairment • Any condition, that makes the performance of exercise dangerous in the opinion of the investigator, e.g., extensive lytic bone metastases • Diagnosis of cognitive impairment due to Parkinson’s disease • History of whole brain radiotherapy • Symptomatic brain metastases

Study methodology

A schematic overview of the study design is shown in Fig. 1.

Fig. 1.

Schematic overview of the GOCog study. ACRONYMS: FACT-Cog=Functional Assessment of Cancer Therapy-Cognitive Function; ACE-III=Addenbrooke's cognitive examination-III; TUG=Timed Up and Go test; CGA=comprehensive geriatric assessment; ADL=activities of daily living; IADL=instrumental activities of daily living; BMI=body mass index; MNA=mini nutritional assessment; GDS=geriatric depression scale; GAD-7=generalised anxiety disorder-7; CCI=Charlson’s comorbidity Index; CIRS-G=Cumulative Illness Rating Scale-Geriatric; ORAS-MSS=Older Americans Resources and Services-Medial Social Support; QLQ-C30=European Organisation for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire Core 30; QLQ-ELD14=European Organisation for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire for Elderly Cancer Patients

Patient screening

Patients will be identified from the outpatient departments during the routine oncology consultations and will be referred to the study team for screening.

Screening includes a focused neurological history and examination to capture a history of prior stroke, epilepsy, Parkinsonism, and other neurological disorders. Symptomatic brain metastases and prior whole‑brain radiotherapy remain exclusionary. If history/examination raise concern for active CNS disease, further neuroimaging or specialist evaluation will be obtained per routine clinical practice. Pre-existing severe cognitive impairment, or any condition that makes the performance of exercise dangerous in the opinion of the investigator, e.g., extensive lytic bone metastases remain exclusionary.

Recruitment will follow a two-step process. First, potential participants will be pre-screened by the oncology staff during clinic visits. Any patient fulfilling the basic eligibility criteria will be referred to the study team, who will provide detailed information about the trial in both oral and written formats. Second, patients who express interest will undergo a formal screening visit, during which the eligibility criteria will be verified, the patient and family will again be counselled in detail about the study, and written informed consent will be obtained.

To maximise participation, the study team will use routine clinic referrals supplemented by outreach through the psycho-oncology and physiotherapy services. Compliance and retention will be encouraged through regular contact with participants and caregivers, flexible scheduling of assessments, and integration of intervention activities into routine cancer care.

Randomisation and stratification

All patients who satisfy the eligibility criteria and consent to participate in the study will be randomised 1:1 between either the intervention arm (exercise and cognitive training) or the control arm (usual care) using simple computer-generated randomisation. Patients will be stratified for age (60–69 years and 70 years and above), sex (male and female), ECOG PS (0–1 and 2), disease (lung cancer vs. gastrointestinal cancer vs. others), and type of chemotherapy regimen (combination chemotherapy vs. monotherapy), to ensure balanced allocation across clinically relevant subgroups. Randomisation will be performed by an independent biostatistician (in the Central Research Secretariat at Tata Memorial Centre, Mumbai), who will generate the randomisation sequence centrally. The details of each patient will be sent to the biostatistician, who will then email the arm that the patient is randomised to.

Cognitive assessment

All participants will undergo a detailed cognitive assessment at baseline using FACT-Cog and ACE-III. FACT-Cog takes 10 min to administer, and the ACE-III tool takes approximately 25 min to administer. The FACT-Cog can be filled out by the patient. In case the patient requires help or does not understand some or all of the questions, the FACT-Cog will be administered in the form of an interview by the study personnel and the patient’s responses will be recorded, as per the instructions on the Functional Assessment of Chronic Illness Therapy (FACIT) website. ACE-III evaluates cognition in the following domains: memory, attention, fluency, language, and visuospatial. ACE-III will be administered by the trial personnel. The maximum possible score on the ACE III is 100. A score between 72 and 100 is considered normal; 61 to 71 is considered as mild cognitive impairment, and scores below 61 are considered as major neurocognitive disorder [70]. Participants identified with mild cognitive impairment at baseline will remain in the trial and receive their randomised allocation. Those in the intervention arm will receive the standard cognitive‑rehabilitation modules (visual perception, memory, language, attention, executive function), caregiver‑assisted adaptations as needed, and psychoeducation/mindfulness components tailored to cognitive ability.

Any participant in the intervention arm, during follow up whose ACE-III score falls into the major neurocognitive disorder range (< 61) or whose clinical presentation suggests progressive neurological disease will be referred promptly to neurology/psycho-oncology and the treating oncologist; such referrals and outcomes will be recorded and reported.

Geriatric assessment

All participants will undergo a geriatric assessment (GA), as per the ASCO and SIOG guidelines for comprehensive geriatric assessment [67, 71]. The demographic and anthropometric measurements, including height, weight, body mass index (BMI), mid-arm circumference, and mid-calf circumference will be measured. The domains that will be assessed as part of the GA include function, falls, fatigue, nutrition, psychology, comorbidities, cognition, medications, social support, and geriatric syndromes. The assessment of function will include evaluation of the basic and instrumental activities of daily living using the Katz and Lawton scales, respectively (both tools filled out by the patient or caregiver). Additionally, one performance-based measure (timed-up-and go test) and/or a short physical performance battery (SPPB) will be assessed (done by the trial personnel). Falls will be evaluated by asking if the patient had a fall in the past one year. Nutritional status will be assessed by measuring the BMI and the mini nutritional assessment scale (MNA) (administered by the trial staff). Psychological status will be assessed by screening for depression and anxiety using the Geriatric Depression Scale-Short Form (GDS) and the Generalised Anxiety Disorder 7 (GAD-7) scale (both filled out by the patient/caregiver). Comorbidities will be evaluated using Charlson’s comorbidity index (CCI) and the Cumulative Illness Rating Scale for Geriatrics (CIRS-G) (both filled out by the trial staff). Social support will be assessed using Older Americans Resources and Services Medical Social Support (OARS-MSS), and Quality of Life using the European Organisation for Research and Treatment of Cancer QLQ-C30, v.3.0, and QLQ-ELD14 (all filled by the patient/caregiver). Fatigue will be assessed using an 11-point Likert scale ranging between 0 and 10. Medications will be reviewed and assessed for appropriateness using the American Geriatric Society (AGS) Beer’s criteria (administered by the trial staff); polypharmacy will be defined as five or more medications. Details of the instruments used, method of administration and licensing/authorisation are provided in Supplementary file 1.

Interventions

Participants randomised to the intervention arm will receive a structured multidomain program in addition to usual oncological care. This program combines exercise training and cognitive training, both designed to be feasible for older adults undergoing chemotherapy.

Intervention group - exercise training

Participants in this group will receive a mixed type of exercise intervention in addition to usual care. The first session will be supervised, followed by instructions to perform unsupervised exercise, along with the types of exercises to be done, frequency, and the time to be spent. Patients will be advised to maintain a diary, which will include date, type of exercise done (resistance or aerobic), duration of exercise, if not done, and the reason for it. Following the first session of supervised physiotherapy, the patient will have the option to continue to come to the physiotherapy department for subsequent sessions of supervised exercises, if this is feasible, or if they wish to do so; or to do unsupervised exercises at home.

Progressive resistance exercises

Resistance exercises will target the major muscle groups either by doing free exercises (using the patient’s own body weight) and/or with TheraBands (Thera station). Use of body weight as resistance has proven to be an effective type of strength training, hence will be recommended to patients who may not be able to use TheraBands. Assessment will be done using the Omni scale and patients will be advised to do the exercises between “Somewhat easy” and “Somewhat hard” on the Omni scale. Patients will be asked to perform six to eight repetitions in two sets with three to five minutes of rest interval between the sets, three times/weeks. Progression to the next intensity level will be done if participants are able to do two or more than the usual repetition for consecutive resistance exercise sessions; in such cases, the resistance will be increased accordingly.

Aerobic exercise training

Aerobic capacity assessment will be done by administering the 6-minute walk test (6MWT) wherein the distance covered, vitals and Perceived Rate of Exertion (PRE) using the Modified Borg scale will be recorded. Patients will complete supervised aerobic exercises such as walking (treadmill) or cycling for 30–60 min and will then continue this as unsupervised exercise 3 days/week. Moderate intensity aerobic training at 60–70% of heart rate reserve will be prescribed according to the patient’s condition and during training. Heart rate reserve will be calculated using the standard Karvonen’s formula:

where is estimated clinically (e.g., ) and is measured at baseline prior to exercise.

(HRR indicates the heart rate reserve; indicates the maximum heart rate; indicates the resting heart rate; HR indicates the heart rate)

Participants will be encouraged to maintain their aerobic activity perceived exertion level between “Somewhat Hard” to “Slightly Hard” (level 4 - level 6) on the Modified Borg scale. If patients are unable to exercise for 30 min at a stretch, they will be encouraged to exercise for a shorter duration at more frequent intervals, e.g., if a patient is unable to walk for 30 min, the patient will be advised to walk twice in a day for 15 min each time. Additionally, performing alternative aerobic activities like walking, swimming, cycling, dancing, or running is permissible.

Risks and safety measures

The first session of the physical exercise training will be administered under supervision in the Department of Physiotherapy under controlled conditions. Participants will be screened before the exercise testing or training session for the following criteria (which, if present, will be criteria to cancel that particular exercise session) by the physiotherapist to ensure safety: diastolic blood pressure < 45 or > 95 mm Hg, resting heart rate (HR) > 115/min, temperature > 38֯ C, resting respiratory rate > 30/min, oxygen saturation (SpO₂) < 92% on room air or new/worsening dyspnoea, or clinical evidence of infection requiring treatment, fresh bleeding, and in case blood tests are available (blood tests done within the past 96 h will be considered): haemoglobin (Hb) below institutional transfusion/clinical thresholds (for example, symptomatic Hb < 8 g/dL), total leucocyte count < 1.0 × 10⁹/L or platelets < 50 × 10⁹/L. If any one of these criteria is met, participants will not be allowed to exercise or undergo physical function tests on that day.

Intervention group - cognitive intervention

Home-based cognitive training

All the participants will perform structured activities focused on domains of attention, language, memory, visual perception, executive functioning, and activities of daily living. This intervention will be given by the psycho-oncologist for patients to practice at home on alternate days. The home-based activities advised are detailed in Table 2. Examples of cognitive exercises include backward counting, reading aloud and explaining passages, drawing shapes, solving Sudoku, recalling recent events, and engaging in routine household or mindfulness activities. Caregivers play an active role by facilitating tasks such as asking for similarities and differences between objects or prompting memory recall. Activities are performed on alternate days, with flexibility to adapt to literacy levels and patient preferences.

Table 2.

Home-based cognitive training exercises prescribed to the intervention group in the GOCog trial: Geriatric Oncology multidomain intervention study to prevent Cognitive impairment among older Indian patients with cancer receiving chemotherapy: A multicentric randomised controlled trial

Number	Domains	Home based activities for patients
1	Attention	Caregiver to instruct patient to count from 20 − 1 backwards
2	Language	Literate patient: (1) Reading aloud one paragraph from newspaper/book (2) To explain in information in the paragraph to the caregiver Illiterate patient: Reciting paragraph or poem or song
3	Visual perception	Drawing shapes, designs
4	Executive functioning	1) Caregiver to ask for similarities and differences of different objects for e.g., sun & moon; apple and orange 2) Literate patient: Sudoku
5	Memory	Recall names, any phone numbers Recall one event from 1–2 days ago
6	Activities of daily routine	Brushing, dressing, and grooming; one household activity, mindfulness activities

Compliance monitoring

Participants will maintain diaries documenting the type, duration, and frequency of exercises and cognitive tasks. Where feasible, step counts will be recorded using smartwatches or smartphone applications.

Control group

Participants randomised to the control arm will receive usual oncological care without structured exercise or cognitive training interventions, but their clinical management will otherwise remain unchanged. They will undergo the same baseline and follow-up assessments as the intervention group, including geriatric assessment, cognitive testing (FACT-Cog and ACE-III), quality of life measures (QLQ-C30, QLQ-ELD 14), and function assessment (Timed Up and Go test [TUG], SPBB and 6MWT). This ensures comparability of outcomes between groups while isolating the effect of the multidomain intervention.

Cancer-directed therapy

Patients will be started on cancer-directed therapy, as per the decision of the treating oncologist. The therapeutic regimen with the dose and frequency will be documented.

Cognitive reassessment

Patients will undergo reassessment of cognition using FACT-Cog and ACE-III after 3 months (+/- 3 weeks). A change in the FACT-Cog of 10 from the baseline will be considered as a minimal clinically significant change.

Imaging

No additional scans will be done for the purpose of the study. In patients who are undergoing 18 F-FDG PET scans for evaluation of their underlying malignancy, the information from the scan pertaining to cognition will be used. In patients who are undergoing staging scans, 18 F-FDG brain PET will be evaluated qualitatively and quantitatively using CORTEX ID. This will provide 3D SSP models for uptake ratio and z score images. Predefined regions will be optimised for FDG and beta amyloid analysis. The routine 18 F-FDG PET scan will provide regional quantitative results. We will make comparisons with normal 18 F-FDG databases. We will also do quantitative comparisons of longitudinal studies. The cortical FDG uptake will be presented using volumes of interest, voxel-based or 3D stereotactic surface projection maps of the brain. CORETX ID SUITE is an ideal image interpreter in serial PET studies conducted on patients for cognitive decline. Participants who develop new CNS disease during follow‑up (e.g., symptomatic brain metastases, stroke, seizures) will have their imaging and biomarker data flagged; primary analyses will include all participants (intention‑to‑treat) and sensitivity analyses will exclude participants with new CNS disease to assess robustness. FDG‑PET will be used opportunistically and analysed as an exploratory correlate; it is not a diagnostic gold standard for cognitive function and will not influence primary outcome analyses.

Biomarkers

In this study, we are proposing to use a multimodal panel for cognitive deficit testing using IL-6 (inflammatory), 8-OHdG (oxidative stress), BDNF (Neurotrophic factor), NfL (neuronal injury), AChE (cholinergic) and other markers: Vitamin B12, TSH, T3 and T4. These biomarkers from patients will be assessed using the ELISA technique, while Vitamin B12, TSH, T3 and T4 will be included in the routine blood test. For the ELISA-based assays, approximately 10 mL of peripheral blood will be collected at baseline and at the end of treatment (3 months). Plasma/serum will be separated as per the assay requirements. Biomarker analyses are exploratory; subgroup sizes and missing data will limit inference, and results will be presented with appropriate caveats.

Safety assessment

Adverse events

Information about all adverse events will be collected, recorded, and followed up as appropriate. Grading of adverse events will be according to the Common Terminology Criteria for Adverse Events (CTCAE), v.5. An adverse event is any undesirable sign, symptom or medical condition occurring after starting study treatment, even if the event is not considered to be treatment related.

Medical conditions/diseases present before starting study treatment will be only considered adverse events if they worsen after starting study treatment. Clinical events occurring before starting study treatment but after signing the informed consent form will be recorded on the Case Report Form. Abnormal laboratory values or test results will constitute adverse events only if they induce clinical signs or symptoms or require therapy and will be recorded on the Adverse Events Case Report Form under the signs, symptoms or diagnosis associated with them.

As far as possible, each adverse event will be described by:

1. Its duration (start and end dates)

2. The severity grade- as per CTCAE v.5

3. Its relationship to the study drug (suspected / not suspected),

4. The action(s) taken

Serious adverse events

Information about all serious adverse events (SAE) will be collected and recorded on the SAE Reporting Form and will be reported to the ethics committee within 24 h of learning of its occurrence. An SAE is defined in general as an untoward (unfavourable) event that is fatal or life-threatening, required or prolonged hospitalisation, significantly or permanently disabling or incapacitating, may jeopardise the subject and may require medical or surgical intervention to prevent one of the outcomes listed above. SAEs will be reported starting from the time the patient signs the informed consent form until the completion of the study, i.e., completion of 3 months. Events that are clearly unrelated to participation in the study, i.e., social admissions for logistic purposes do not need to be filed as SAEs. Progressive disease or hospitalisation/death due to progressive disease is waived from SAE reporting for the purpose of this study. Adverse events or SAEs that are clearly related to the cancer-directed therapy or to the underlying cancer diagnosis do not need to be reported as SAEs for the purpose of this study. For the purpose of this study, the following events will be considered to be SAEs, as long as they fulfil the standard criteria for SAEs in terms of severity:

• Injury (fracture/muscle tear/sprain/etc.)

• Dizziness or loss of consciousness

• Dyspnoea

• Hypoxia

• Cardiac event, like angina, myocardial infarction, arrythmia

• Dehydration

Completion of the trial

Patients will be considered to have completed the study if the following criteria are fulfilled:

• Completion of 3 months – with a baseline FACT-Cog and 3-month FACT-Cog questionnaires filled out

• Withdrawal of consent

• Death

Subsequent cancer-directed therapies

If the patient experiences disease progression, subsequent workup, and management is at the discretion of the treating physician. Patients will be followed up as per institutional policy, and survival data will be collected.

Timing of assessments

All participants will undergo baseline assessments prior to chemotherapy initiation, including FACT-Cog, ACE-III, geriatric assessment, imaging, biomarker assessment, and quality of life measures. Follow-up assessments will be conducted at 3 months (± 3 weeks). Survival outcomes (progression free and overall survival) will be tracked longitudinally through routine oncology follow-up (Table 3). Imaging and biomarker analyses will be performed opportunistically in patients undergoing FDG-PET scans or routine blood investigations as part of their cancer care.

Table 3.

Overview of outcomes and time points of data collection

Outcome category	Outcome measure(s)	Baseline (T0)	3 months (T1)	Long-term follow-up
Primary outcome	FACT-Cog (Functional Assessment of Cancer Therapy – Cognition)	✔	✔	-
Secondary outcomes	ACE-III (objective cognition)	✔	✔	-
	Geriatric Depression Scale – Short Form (GDS-SF)	✔	✔	-
	Katz ADL and Lawton IADL scales	✔	✔	-
	Timed Up and Go / Short Physical Performance Battery (SPPB)	✔	✔	-
	Fatigue (11-point Likert scale)	✔	✔	-
	EORTC QLQ-C30 (v3.0) and QLQ-ELD14	✔	✔	-
	Geriatric assessment (nutrition, medications, anxiety, comorbidities, social support)	✔	✔	-
	Progression-free survival			✔ (ongoing)
	Overall survival			✔ (ongoing)
Tertiary outcomes	FDG-PET imaging (cortical metabolism, opportunistic during routine staging scans)	✔ (if available)	✔ (if available)	✔ (if repeated)
	Biomarkers (oxidative stress, inflammation, neuronal injury markers)	✔	✔	✔ (if repeated)

Sample size calculation

Our primary endpoint is the difference in the change in the mean FACT-Cog total score from baseline to 3-months in the intervention arm compared to that in the standard arm. Based on the study by Janelsins et al. [26]., we assume that the mean change (decrease) from baseline to 3-months in the FACT-Cog total score will be 15.9, with a standard deviation of 30.8 in the standard arm [26]. We hypothesise that the intervention group will experience a mean change of 5 points, i.e., a drop of 10 points less in the cognition score from baseline to 3 months of chemotherapy, which is considered the minimal clinically significant change. In order to test this hypothesis, an estimated total sample size of 364 (182 in each group) will be required to compare the mean change, considering a 30% attrition rate (based on clinical experience and the fact that this study will be conducted in older patients with cancer). This sample size will achieve an 80% power to detect differences between the mean change using a z-test with a 5% significance level. The first 50 patients randomised to the interventional arm will be considered for the feasibility portion of the study. Compliance to the interventions in at least 60% of the patients in the feasibility study will be considered sufficient to proceed with the rest of the study. The details of the feasibility study will be submitted to the institutional ethics committee.

Statistical analysis

Data will be analysed using the Statistical Package for the Social Science (SPSS) and R Studio or other suitable statistical program for analysis.

All analyses will be conducted according to the intention-to-treat principle, with a per-protocol analysis performed as a sensitivity check for participants achieving at least 60% compliance with the intervention. Demographics and other clinical details, cognitive status (normal and mild cognitive impairment) will be presented with descriptive statistics, using absolute numbers and simple percentages. Post intervention FACT-Cog and ACE-III scores will be represented as mean with standard deviation.

For the primary hypothesis, to compare the mean changes between two time-points between the two groups we will use repeated-measures ANOVA.

For the secondary endpoint analysis, chi-square test or t-test/Mann Whitney U test will be used for categorical and continuous variables, respectively.

Analysis of the change in the quality-of-life score (on QLQ-C30 and QLQ-ELD14) as well as FACT-Cog will be done as per the published methodology provided on the EORTC and FACIT websites, respectively. Evaluation of progression free survival (calculated as the time from the date of randomisation to date of disease progression either objectively on scan or date of symptomatic deterioration in the absence of objective evidence of disease progression or date of death from any cause) and overall survival (calculated as the time from the date of randomisation to date of death from any cause) will be performed using the Kaplan-Meier methodology [72, 73]. The sample size was calculated for the primary FACT-Cog endpoint; tertiary imaging and biomarker analyses have not been powered for definitive hypothesis testing. We will report effect sizes, 95% confidence intervals, and perform sensitivity analyses; any results from exploratory analyses will be explicitly labelled as hypothesis-generating. Sensitivity analyses will be performed to exclude participants with new symptomatic CNS disease or prior whole-brain radiotherapy from imaging analyses. Exploratory endpoints such as FDG-PET imaging will be analysed using mixed-effects models and voxel-based methods, while biomarker levels will be compared using parametric or non-parametric tests, with correlation analyses exploring associations with cognitive outcomes.

Missing data will be handled using multiple imputation under the assumption of missing at random, with sensitivity analyses performed to test robustness. Pre-specified subgroup analyses will examine the differential effects of age, sex, ECOG PS, cancer type, and chemotherapy regimen and other factors that affect the efficacy of the multidomain intervention on cognitive dysfunction by logistic regression analysis. The association between intervention and survival will be performed using the Kaplan-Meier method and compared with the log-rank test, and Cox proportional hazard model [74, 75]. For all statistical tests, p-value ≤ 0.05 will be considered significant.

Protocol amendments

Any important changes to the study protocol (e.g., changes in the eligibility criteria, outcomes, sample size, study procedures, or administrative aspects that may impact participant safety or study conduct) will be formally documented and submitted to the Institutional Ethics Committee and relevant regulatory authorities for approval before implementation. Updated protocol versions will be circulated to all participating study investigators, and other study team members. The trial registry (CTRI) will also be updated with all approved amendments.

If protocol changes affect participant risk, consent, or study procedures, updated participant information sheets and consent forms will be drafted and submitted to the ethics committee for approval. Once approved, re-consent will be obtained as required. The Data Safety Monitoring Board will be notified of all amendments relevant to safety oversight.

Dissemination policy

The findings of the GOCog study will be disseminated through peer-reviewed publications, conference presentations, and institutional reports. Results will be shared with participating centres, funding agencies, and relevant stakeholders. Only de-identified data will be reported, and authorship will follow the International Committee of Medical Journal Editors (ICMJE) guidelines.

Patient and public involvement in the design of the study

Between Oct 2022 and Feb 2023, we interviewed 10 older patients with cancer who were receiving systemic cancer-directed therapy and who had come for a GA. We asked patients regarding their viewpoints on the various aspects of the study protocol trial design, including how feasible it would be to come to the hospital on a regular basis for supervised exercise sessions, how often it would be possible to do unsupervised exercises (physical and cognitive) at home, whether the interventions would be useful, whether they had access to a smartphone or a device with an internet connection, whether they could attend virtual group exercise sessions, and any suggestions that they might have. All 10 patients thought that the interventions would be useful, most said that it would be possible to attend at least one or two supervised exercise sessions in the hospital but would find it difficult to attend the hospital regularly for supervised exercise sessions. All 10 patients thought that they would be able to do unsupervised exercises at home without difficulty. The frequency of home exercises suggested by the patients ranged from 3 to 5 times a week (6 patients, 60%) to everyday (4 patients, 40%). The suggested length of each exercise session ranged from 20 min (2 patients, 20%), to 30 min (6 patients, 60%), to 50 to 60 min (2 patients, 20%). Five patients (50%) had access to smartphones or other devices with an internet connection and reported that they would possibly be willing to join virtual group exercise sessions, if available. The only suggestion offered to improve the study processes was that regular reminder phone calls from the hospital staff may be helpful to improve compliance to the home exercise program.

Ethical considerations

The Investigator or a person designated by him/her will collect informed consent from all participants, prior to which the Investigator or co-investigator will inform each participant of the objectives, benefits, risks, and requirements of the study. He/she will also provide the participant with an information sheet in clear, simple language. The study participant will be allowed ample time to inquire about details of the study and to decide whether or not to participate in the study. The study will not commence until approval has been obtained from the Institutional Ethics Committee at each individual site. The trial will be conducted according to the principles laid down by the International Conference on Harmonisation Good Clinical Practice guidelines, the Declaration of Helsinki, and the guidelines established by the Indian Council of Medical Research (ICMR). The study will be monitored by the independent data safety and monitoring committees at each institution. Monitoring will be performed annually as per the standard operating guidelines of the ethics committee.

Confidentiality

Personal information about potential and enrolled participants (including any identifiers, contact information, and clinical data) will be collected only by authorised study personnel and recorded in secure, password-protected electronic databases with role-based access. Hard-copy documents will be stored in locked, access-restricted research facilities. Each participant will be assigned a unique study identification code; all analytical datasets will use coded (pseudonymised) data without direct identifiers. Data transfer between sites and the coordinating centre will occur through encrypted channels.

Identifiable information will not be shared outside the study team except when required by regulatory authorities or ethics committees for monitoring or auditing.

After trial completion, identifiable data will be stored securely for the duration required by institutional and regulatory policies and then destroyed according to data-retention guidelines. Coded datasets may be retained for scientific analysis and reporting.

Risk-benefit analysis

The benefits of a multidomain intervention in preventing chemotherapy-related cognitive decline is not clearly defined. Though chemotherapy may lead to prolongation of survival, cognitive decline may lead to increased dependency, impaired functionality, worsened quality of life and increased caregiver burden. If a multidomain intervention leads to prevention of cognitive decline, and maintenance of quality of life, this will be worthwhile.

Reimbursement

In patients randomised to both the arms, the chemotherapy treatment is standard, and therefore, patients will have to bear the expenses of the therapy. All work-up including blood tests and imaging in patients in both the arms is standard and will be paid for by the patient. For all patients, the cost of standard testing and therapy, like analgesics, supportive medications, follow-up testing and imaging etc. will be borne by the patient. Any equipment needed for the study, like Thera-bands or wearables will be provided from the study budget. The cost of serious adverse events and hospitalisation of the patients on the experimental arm that are related to participation in the study will be covered by the study budget.

Ancillary and post-trial care

Participants who experience any trial-related injury or harm will be provided appropriate medical care as per institutional policy. The sponsor/institution will provide compensation for trial-related injuries, in accordance with applicable laws and ethics-committee-approved insurance/indemnity arrangements. Participants will not incur any treatment costs for managing study-related adverse events. Ancillary care (such as referral to specialists, psychosocial support, or non-study clinical care identified during study procedures) will be provided or facilitated as clinically indicated. As the intervention in this study comprises exercise and cognitive training, post-trial access is not relevant. Participants will return to standard-of-care management after the completion of the study.

Compensation

We will follow the standard compensation policy of the institution.

Discussion

CRCD, often termed “chemobrain,” is a well-recognised adverse effect of cancer therapy that poses significant challenges for survivorship, particularly in older adults. Cognitive decline can manifest in domains such as memory, attention, executive function, and processing speed, with consequences for treatment adherence, independence, and quality of life [1–4]. The clinical characteristics and pathophysiology of CRCD have been extensively described, highlighting its impact beyond central nervous system malignancies [5, 6].

The mechanisms underlying CRCD are multifactorial. Chemotherapy agents such as cyclophosphamide, doxorubicin, cisplatin, and 5-fluorouracil have been shown in preclinical models to impair hippocampal neurogenesis, induce mitochondrial dysfunction, and disrupt cytokine regulation, leading to long-lasting cognitive deficits [8–23, 76]. Neuroimaging studies using FDG-PET have demonstrated hypometabolism in regions such as the hippocampus, posterior cingulate cortex, and temporoparietal lobes, which correlate with cognitive decline and may predict progression to dementia [28–545]. Biomarker studies further implicate systemic inflammation, oxidative stress, and neuronal injury, with elevated cytokines (e.g., IL-6), oxidative stress markers (e.g., 8-hydroxy-2′-deoxyguanosine), and neurofilament light chain associated with cognitive impairment [46–60].

Defining CRCD remains challenging due to variability in affected domains and assessment tools. The ICCTF has recommended harmonised criteria for cognitive testing [25], yet cultural and linguistic adaptations are necessary in diverse settings such as India [24, 70]. Tools such as FACT-Cog provide patient-reported outcomes, with established minimal clinically important differences [26, 27], while objective measures like ACE-III offer domain-specific evaluation [70].

Management strategies for CRCD are evolving. Surveys indicate that up to 75% of cancer survivors report cognitive complaints and express a desire for supportive interventions [61]. Non-pharmacologic approaches, particularly exercise and cognitive training, have demonstrated meaningful benefits. Exercise improves cerebral blood flow, reduces inflammation, and promotes neurogenesis [64], while cognitive training enhances executive function and cortical connectivity [62]. Multidomain interventions, such as the FINGER trial, have shown efficacy in preventing cognitive decline in at-risk older adults [64]. In oncology, prospective studies confirm that maintaining physical activity during chemotherapy is associated with better cognitive outcomes [65].

Guidelines from ASCO and SIOG emphasise the importance of incorporating cognitive assessment into the GA [66, 67]. Early identification of cognitive impairment facilitates shared decision-making and personalised treatment planning. Data from geriatric oncology clinics in India reveal that nearly 29% of older patients have baseline cognitive impairment prior to chemotherapy [69], underscoring the need for targeted interventions in this population.

The GOCog study will build upon this evidence by evaluating a pragmatic, multicentric randomised controlled trial of a multidomain intervention (exercise and cognitive training) in older Indian patients receiving chemotherapy. By integrating subjective and objective cognitive assessments, functional measures, FDG-PET imaging, and biomarker analysis, the study aims to generate robust evidence on both clinical efficacy and mechanistic pathways. This design addresses key gaps in the literature: the underrepresentation of older adults in CRCD research, the lack of culturally adapted cognitive tools, and the limited data on multidomain interventions in oncology settings.

In conclusion, CRCD represents a major survivorship challenge with biological, functional, and psychosocial dimensions. The GOCog trial is expected to provide high-quality evidence on the effectiveness of multidomain interventions in mitigating cognitive decline among older adults with cancer. If successful, this approach could inform clinical practice guidelines and contribute to the development of integrated supportive care models in geriatric oncology.

Abbreviations

ACE-III

Addenbrooke’s Cognitive Examination III

ACh

Acetylcholine

AChE

Acetylcholinesterase

AGS

American Geriatric Society

ASCO

American Society of Clinical Oncology

ASL-MRI

arterial spin labelled perfusion magnetic resonance imaging

BBB

blood-brain barrier

BDNF

Brain-derived neurotrophic factor

BMI

body mass index

CCI

Charlson’s comorbidity index

CIRS-G

Cumulative Illness Rating Scale for Geriatrics

CRCD

cancer-related cognitive decline

CTCAE

Common Terminology Criteria for Adverse Events

CTRI

Clinical Trials Registry of India

ECOG

Eastern Cooperative Oncology Group

FACIT

Functional Assessment of Chronic Illness Therapy

FACT-Cog

Functional Assessment of Cancer Therapy-Cognition

FINGER trial

Finnish Geriatric Intervention Study to Prevent Cognitive Impairment and Disability

18F-FDG PET

18-Fluorodeoxyglucose Positron Emission Tomography

GA

geriatric assessment

GAD-7

Generalized Anxiety Disorder 7

GDS-SF

Geriatric Depression Scale-Short Form

HR

heart rate

ICCTF

International Cognition and Cancer Task Force

ICMJE

International Committee of Medical Journal Editors

ICMR

Indian Council of Medical Research

MDA

Malondialdehyde

MMSE

Mini-Mental Status Examination

MNA

mini nutritional assessment scale

6MWT

6-minute walk test

NCCN

National Comprehensive Cancer Network

NfL

Neurofilament light chain

OARS-MSS

Older Americans Resources and Services Medical Social Support

PRE

Perceived Rate of Exertion

PS

performance status

8-OHdG

8-hydroxy-2’-deoxyguanosine

ROS

reactive oxygen species

SAE

serious adverse events

S100B

S100 calcium-binding protein B

SD

standard deviations

SIOG

International Society of Geriatric Oncology

SPIRIT

Standard Protocol Items: Recommendations for Interventional Trials

SPPB

short physical performance battery

SPSS

Statistical Package for the Social Science

T3

triiodothyronine

T4

thyroxine

TSH

thyroid stimulating hormone

TUG

Timed Up and Go test

Authors’ contributions

VN: study conception and design; VN, AP, VS, AC, FNN, AD, LS, VR, SM, AM, JD, MV, VR, RT, TB, JD, SS, KN, AY, SG, SM, MS, KP: acquisition of the data; VN, AS, AP, KP: analysis of the data; VN, NM, KP: interpretation of data; VN, VS, ARR, MP, MM: drafted the work or substantively revised it; All authors: approved the submitted version (and any substantially modified version that involves the author’s contribution to the study); All authors: agreed both to be personally accountable for the author’s own contributions and to ensure that questions related to the accuracy or integrity of any part of the work, even ones in which the author was not personally involved, are appropriately investigated, resolved, and the resolution documented in the literature.

Funding

The study is funded by the Indian Council of Medical Research (ICMR) under the small grant research scheme. The funding body has provided financial support for study implementation but has no role in the design of the study, data collection, analysis, interpretation of results, or the decision to submit manuscripts for publication. The Tata Memorial Centre serves as the primary sponsor, ensuring institutional oversight and infrastructure support.

Data availability

No datasets were generated or analysed during the current study.

Declarations

Ethics approval and consent to participate

The study protocol (Version 5.0, dated July 11, 2025) was reviewed and approved by the Institutional Ethics Committee (IEC) of Tata Memorial Centre, Mumbai (study 4142), as well as the IECs of all collaborating centres prior to initiation of recruitment. The trial was prospectively registered with the Clinical Trials Registry – India (CTRI/2023/12/060849). Written informed consent will be obtained from all participants before enrolment. Consent will include agreement to participate in the study, undergo cognitive and functional assessments, and allow use of anonymised data for analysis and publication. For participants with limited literacy, the consent process will be conducted in the presence of an impartial witness and documented through signature or thumb impression.

Consent for publication

Not applicable.

Competing interests

The authors declare no competing interests.