The ESMO/SIOG Cancer in the Elderly Working Group pragmatic strategies for clinical trial designs and endpoints in older adults with cancer

Abstract

Background

Despite cancer affecting mostly older people, patients aged 70 years or older are under-represented in contemporary trials even in the absence of age restrictions. Moreover, trials dedicated to older adults with cancer, including geriatric assessment and management, are limited because of either clinician, patient, or sponsor bias. This article outlines pragmatic strategies to improve trial design and endpoints to facilitate participation of older adults with cancer in clinical trials.

Methods

The joint European Society for Medical Oncology (ESMO) and International Society of Geriatric Oncology (SIOG) Cancer in the Elderly Working Group assembled a group of international experts to propose strategies for clinical trial designs and endpoints in older adults with cancer. Expert panel discussions based on review of the evidence were held to reach a consensus.

Results

Several obstacles to trial participation such as system barriers (e.g. strict eligibility criteria, poor design, time-consuming procedures) and clinician and individual barriers (e.g. age bias, toxicity concerns, patient preferences, caregiver influences, digital divide) have been identified. Strategies to improve trial accrual and retention include streamlining recruitment, enhancing patient support, leveraging digital tools, and engaging caregivers and patient advocates.

Conclusions

We recommend investing in geriatric oncology clinical trial designs that incorporate traditional survival endpoints, as well as prioritise outcome measures affecting quality of life and function in line with the patient goals and preferences.

Highlights

• •Inclusion of older adults in clinical trials ensures that research findings are relevant and applicable in this population.
• •Engaging patients and caregivers in trial design ensures outcomes that reflect the priorities and needs of older adults.
• •Adaptive and pragmatic trial designs improve inclusion and participation of older adults in cancer research.
• •Trial designs should include geriatric assessment and management to inform treatment decisions in clinical trials.
• •Consider various strategies to implement trial endpoints and designs that are meaningful to older adults.

Introduction

The burden of cancer continues to rise with the global ageing population where >20% of all new cancers will be diagnosed among people aged ≥80 years.^1,2 Multimorbidity, frailty, limited life expectancy, and higher risk of severe toxicities make the management of older adults with cancer more complex.3, 4, 5 Moreover, cancer and its treatment may accelerate the ageing process, worsen pre-existing comorbidities, or even precipitate or aggravate frailty, which can negatively impact the outcomes.⁶ Although cancer is more prevalent in the older population,⁷ older patients remain under-represented in clinical trials that set the new standards for cancer treatment.8, 9, 10, 11 Thus, many cancer management strategies are extrapolated from data derived from fit, younger patients, limiting the applicability of these results in more frail, older patients.¹²

Additionnally, some older people may have priorities that are not addressed in trials that included only younger patients.¹³ Most clinical oncology trials report traditional endpoints relating to cancer and its treatment, such as survival, response rates, and toxicity, whereas patient-related endpoints that emphasise quality of life (QoL) or functional independence are not routinely captured or reported.^8,11,14 This article provides an overview of clinical trial design strategies that considers the diversity of the population of older adults with cancer, along with the tools used to support their implementation and enhance trial participation, recruitment, and retention.

Trial eligibility

Common barriers to clinical trial participation include overly strict eligibility criteria, suboptimal trial design, complex patient information and consent forms, burdensome trial procedures, limited access to trial opportunities, personal biases, and concerns about treatment toxicity (Table 1).^12,15 Many previous trials explicitly excluded patients based on chronological age. Despite current trials imposing no upper-age limit in inclusion criteria, age disparity remains. Among 7747 cancer trials registered between 2008 and 2021, only 1.5% (n = 116) of the trials included patients aged ≥60 years.¹⁶ Comorbidities, organ dysfunction, frailty, prior malignancies, and polypharmacy that are prevalent in older adults could often exclude them from trial participation. This occurs despite the lack of supporting scientific rationale other than to mitigate adverse events from experimental treatments and enhance the internal validity of clinical trials.¹⁵ However, this approach greatly limits the external validity of these trials.¹⁷ The broadening of eligibility criteria should be clinically justified, with study rationale reinforced with strong preclinical or pharmacokinetics data.

Table 1.

Proposed solutions to barriers in clinical trial participation of older adults with cancer

Barriers	Associated factors	Proposed solutions
Trial design	•Strict eligibility criteria (e.g. age cut-off, performance status, comorbidities, polypharmacy) •Trial availability and competitiveness •Complicated PICF •Unsuitable trial design and endpoints	• Use various trial designs to accommodate older patients - Embedding GAM - Treatment stratification; reduced, adjusted, or stepwise dose - Adaptive design - Pragmatic design •Expand eligibility criteria - Include patients with ECOG performance status 2 or comorbidities if they do not impact patient safety and if clinically reasonable/justifiable - Justification of eligibility criteria (e.g. CrCl <50 through pharmacokinetics or preclinical data) •Improve language and readability and simplify PICF •Implement strategies to mitigate and manage treatment complications •Consult patients, caregivers, patient advocates, and clinicians on trial design and endpoints •Follow the EIR
Clinician	•Age bias •Concern for toxicity/tolerance to treatment •Time constraints •Need to start treatment sooner •Preference for other treatment over trial •Lack of infrastructures or funding to conduct trials	•Educate clinicians and researchers •Consultation with geriatricians or geriatric oncology specialists •Use simple tools to describe patient population such as G-CODE, the ASCO Practical Geriatric Assessment •Monitor and optimise management of comorbidities •Implement geriatric assessment tools and management •Invest in research funding
Patient and caregiver	•Limited knowledge and understanding of trials (e.g. against experimentation) •Issues with transportation and/or mobility •Issues with burden of trial (extra tests, lengthy visits) •Time toxicity •Financial constraints •Concern for toxicity/tolerance to treatment •Preference for alternative and complementary therapies •Self-bias (e.g. believing that they are too old to participate)	•Community awareness and education •Use of digital technology for remote access and real time monitoring •Community support •Cover patient care cost •Offer subsidised travel costs •Advocates for patients and caregivers •Trial coordinators and patient navigators

ASCO, American Society of Clinical Oncology; CrCl, creatinine clearance; ECOG, Eastern Cooperative Oncology Group; GAM, geriatric assessment management; G-CODE, geriatric core dataset; EIR, enrolment to incidence ratio; PICF, patient information and consent form.

Trial designs

Defining the right trial design for older adults can be challenging. Novel trial designs and strategies yield substantial opportunities to expand the evidence on their cancer management. Investigators can use and adapt the PRECIS-2 tool when designing a clinical trial for older adults, ensuring that it matches the intended purpose. This tool evaluates nine domains that can be used to evaluate the effectiveness of an intervention in real-world conditions (pragmatic) or to understand the intervention’s mechanism of action in a controlled environment (explanatory) of a clinical trial’s design.¹⁸ Table 2 shows various trial designs that incorporated interventions to increase the inclusion of older adults in clinical research. We discuss in the following section the key points to be considered.

Table 2.

Summary of various study designs that can be tailored to improve recruitment into clinical trials of older adults with cancer

Clinical study design	Description	Benefits for geriatric oncology trials	Considerations for recruitment of older adults	Limitations/threats
Interventional trials
Pragmatic trials	Real-world trials conducted in routine clinical settings to provide applicable evidence.	-Reflects real-world treatment outcomes, especially in diverse older populations. -Focus on feasibility, effectiveness, and overall health outcomes that matter to older adults.	-Easier to recruit -Less restrictive -Eligibility criteria can include frail and diverse older patients. -Flexibility in treatment delivery can make participation easier for older adults.	-Measure effectiveness not efficacy -Require greater number of participants -Recruitment of a diverse and representative population -Funding
Stratified trials	Trials that anticipate a stratification according to frailty or comorbidity level or prognosis.	-Help to assess pharmacological strategy adapted to frail or multimorbid patients.	-Random stratification according to frailty, multimorbidity or prognosis score	-Complexity in trial design and analysis, as stratification adds layers of variables -Funding
Extended trials or long-term extension studies	Trials that continue beyond the initial period to monitor long-term effects of treatments or interventions.	-Helps assess long-term toxicity, physical and cognitive decline, or survival. -Ensures more data are available to understand the durability of responses in older patients.	-Extended follow-up may deter recruitment if patients fear commitment. -Retention strategies are crucial to avoid attrition due to aging or illness progression.	-Logistical and resource challenges due to extended duration -Funding -Restrictive population included in the clinical trial
Adaptive clinical trial designs	Flexible trial designs where treatments and protocols can be adjusted based on interim results, i.e. dose adaptation such as stepped dosing or de-escalation.	-Increase efficiency and likelihood of identifying treatments suitable for older adults. -Minimise exposure to ineffective treatments and allow personalised treatment modifications.	-Reduce the risk of prolonged exposure to ineffective therapies, which may encourage participation. -Regular assessment enables treatment to be adapted to older adults’ evolving health conditions.	-Complexity in trial conduct and regulatory approvals due to dynamic adjustments. -Require greater number of participants -Funding
Observational cohort studies
Clinical prospective cohort studies/phase IV trials	Studies where participants are followed over time to observe outcomes. In phase IV, participants are exposed to the newly approved drug. Include prospective rRCTs that evaluate therapeutic options available/used in routine clinical care.	-Allows observation of long-term and rare effects of cancer treatments on older adults. -Can assess changes in health status, cognitive function, and quality of life. -Can include comorbidities, polypharmacy and other geriatric variables, if available. -Prioritise treatment strategies	-Monitor risk for frailer patients. -Recruitment could target older populations at high risk of specific cancers.	-Loss to follow up -Continuous engagement is needed -rRCTs are only relevant to older adults if they include geriatric variables
Retrospective cohort studies
Using clinical data warehouse	Cohort studies that rely on health routine data from patients receiving standard care outside of clinical trial environments, often utilising electronic health records.	-Highlights treatment outcomes in non-ideal clinical settings for older adults. -Can consider comorbidities and polypharmacy if data are available.	-Reduced barriers to participation, as data comes from routine care. -Older patients who might not be eligible for traditional trials can still be included in analyses based on real-world data.	-Relies on the accuracy and completeness of routine care data. -Important variables in geriatric oncology e.g. functional status or QoL are rarely captured.
Using emulated target trial framework	It is a causal inference framework to clarify causal research questions by borrowing the structure of an RCT. It helps reduce design-related biases allowing researchers to focus on confounding biases when comparing the effectiveness of treatment strategies using observational data.	-Provides transparency and easily interpretable results for clinicians who are used to interpreting RCTs.	Not applicable as it is a framework.	Limitations are related to the data source used.

This table outlines the potential benefits of each clinical trial design in the context of geriatric oncology and addresses considerations for recruiting older adults into trials. The goal of these designs is to ensure that older adults are well represented in clinical research, leading to more tailored treatments and improved outcomes for this population.

QoL, quality of life; RCT, randomised clinical trial; rRCT, registry-based randomised controlled trials.

Incorporating geriatric assessment

Incorporating geriatric assessment and management (GAM) into care pathways leads to reduced treatment-related toxicities and unplanned hospitalisations, and improved communication and QoL, without affecting survival outcomes.19, 20, 21 While GAM is recommended based on randomised clinical trials,20, 21, 22 it is not yet implemented in routine clinical practice worldwide primarily due to limited resources, as well as scepticism about its utility. Embedding GAM in a trial design will ensure its implementation for all trial participants and allow safer treatment administration. Improved tolerability and well-being contribute to greater patient satisfaction with the treatment process, fostering a more positive overall experience, and potentially improving adherence to therapy. Implementing a self-administered geriatric screening questionnaire [i.e. the Senior Adult Oncology Programme Questionnaire 3 (SAOP3) tool] could also help describe the patient population and save resources when they are not available or limited. It is feasible to use even in phase I studies and provides opportunities for prehabilitation and support to improve safety and trial access.²² These will help clinicians better understand the diversity of older adults encountered in routine practice, leading to more applicable and generalisable findings that inform treatment decisions in everyday oncology care.

Using patient-centred, adaptive approaches

Using lower or stepwise dose interventions or stratification based on geriatric assessment (GA) may improve treatment tolerance. An example is the ESOGIA-GFPC-FECP 08-02 study where older adults with advanced non-small-cell lung cancer had fewer toxicities when given combination chemotherapy, monotherapy, or best supportive care based on GA results compared with those who received treatment based on age and performance status only.²³

In the ELAN-ONCOVAL study,²⁴ older patients with unresectable head and neck squamous-cell cancers were stratified as fit or unfit based on GA. Fit, older patients (ELAN-FIT) were given the adapted EXTREME regimen as first-line treatment and showed overall survival and tolerability that were comparable with younger patients treated with standard regimens.²⁵ In contrast, patients classified as frail (ELAN-UNFIT) showed no failure-free survival benefit when given either cetuximab or methotrexate.²⁶

Similarly, upfront reduction of the dose or the number of chemotherapy agents given to older patients with advanced gastro-oesophageal or colorectal cancers resulted in fewer toxicities and better patient experience without significantly impacting progression-free survival and overall treatment utility benefit as shown in the GO2, MRC-FOCUS2, and PANDA trials.27, 28, 29

The applicability of this strategy in other tumours remains uncertain given the heterogeneity of cancer types and treatment setting and warrants further studies.

Use of existing data

Conducting a prospective trial to address a research question is not always feasible because of costs, time constraints, and ethical concerns. Researchers may therefore rely on existing observational (or real-world) data that have been collected for purposes other than research. These data sources could include records from electronic health care or hospitalisation, or data from cancer registries and insurance claims. Because of the observational nature of this data, great attention should be paid when designing studies to reduce the risk of biases, including confounding, collider bias, selection bias, or immortal-time bias. Population-based or hospital registry can be used to conduct registry-based randomised controlled trials (rRCT). These rRCT integrate the strengths of both traditional RCTs and clinical registries, potentially accelerating the research process, reducing costs, and speeding up evaluation of treatment options and generalizability.³⁰ The use of existing data is, however, only valuable in the older population if geriatric variables are included. The pros and cons of these observational studies are detailed in Table 2.

Introducing synthetic arms

While we advocate for inclusion of older adults in RCTs, participation may not be feasible for all. A synthetic control arm is a simulated control group created by using existing data from historical clinical trials, observational studies, electronic health records, or patient registries instead of recruiting a separate group of patients for a traditional control arm.³¹ This approach may be useful if a traditional control arm is difficult, unethical, or impractical to implement, improving the retention of older adults who may be hesitant to participate in an RCT. Notably, it is important to establish the validity and reliability of the synthetic datasets used for clinical comparisons of different interventions and ensure that the characteristics of the trial participants are comparable.³¹ This field of research is currently under development to overcome the same risk of biases as observational studies.

Integrating shared decision making

Shared decision making (SDM) is a key tenet of practising medicine, especially in patients confronted with difficult trade-offs between treatment efficacy and toxicity. SDM should be integrated in geriatric oncology (GO)-tailored clinical trials to enhance communication between patients, caregivers, and health care providers when discussing treatment options and preferences.32, 33, 34, 35, 36 Tools such as decision aids and educational materials can help with discussions about cancer treatment, goals, and potential side-effects³⁷ to facilitate informed consent and health literacy.³⁸ For example, the Age Gap Decision tool (https://agegap.shef.ac.uk/) was developed to facilitate shared decisions around surgery or chemotherapy for older adults with curable breast cancer.³⁹ By fostering an environment of collaboration, patients (and their caregivers) can actively participate in making treatment choices that align with their health status and priorities.

Including caregivers in trial design

Caregivers play a pivotal role in supporting older adults with cancer, providing physical assistance and emotional support, and helping patients navigate complex health care decisions.⁴⁰ Recognising the caregiver’s role in clinical trial design can enhance the overall care experience for both patients and their families. Clinical trials should include caregiver-reported outcomes to assess the impact of treatments on the caregiver–patient dynamic, as caregivers often experience significant emotional and physical burdens. Studies dedicated to evaluating the impact of cancer on patient–caregiver dyads are called dyadic research,⁴¹ which consider the patient–caregiver dynamic rather than just focusing solely on the patient. This approach acknowledges the interdependence of patients and their caregivers in decision making, treatment adherence, and overall well-being.⁴²

Selecting meaningful trial endpoints

Clinical trial endpoints are outcomes or events that are used to objectively evaluate the effect(s) of an intervention. Wildiers et al. had previously highlighted the relevant endpoints in GO research.¹⁴ Notably, treatment efficacy endpoints commonly used in clinical trials, such as survival or response rates, are focused on the intervention and sometimes may not reflect what matters most to the patient. While these remain relevant for many patients, especially in the curative setting, some older adults may favour preserving QoL, cognition, and functional status over survival gains.^13,43, 44, 45 A crucial element in GO-tailored clinical trials should be an emphasis on factors that influence their treatment decisions, and clinical trials should include measures of physical function (e.g. gait speed, grip strength) and cognition (e.g. assessments of memory, executive function).

Endpoints should also consider the dynamics of patient and treatment outcomes, such as:

• -Time to functional decline, duration of functional decline, time to hospital admission, days spent in hospital over days spent at home, or transfer to residential aged-care facility, which could help better understand the impact of treatment on autonomy and QoL.
• -Time to treatment toxicity or dose interruption, modification, or cessation, which focuses on treatment tolerability.

These assessments are crucial, as treatments may exacerbate frailty and cognitive impairment, or lead to adverse effects such as fatigue or neuropathy.⁴⁶ By systematically evaluating these factors, researchers can ensure that novel treatments do not inadvertently compromise an older patient’s functional independence or QoL. Functional endpoints can be clinician assessed, performance based, or patient reported, with patient-reported outcome measures (PROMs) uniquely capturing the patient’s perspective. The DATECAN elderly initiative was set up to guide researchers and clinicians in assessing the relevant domains where PROMs could be used and integrated in RCTs for older adults with cancer.⁴⁷ The domains considered relevant by the panel of experts were functional autonomy, cognition, depression, and nutrition.⁴⁷

To capture both patient- and treatment-centred outcomes, composite or coprimary endpoints could be used.48, 49, 50 A composite endpoint combines multiple individual outcomes into a single primary endpoint. A patient would have reached the endpoint if they experienced any of the prespecified events. Coprimary endpoints are multiple separate primary endpoints, each of which must be analysed independently. A trial is successful if it meets one or both endpoints, depending on the study design. Overall treatment utility, which combines various components (clinical efficacy, treatment tolerability, and patient-centred outcomes), could be used as a composite or as a coprimary endpoint, depending on the importance given to each parameter within the trial.

Finally, the relevance, feasibility, and acceptability of clinical trial designs and endpoints in older adults will be enhanced by codesigning the trial with various stakeholders including clinicians, nurses, allied health professionals, pharmacists, biostatisticians, patients, caregivers, family members, and patient advocates.

Challenges of incorporating these endpoints in clinical or ‘real-world’ settings

There are significant challenges to implementing GO-tailored endpoints incorporated into clinical trial designs. These challenges include patient-related barriers, digital literacy, technological limitations, logistical issues, and the complexity of adapting trial designs to meet the needs of older patients. Below, we explore some of the key obstacles and potential solutions to facilitate the integration of GO-tailored endpoints in real-world settings.

Potential barriers to implementation

• 1.Digital divide. Digital technologies have been used in health care services and health surveillance, education, and research to disseminate information, assist with health care delivery and data collection, facilitate web-based programmes or remote monitoring, and implement interventions51, 52, 53 to a wider community. However, the needs of older adults have not been given much consideration when designing and developing digital technologies, owing to the outdated assumption that older people are not interested in learning or using digital tools.54, 55, 56 While some older adults have embraced the use of digital technologies, some may have no access or be less likely to trust digital devices or participate in online platforms for data collection, widening the ‘digital divide’. Without alternative methods of participating, such as telephone-based assessments or caregiver-assisted surveys, these patients may be excluded from the trial process, limiting the applicability of study results. This was observed in the FASTOCH study, which evaluated the feasibility of using electronic PROMs in patients aged ≥75 years undergoing active cancer treatment.⁵⁷ The study showed that although participation was not hindered by age, 61% declined to use the electronic PROMs due to lack of internet access.
• 2.Geographical and financial barriers. Geographical barrier is one of the most frequently reported challenges to trial participation, especially in older patients. Living near a health care centre where clinical trials are conducted is associated with an increased chance of enrolment.^58,59 Moreover, many older adults and their caregivers may face financial barriers to cover the extra costs for transportation or accommodation when participating in clinical trials.
• 3.Ageism. The Global Report on Ageism outlines a framework to combat ageism and contribute to improving health, increasing opportunities, reducing costs, and enabling people to flourish at any age.⁶⁰ Ageism towards older adults with cancer may arise consciously or unconsciously from clinicians, patients, or caregivers, which could impact treatment decisions, health care interactions, and patient outcomes.⁶¹

Some oncologists may not consider patients for clinical trials because of age, and the perception that older patients will not be interested in trials and that trial participation may pose undue burden on older patients.^62,63 Moreover, GA may be perceived by researchers and clinicians as an added barrier, especially when there is a lack of time, financial resources, and organisational support to conduct this in research.

Recommended tools and strategies to facilitate implementation

Several tools and strategies have been identified to overcome these barriers and facilitate the incorporation of GO-tailored endpoints into clinical trials, as shown in Figure 1:

• 1.Adoption of digital tools for capturing data. There will be less concern for a digital divide as more older adults become accustomed to technology over time. Indeed, digital tools can resolve several barriers if they are adapted to user preference. Technology can streamline the capture of trial data by enabling remote and decentralised approaches, which are particularly valuable when adapted to the needs of older adults, as discussed below.⁶⁴ Mobile apps and online platforms can be used to track physical activity, monitor symptoms, and collect PROMs in real time. For instance, simplified interfaces with larger fonts and clear instructions can enhance usability for older adults. A digital platform that is easy to navigate and understand will allow patients to actively participate in their care and well-being. Additionally, digital tools can allow better care coordination with their health care providers, reduce duplication and errors, and create continuous data collection between clinic visits, providing a more comprehensive picture of the patient’s health status.65, 66, 67, 68 While a new generation of older adults have more experience with using digital devices such as smartphones, some may still require assistance when completing PROMs, and alternative solutions such as paper-based tools should be made available to ensure inclusivity.⁶⁹ Researchers should provide the device or ensure access to the technology at no added cost to the patient, to encourage use. Moreover, support and mentoring should be offered to enhance patient trust, confidence, skills, and online safety in using technology and facilitating digital engagement.⁷⁰
• 2.Passive collection of patient information. Passive data collection through portable devices or sensors can help gather critical information without requiring active patient involvement. Wearable devices that monitor health metrics such as physical activity, vital signs, sleep patterns, or falls detection can provide valuable insights into a patient’s physical health and function.⁷¹ Patient support must be readily available to motivate continued use, enhance user experience, and adapt to user preference.⁷² Passive data collection into electronic health reports or medical claims for following up toxicities, hospitalisations, functional decline, or survival may limit the required frequency and duration of clinic visits, thereby reducing the burden to patient and caregiver.73, 74, 75 Collected data must be securely stored and compliance with privacy must always be maintained.
• 3.Decentralised clinical trials. Decentralised clinical trials allow patients to participate from their homes or local health care facilities, reducing the need for travel, which is particularly beneficial to older adults with mobility issues and/or geographic and transport barriers.⁵⁹ Utilising telemedicine, remote assessments, and home-based sample collection or local imaging can help accommodate frail patients and those with limited access to trial sites. This design has been evaluated in clinical trials in diseases other than cancer and has shown feasibility.⁷⁶
• 4.Simplified GA tools. To address the barriers based on clinicians’ limited time for GAM, alternatives using simple tools could be implemented. The geriatric core dataset (G-CODE) was developed based on a Delphi consensus among international experts to describe the older population included in clinical trials,⁷⁷ which allowed standardisation of geriatric data results and enabled comparison across trials. This includes assessment of social environment, function, mobility, nutrition, cognition, mood, and comorbidities. Recently, the American Society of Clinical Oncology issued a Practical Geriatric Assessment (PGA) based on four items: nutrition, mobility, cognition, and chemotoxicity.⁷⁸ Both tools are easy to use and take ∼10 min to complete. Notably, geriatric screening tools such as the G8 or VES-13^79,80 are simple and quick, and may be used in centres with fewer resources, albeit they are not as comprehensive as the G-CODE or PGA.
• 5.Engaging caregivers and patient advocates. Caregivers and patient advocates play critical roles in ensuring trial participation and accurate data collection. By involving caregivers more directly, clinical trials can enhance the quality of the data collected, especially for patients with cognitive or sensory impairments. Furthermore, caregivers can provide valuable insights into patients’ daily functioning and QoL, and can also assist with navigating digital tools, completing PROMs, and helping patients adhere to trial procedures.⁶⁹ The Dyadic Cancer Outcomes Framework was developed to guide research and develop interventions to improve the health, psychosocial, and relationship outcomes of patients and caregivers.⁴¹ Patient advocates act as partners in research, and can raise awareness about the importance of GO-tailored trials and improve patient trust in the research process.⁸¹
• 6.Improving awareness and education about clinical trials. Many older adults and their caregivers may have misconceptions or lack awareness about clinical trials. Educational initiatives focused on older adults can help demystify the process and encourage participation. Existing networks may be used to disseminate information through community centres, organisation groups for seniors, or media, and to build relationships with the community, ensuring that older adults are well informed about the potential benefits and risks of participating in clinical trials.⁸²
• 7.Mitigating challenges of trial logistics. Providing practical support for patients and caregivers can alleviate some of the logistical challenges they may encounter, such as coordinating medical appointments, managing treatment schedules, or providing transport to clinical trial sites. Offering services like respite care, counselling, and peer-to-peer online support can reduce the burden on patients and caregivers83, 84, 85 and increase the likelihood of sustained trial participation.
• 8.Offsetting the cost of travel and trial participation. Offering reimbursement of travel and any additional costs associated with trial participation,^86,87 combining appointments or providing telehealth options can help offset these financial obstacles, making participation more feasible, especially for older, lower income patients.⁸²
• 9.Limiting ‘time toxicity’ and reducing participation burden. Patients undergoing cancer treatment often experience ‘time toxicity’,⁸⁸ where frequent medical appointments, travel, and lengthy assessments interfere with daily living.⁸⁹ This burden can be reduced through conducting trial-related assessments on the same day as the patient’s routine clinical visit, or by using alternative monitoring approaches, such as local pathology and imaging centres, home visits, and combining appointments or telehealth consultations. These alternatives minimise the disruption to patients’ lives and make it convenient for older adults to remain engaged in trials.⁸²
• 10.Use of clinical recruitment coordinator or patient (trial) navigator. Designating trial coordinators or patient navigators can help guide older adults through the trial process, from enrolment to participation. These individuals can assist with completing documents, scheduling appointments, and addressing any concerns patients or caregivers might have. Coordinators can also play a key role in liaising between the research team and the patient, ensuring that older adults remain informed and comfortable with trial procedures.⁹⁰ While patient navigation strategy has long been utilised to improve care coordination, quality of care, and patient satisfaction, its role in enhancing trial participation in an RCT is underway.⁹¹ The effectiveness of a navigation intervention for older adults with cancer and their caregivers is being studied in the EU NAVIGATE trial.⁹²
• 11.Flexibility with recruitment and tools to facilitate engagement. Offering flexible entry criteria, such as adjusted dosing regimens or inclusive comorbidity profiles, can help ensure that more older adults are eligible to participate in trials. Similarly, simplified patient information and consent forms translated into simple and native language will help improve readability and understanding of the research⁹³ and may increase the participation of a culturally and linguistically diverse older population. Other simple adjustments, such as providing tools such as magnifying glasses, hearing aids, or amplifiers, and using larger fonts, can greatly enhance older adults’ engagement with trial information and data collection.
• 12.Investing for research funding. Trials dedicated to older adults are mostly sponsored by academic researchers and public grants, as older adults are less likely to be included in industry-sponsored studies.^94,95 However, academic-initiated trials are more likely to terminate early and struggle with patient retention. This highlights the challenges of inadequate incentives, prolonged enrolment periods, and high costs of conducting trials in this population.^95,96 Adding an older adult enrolment supplement to the site budget would cover the extra effort for screening, treatment, and follow-up—including extended visits, additional testing, and GA tools—thereby improving feasibility and incentivising centres to increase enrolment of older adults. This supplemental support could be included in public/academic grants and, to an even greater extent, by industry (pharmaceutical) sponsors.
• 13.Regulatory levers to improve older adult representation. Although the Food and Drug Administration and the European Medicines Agency issued guidance years ago to improve the representation of older adults in clinical research, progress has been limited. We therefore recommend that all interventional oncology trials enrolling patients aged ≥70 years be required to collect and report a geriatric dataset—at a minimum a brief screen (e.g. G8) or a standardised composite (e.g. G-CODE), basic function [activities of daily living (ADL)/instrumental ADL or timed up and go test], comorbidity, and polypharmacy summaries, and age-stratified efficacy, safety, and discontinuation outcomes. This small, standardised set can be embedded in routine workflows with modest burden, yet would generate interpretable, population-specific evidence to guide dosing, monitoring, and decision making, and to support regulatory approval explicitly informed by data from older adults. Aligning this requirement with protocol templates and site budgets (e.g. an older adult enrolment supplement) would further incentivise sponsors and centres to implement it consistently.
• 14.Monitoring the enrolment to incidence ratio (EIR) of older adults. Many subgroups have been under-represented despite the increased burden of cancer incidence in the older population as shown in many landmark trials.^97,98 Monitoring the EIR, which tracks the percentage of older patients included in the trial against the percentage of incident cases in the population, can provide valuable feedback on trial inclusivity. This approach ensures that the recruitment of older adults in clinical trials reflects the true incidence of cancer in this age group. By establishing benchmarks for EIR, sponsors, cancer agencies, and researchers can track and improve the participation of older adults in trials, making the results more representative of the real-world population.

Figure 1.

Tools to facilitate the implementation of geriatric oncology-tailored endpoints and designs in clinical trials.

Future directions

Adequate representation of older adults in clinical trials and their involvement in trial designs will ensure that the study measures outcomes that are meaningful to them. As not all drugs can be safely administered to older patients, evidence on the impact of emerging cancer treatments on key health domains of older adults is needed to inform routine clinical practice and shared decisions.⁹ The assessment of frailty will help clinicians better understand the needs of older participants and identify those at risk for adverse outcomes, allowing tailored interventions and more meaningful analyses of the treatment safety and efficacy outcomes. Moreover, the tools used to assess frailty across oncological trials must be specified to facilitate consistency and validity.⁹⁹

Inclusion of older participants in early phase trials would establish not only evidence on drug–drug or drug–disease interactions, but also inform on age-specific pharmacokinetics and vulnerability to toxicities.¹⁵ Translational studies incorporating senescence-associated biomarkers may be used as ancillary studies to help clinicians better understand the biological mechanisms of ageing and cancer, and their effects on treatment outcomes.^100,101

Conclusion

Incorporating GO-tailored endpoints into clinical trial designs has many challenges, as many older adults may face technological, logistical, or financial barriers to participation. By adopting innovative tools and strategies to capture data, simplifying trial processes, providing support, and engaging patients and their caregivers in study designs, the participation of older patients in clinical trials can be significantly improved. Addressing these barriers will ensure more inclusive trials and generate additional relevant data for this growing population. Prospective studies on the availability, accessibility, and acceptability of these interventions in older adults with cancer are warranted.