‘Oncological trials—designed for result or clinical relevance?’ Free

Key Points

• Increasing age is associated with poorer cancer outcomes including survival and tolerance of treatment.

• Older adults are often excluded from early phase studies and RCTs by restrictive inclusion criteria.

• Only 1% of interventional trials were older-patient-specific.

The UK has an ageing cancer population—by 2040; it is estimated that over three-quarters of cancer survivors will be aged 65 and older. A similar pattern is seen across the world [1]. Increasing age is associated with poorer cancer outcomes including survival and tolerance of treatment. This is primarily due to tumour extrinsic factors including delayed presentation and diagnosis, lack of availability of geriatric assessment, and individual patient factors [2].

Randomised controlled trials (RCTs) determine the standard of care treatment for this population, yet older adults are often excluded from early phase studies and RCTs by restrictive inclusion criteria relating to age, co-morbidity, organ function and prior malignancy [3, 4]. This exclusion is most evident in early phase trials, which determine the drug dose to take forward. The older adults that are included tend towards one end of the ‘fitness’ spectrum and are not representative of the real-world patients encountered in a surgical or oncology clinic [5]. This mismatch has been well described and assumes greater importance with the move towards more complex anti-cancer regimens. These regimens now often involve multi-modal approaches and/or combinations of systemic therapy, where even minor changes in patient’s pharmacokinetics and pharmacodynamics can have catastrophic effects on morbidity and mortality. Clinicians and patients are therefore required to make potentially life-changing decisions without adequate information.

The relevance of the traditional disease-centric endpoints used in clinical trials such as overall or progression-free survival has also been questioned. Several studies have suggested that older adults with cancer may prioritise quality of life and maintaining independence and function over length of life [6, 7]. These older patient relevant outcome measures are rarely reported in primary study results. Recently, more patient focussed novel outcome measures have been described such as overall treatment utility (OTU) or days spent at home, but have not yet been widely adopted.

As healthcare professionals who are involved in the care of older adults with cancer, we must consider whether current oncological trial design and outcome measures are motivated by maximising chances of obtaining a positive result, or by the most relevant outcome for the population.

In this issue of Age and Ageing, Yang et al. contribute to our knowledge of this topic and should be commended for their work. They performed a cross-sectional analysis of the ClinicalTrials.gov trial registry over a 20-year period (2000–2019) to assess the frequency and characteristics of age-specific non-interventional oncological trials. They found that only 1% of the 49,273 eligible interventional trials were older-patient-specific (using variable age cut-offs). Of these, most (58.7%) were phase 2 studies and enrolled fewer than 100 patients. 40% were conducted for haematological disease. The older-patient-specific trials were less likely to be funded by industry (26.9% vs 37.1%, P < 0.001) or the National Institute for Health (14.9% vs 17.6%, P < 0.001), and thus the majority required funding from other sources e.g. academic institutions. There was no correlation between the number of trials for a given cancer type and the relative incidence or mortality rate. Concerningly, few of the trials included endpoints that could be considered clinically relevant and meaningful to an older patient, e.g. function, cognition or healthcare utilisation.

The study provides a useful comparison of clinical trials involving older people with cancer, versus their younger counterparts, and highlights the inadequacies that still exist in cancer trial registration. However, several limitations should be acknowledged. Firstly, while the ClinicalTrials.gov database is the largest in the world, several others exist and were not included. Secondly, the choice to focus only on interventional studies meant that non-interventional studies specifically focusing on the role of geriatric assessment were not included. Finally, it should also be noted that the non-age specific studies may have pre-planned subgroup analyses of older adults, which can provide useful data for clinical decision making in older adults.

Overall, the data presented by Yang et al. support and confirm previous literature on smaller datasets and highlight the challenge for the geriatric oncology community. How can we practise realistic medicine without the evidence we need to facilitate shared decision-making?

There needs to be a focus on encouraging industry and national research bodies to fund trials targeted to and designed for the older patient population—prioritising clinical relevance over results and profit. This need has been recognised by the U.S. Food and Drug Administration with their recent announcement of recommendations urging companies to boost representation of adults aged over 65 and especially aged over 75, particularly in experimental cancer treatments [8]. Fair trial representation of older adults is all the more important as data emerge demonstrating the differences in the biology of various tumour groups with advancing age [2].

Positive steps are being made with several recent examples of UK-based trials designed for older adults such as Bridging the Age Gap in early breast cancer [9] and the GO2 trial in advanced gastroesophageal cancer [10]. In addition, guidelines related to improving the inclusion of older adults in trials have been published by key organisations such as the American Society of Clinical Oncology (ASCO), the International Society of Geriatric Oncology (SIOG) and the European Organisation for Research and Treatment of Cancer (EORTC) [11–13]. However, implementing change and obtaining data will require time and patience.

While we wait, what can geriatricians and oncologists do to try to improve the cancer journey for our older adults with cancer? Firstly, we must advocate for our patients. To do this, multi-disciplinary and inter-speciality communication is essential—in both directions. Secondly, we must educate both the current and future workforce regarding principles of oncological management and the role of geriatric assessment and intervention. Finally, with the recent publication of several studies demonstrating the benefits of geriatric assessment and intervention in cancer management, screening for frailty with targeted intervention is now a standard of care for all older adults with cancer [14]. By doing this, we can take a step towards making more clinically relevant and tailored management decisions with, and for, our older adults with cancer.

Declaration of Conflictsof Interest

None.

Declaration of Sources of Funding

None.

References