The underrepresentation of older patients (≥ 65 years) in clinical trials has been well documented for more than 20 years. This has been an issue at all phases of drug development, including pivotal trials for drug approvals,1 despite the fact that many of these new therapeutics will primarily be used in these older patients. Some inroads have been made, but it continues to be a problem that defies a satisfactory solution.
Stuart M. Lichtman, MD, FACP, FASCO
Investing in Our Older Patients
All patients on a clinical trial are a valuable resource. They submit to the rigors of a clinical trial, usually in the hope of improving their situation, while at the same time contributing to cancer care. At study completion, the results are reported to help clinicians make important patient care decisions, particularly if the study is a success and the new therapy is approved. The fact that older patients (particularly those ≥ 75 years) have been a very small fraction of clinical trial patients has led to a paucity of high-quality data. Clinical trial results report recommended doses and schedules that the younger, healthier clinical trial participants tolerated and benefited. It is critical for clinical trial data to be reported to maximize the value of patient participation and provide the treating physician with the best information possible to care for the patients—and this is critical when the older patients are participants. In recent years, ASCO has addressed this situation by issuing a call to increase the evidence base for older patients with cancer.2 ASCO also has published guidelines addressing trial design and patient evaluation and care.3
There are two important issues that are missed opportunities in geriatric oncology research and care; they are interrelated but will be addressed separately. The first is that clinical trials do not take into account the potential of older patients taking part. This will not apply to every trial, but it does apply to studies in which older patients will be a significant part of the study—not necessarily the majority of trials, but approximately 15% to 20% of them. They can be single-agent studies, randomized phase II, or, most importantly, pivotal randomized phase III studies. They can be in solid tumors or hematologic malignancies. It is most crucial for this issue to be addressed in those diseases that are inherently malignancies of older patients, such as prostate cancer and multiple myeloma.
Flaws in Clinical Trial Design
The typical clinical trial design, such as in Cancer Therapy Evaluation Program (CTEP) templates, requires basic demographic information such as age, sex, race, comorbidities, laboratory studies, and pertinent medical history. It will rarely require the recording of medications, social supports, insurance, or financial information and definitely no attempt to evaluate functional status. It is impossible to recreate a database without this latter type of information. At the study end, the response rates and toxicity are tallied.
How can we best use this information? We rely on the results of these trials to help us decide and plan therapy. We feel obliged to use the dose and schedule results. Unfortunately, the more granular information needed for individual treatment does not exist. Clinicians need to take into account a patient’s functional age along with a patient’s chronologic age, because as we know, some older patients have the get-up-and-go of a younger person, and some younger persons may actually function at an older age level. A brief functional assessment will allow the clinician to make this judgment.
This relatively simple intervention would greatly enhance the information available at little cost or extra expenditure of time by the clinical staff. It has been amply demonstrated that self-administered geriatric assessment is accurate and cost- and time-effective. The small amount of extra time spent is compensated by the valuable information obtained. Office staff can be trained to do the functional assessments such as get up and go and handgrip. The simple act of watching patients walk, assessing their gait, and determining whether there is difficulty getting on the exam table can provide valuable information. These functional assessments can easily be incorporated into clinical trials. They have repeatedly been found to be highly predictive of various outcomes. It’s time to stop saying that geriatric assessment is too time-consuming. It is time well spent.4
Missed Opportunity in Trial Data Reporting
The other significant missed opportunity is the analysis and reporting of clinical trial data. This is particularly egregious, as the information exists but needs to be extricated with a few simple steps and forethought. I commented on this back in 2012,5 instigated by a published clinical trial in which older patients were a significant part of the trial (with a median age of 58 and a range to 82 years), and yet no age-related data were reported. No age-related analysis was reported for efficacy or toxicity; age distribution was not reported. The drugs used in this trial included cisplatin and bevacizumab, which have increased toxicity in older patients. These data would be particularly important in trials of this kind. Since we accept the fact that clinical trial patients do not represent the patients seen in practice, then the older patients in this study must have been particularly fit to potentially tolerate these medications.
However, where does that leave the clinician seeing a patient in routine practice who may want to use this regimen?
Which patient, which schedule, what dose, and what dose modification? No information was provided. Some studies will only report a median age and range. It is a disservice to the participants in the study and the subsequent patients who will be treated based on this study to report the results in this inadequate way. A review of clinical trial publications confirmed the inadequacy of the reporting of data for older patients.6 An analysis of the results by age should be simple from a statistical perspective and not add to the cost of the trial. I think it would actually enhance the results and make them more usable and practical. The unjustified inadequacy of these publications needs to stop.
A Path Forward
How can this issue be remedied?
The clinical trial design needs to include geriatric baseline parameters, as suggested by ASCO. CTEP has also modified its template to include these items. Those responsible for review studies (ie, institutional review boards, the National Cancer Institute, etc.) should require these data be obtained in the appropriate studies. In my opinion, the one thing that will be a game-changer is that journal editors and reviewers also require this information. If one of the requirements for publication is age-appropriate data and analysis, it will encourage the trial designers to incorporate these items. The journals require the studies to conform to ethical standards; I submit that the ethics of the trials need to include the complete use of the data obtained. The readers need to demand this.
It is gratifying to see that the U.S. Food and Drug Administration has recently released guidance for the inclusion of older patients on the study.7 It is mandatory for follow-up monitoring of these recommendations to ensure compliance. Investigator-initiated and cooperative group trials also need to heed these recommendations.
To refer back to an earlier commentary I wrote for The ASCO Post, “If not now, when?”8 Such simple and low-cost interventions will yield great dividends in the care of older patients. It needs to start now.
Dr. Lichtman was Attending Physician in the Department of Medicine, Memorial Sloan Kettering Cancer Center, Professor of Medicine, Weill Cornell Medical College (retired). He is Past President of the International Society of Geriatric Oncology (2016–2018).
REFERENCES
1. Scher KS, Hurria A: Under-representation of older adults in cancer registration trials: Known problem, little progress. J Clin Oncol 30:2036-2038, 2012.
2. Hurria A, Levit LA, Dale W, et al: Improving the evidence base for treating older adults with cancer: American Society of Clinical Oncology statement. J Clin Oncol 33:3826-3833, 2015.
3. Mohile SG, Dale W, Somerfield MR, et al: Practical assessment and management of vulnerabilities in older patients receiving chemotherapy: ASCO guideline for geriatric oncology. J Clin Oncol 36:2326-2347, 2018.
4. Hamaker ME, Wildes TM, Rostoft S: Time to stop saying geriatric assessment is too time consuming. J Clin Oncol 35:2871-2874, 2017.
5. Lichtman SM: Call for changes in clinical trial reporting of older patients with cancer. J Clin Oncol 30:893-894, 2012.
6. BrintzenhofeSzoc K, Krok-Schoen JL, Canin B, et al: The underreporting of phase III chemo-therapeutic clinical trial data of older patients with cancer: A systematic review. J Geriatr Oncol 11:369-379, 2020.
7. U.S. Food and Drug Administration: Inclusion of older adults in cancer clinical trials. Available at https://www.fda.gov/regulatory-information/search-fda-guidance-documents/inclusion-older-adults-cancer-clinical-trials. Accessed May 12, 2022.
8. Lichtman SM: Geriatric assessment: What are you waiting for? The ASCO Post. July 10, 2020. Available at https://ascopost.com/issues/july-10-2020/geriatric-assessment-what-are-you-waiting-for/. Accessed May 12, 2022.
Disclaimer: This commentary represents the views of the author and may not necessarily reflect the views of ASCO or The ASCO Post.
