Cancer Clinical Trials: A Relevant Need to Clearly Define the Value to Individual Patients

Maurie Markman, MD

It would be difficult, if not impossible, to mount an argument against the importance of well-designed and conducted clinical trials as a critical component in the establishment of modern cancer care. How would we have possibly learned the value of individual anticancer drugs or combination regimens, the appropriate doses, schedules and duration of treatment to optimize effectiveness? How would we have developed an understanding of anticipated adverse effects (AEs) as well as strategies to minimize their effects on a patient’s quality of life?

Yet, despite the accolades provided to the clinical research paradigm as an essential strategy to enhance the opportunity for meaningful outcomes, serious questions must be asked about the current state of interventional trials in the oncology sphere and how to improve their future value.

We begin this all-too-brief discussion by looking at published analyses, which have highlighted the issue of the actual relevance of reported results (both efficacy and toxicity) to the real-world population of patients with cancer. Yes, the trial may have led to regulatory approval of a new drug for commercial sale or an additional indication for a previously approved agent. And completion of a well-designed and conducted study hopefully will lead to a subsequent peer-reviewed publication for all to view.

But were the patients who agreed to become participants in the study objectively representative of the population routinely encountered in most clinical practices in the United States? In fact, it is now widely acknowledged that older patients (debatably defined as aged 55 to 70 years), the group most likely to be affected by cancer, remain seriously underrepresented in interventional cancer trials.¹

Further, both older and younger patients with cancer with common clinically relevant comorbidities (eg, mild to moderate cardiac, pulmonary, renal or hepatic dysfunction; moderate to severe diabetes or obesity) are frequently either directly excluded or more indirectly “not encouraged” to participate because of concern for excessive risk to their health or the potential that negative outcomes (including fatalities) would be difficult to interpret.² Finally, available data demonstrate the relative absence in cancer trials of other potentially relevant subgroups (eg, those based on ethnic background, socioeconomic status, geographical location, history of a prior successfully treated cancer).^1,3

For example, a recent report titled “State of Geographic Access to Cancer Treatment Trials in the United States: Are Studies Located Where Patients Live?” noted that in 2022, 70% of US counties were without any reported trials involving 19% of individuals 55 years or older.⁴ The investigators commented that 86% of nonmetropolitan counties had no available cancer trials. Further, and of potentially great practical relevance, 26% of individuals 55 years or older lived more than an hour from an oncology site with a reported availability of more than 100 active cancer studies.

This issue of accessibility to clinical trials naturally leads to the question being highlighted in this commentary: Although results of clinical trials have led to major advances in cancer care, what is the value today to an individual patient associated with participation in an antineoplastic therapeutic study?

The long-standing mantra of many within the cancer research community that clinical trial participation is the best form of cancer care has been challenged recently, both by the presentation of objective data revealing quite modest/limited survival benefits^5,6 and rather blistering commentaries accompanying these peer-reviewed publications.^7,8

^{How Does One Respond to These Criticisms?}

Although limited space does not permit a rigorous critique of either the reported analyses or the associated editorials, it is relevant to acknowledge that interventional cancer trials are designed to favorably affect clinically relevant outcomes for the individual participants and to produce “generalizable knowledge” to be reported in the peer-reviewed literature that might be of benefit to future patients. As a result, objective data generated in so-called “negative trials” will hopefully be of value in the development of subsequent investigative efforts in a particular area.

In the opinion of this commentator, a second point related to the reported findings of only “modest survival benefits” associated with randomized cancer clinical trial participation should be viewed as encouraging news, rather than a distressing observation.

This conclusion is based on the profoundly important ethical principle of equipoise that declares oncologists should only consider recommending a patient participate in a randomized interventional trial if they personally do not have a strong belief (based on available clinical data and the oncologist’s own experience) in the superiority of one of the study arms compared with the others.⁹ In the absence of a clinical reason to select a particular study arm, randomization is an ethically justifiable approach to the selection of disease management (“flip of a coin”) in a specific clinical setting. Again, in the opinion of this commentator, the finding of limited overall survival differences in the reported analysis is consistent with the oncology community’s consideration of, and support for, this important ethical principle.

But perhaps the most important point to be made in response to the criticism is to firmly acknowledge that for a number of both practical (eg, time/ effort required, limited family support systems, cost considerations) and quite individualized (eg, concern about a specific listed adverse effect) reasons, clinical trial participation may simply not always be the best option for an individual even if a relevant study is available.

When discussing potential entry by a patient with cancer into a therapeutic clinical trial, it is essential that the potential risks and benefits, the knowns and unknowns, are carefully and clearly described, and all questions are answered to the best of the clinician’s/investigator’s ability to do so. No, participation in an interventional cancer study is not necessarily the best approach for every patient, but whenever realistically feasible, a locally available, well-designed, carefully monitored investigative effort hopefully will be a meaningful option to be considered.

Maurie Markman, MD, is president of Medicine & Science at City of Hope Atlanta, Chicago, and Phoenix.

References

1. Murthy VH, Krumholz HM, Gross CP. Participation in cancer clinical trials: race-, sex-, and age-based disparities. JAMA. 2004;291(22):2720-2726. doi:10.1001/jama.291.22.2720
2. Jaoude JA, Kouzy R, Mainwaring W, et al. Performance status restriction in phase III cancer clinical trials. J Natl Compr Canc Netw. 2020;18(10):1322-1326. doi:10.6004/jnccn.2020.7578
3. Perez M, Murphy CC, Pruitt SL, Rashdan S, Rahimi A, Gerber DE. Potential impact of revised NCI eligibility criteria guidance: prior malignancy exclusion in breast cancer clinical trials. J Natl Compr Canc Netw. 2022;20(7):792-799. doi:10.6004/jnccn.2022.7017
4. Kirkwood MK, Schenkel C, Hinshaw DC, et al. State of geographic access to cancer treatment trials in the United States: are studies located where patients live? JCO Oncol Pract. Published online October 2, 2024. doi:10.1200/OP.24.00261
5. Iskander R, Moyer H, Fergusson D, McGrath S, Benedetti A, Kimmelman J. The benefits and risks of receiving investigational solid tumor drugs in randomized trials: a systematic review and meta-analysis. Ann Intern Med. 2024;177(6):759-767. doi:10.7326/M23-2515
6. Iskander R, Moyer H, Vigneault K, Mahmud SM, Kimmelman J. Survival benefit associated with participation in clinical trials of anticancer drugs: a systematic review and meta-analysis. JAMA. 2024;331(24):2105-2113. doi:10.1001/jama.2024.6281
7. Shalowitz DI, Miller FG. Are patients with cancer best managed in a clinical trial? JAMA. 2024;331(24):2077-2078. doi:10.1001/jama.2024.1235
8. Wilson BE, Eisenhauer EA, Booth CM. Study participants, future patients, and outcomes that matter in cancer clinical trials. JAMA. 2024;331(24):2081-2083. doi:10.1001/jama.2024.1281
9. Hellman S, Hellman DS. Of mice but not men. Problems of the randomized clinical trial. N Engl J Med. 1991;324(22):1585-1589. doi:10.1056/NEJM199105303242208