Radiotherapy needs level-1 evidence to support its modality. However, most randomized clinical trials in oncology in the US are industry funded and assess systemic therapies alone.¹ Without the financial backing of pharmaceutical companies, the majority of studies seeking to establish new standards of care for radiotherapy are conducted through National Cancer Institute (NCI)鈥揻unded cooperative groups. Yet even among cooperative group trials, systemic therapies dominate.² With fewer radiotherapy trials enrolling, one might expect existing studies to accrue quickly, yet this is not the case. Illustrating this point, among all currently enrolling radiotherapy cooperative group trials activated at least 6 months ago, two-thirds have achieved less than half of expected accruals and 40% have enrolled no more than 25% projected to date. In this Viewpoint, we discuss reasons for accrual difficulties and propose solutions.

If a patient with BRAF-variant metastatic colorectal cancer wishes to receive immunotherapy in combination with doublet therapy, they must enroll in a randomized clinical trial (). Consider a similar patient contemplating local therapy to metastatic sites. Stereotactic ablative radiotherapy (SAbR) is hypothesized to improve outcomes for this population and a randomized trial is also assessing this strategy (). However, SAbR is also available outside of a clinical trial, and therefore patients (and oncologists) may find it difficult to enroll in a study where they have a 50% chance of not receiving the experimental therapy. Unfortunately, in addition to slowing accrual, ability to receive study therapy outside of a clinical trial could also skew enrollment demographics, impacting research validity.

Patients would be more receptive to enrolling in a randomized clinical trial if the medical community demonstrated greater honesty and transparency regarding the existing strength of evidence supporting novel radiotherapy technologies. However, these characteristics are often misaligned with financial incentives. As an example, some proton radiotherapy centers tout drastic improvements in overall survival with protons (vs photons) across disease sites, which has never been demonstrated.³ Across oncology specialties, cancer centers spend an increasing sum on advertisements often promoting anecdotal, exceptional results as expected outcomes for a particular clinical scenario.⁴ When patients are faced with medical advertisements, which are assumed to be based on expert consensus and rigorous evidence, they may find it difficult, even unethical, to be offered a randomized trial.

Unlike most studies of systemic therapy, where the cost of drug and delivery is sponsored by the pharmaceutical company, radiotherapy in a trial must be paid for by insurance. While occasionally this coverage difference permits experimental treatments to be given outside of a clinical trial, other times insurance denials preclude trial enrollment. Therefore, centers may be hesitant to open trials when there are concerns regarding insurance coverage, and individual physicians may be dissuaded from recommending such a trial to their patient.

All radiation is not created equal, and nuances related to target volume delineation, tumor coverage, dose to normal organs, motion management, and more, affect the safety and efficacy of treatment.⁵ Clinical trials aim to standardize these factors through mandating specific regimens and delivery techniques. However, such requirements may be at odds with a radiation oncologist鈥檚 typical practice and/or too onerous to implement, discouraging trial participation.

What are potential solutions for increasing enrollment onto radiotherapy studies? As a community, we should convey data-driven recommendations to patients, rather than overpromise the benefit of novel radiotherapy techniques based on dosimetric advantages and anecdotal clinical outcomes. We also propose implementing the following policy changes.

Clinical trials range from phase 1 to 4, assessing therapies at the earliest phase in humans (phase I) to postmarketing approval after demonstrated efficacy (phase 4). Most NCI-sponsored radiotherapy cooperative group trials are randomized phase 2 or 3, meaning there are published data suggesting benefit to warrant further assessment in a randomized fashion (ie, they are not early 鈥渆xperimental鈥� studies). Insurance coverage should never present as a barrier to enrollment on such trials. While individual prior authorization reviewers can make such exceptions in favor of NCI-sponsored trials on a case-by-case basis, the reality is that necessitating peer review is burdensome, uncertain, and delays patient care. A policy change mandating insurance coverage would circumvent this challenge.

Institutions are given approximately $2000 to $4000 for each patient enrolled in a cooperative group trial. This sum is multitudes lower than for pharmaceutical studies, which reimburse up to $50鈥�000 or more per patient. While there are other benefits to enrolling in cooperative group trials (such as maintaining a cancer center鈥檚 NCI status), the considerably lower patient reimbursement rate remains a barrier. As an example, EA2183, a randomized trial assessing the addition of SAbR to systemic therapy for oligometastatic cancer, was activated 48 months ago, is currently open at 447 sites, and has enrolled 20 patients (average, 0.04 patient/site). While the reasons for slow accrual are multifactorial, the 430 centers accruing 0 patients have experienced negative financial impact. We argue increasing patient reimbursement would improve enrollment and net costs for institutions.

One sector of radiotherapy that possesses greater financial resources, akin to the pharmaceutical industry, is device companies. Yet ironically, devices have the lowest bar for US Food and Drug Administration approval through the 510K pathway, which requires only demonstrated equivalence to current treatments rather than superiority.⁶ Thus, as it stands, there is a negative incentive for companies to conduct and enroll on randomized trials assessing their device. The result is the approval, and use, of radiotherapy devices in scenarios that are untested and could even hurt patients. Short of reforming the 510K pathway, we argue that companies should be required to conduct trials demonstrating superior efficacy of their product. This rule would incentivize companies to open studies and enroll, leading to generation of better evidence for radiotherapy technologies.

Radiotherapy requirements on trial must include only essential elements thought to affect clinical outcomes, which differs across disease settings. For example, in studies assessing dose-escalated radiotherapy for locally advanced pancreas cancer, target coverage and dose to adjacent sensitive luminal structures are priorities. In contrast, for a trial of nonoperative management for rectal cancer, timing of radiotherapy including interval to response assessment may prove more critical to treatment efficacy. Liberalizing protocol requirements, when feasible, would facilitate trial enrollment. After trial completion, radiotherapy quality assurance must be undertaken to accurately interpret clinical outcomes and to inform future trial design.⁷

Radiotherapy is rapidly evolving, and prospective studies are needed now more than ever to assess new treatment strategies. Randomized clinical trials generate the highest level of evidence in medicine, but there 2 major threats to their success: (1) a poorly designed study and (2) one that does not enroll. Although radiotherapy is not immune to the former issue, arguably the greatest challenge we face is in patient accrual. We support the urgent implementation and assessment of strategies aimed at facilitating trial enrollment. Clinicians, payers, and most importantly, patients deserve better evidence to inform treatment decisions regarding radiotherapy.

Corresponding Author: Nina N. Sanford, MD, Department of Radiation Oncology, University of Texas Southwestern, 2280 Inwood Rd, Dallas, TX 75390-9303 (nina.sanford@utsouthwestern.edu).

Published Online: September 12, 2024. doi:10.1001/jamaoncol.2024.3663

Conflict of Interest Disclosures: Dr Sanford reported consulting/speaking fees from AstraZeneca and Signatera outside the submitted work. Dr Hall reported personal fees from Aktis Oncology outside the submitted work and is a shareholder of Sonoptima. No other disclosures were reported.