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Collaboration needed to complete clinical trials of proton therapy
A multistakeholder approach is needed to ensure complete enrollment of seven randomized clinical trials that will test the comparative clinical effectiveness of proton therapy, according to a report published in Journal of Clinical Oncology.
If the trials are completed, definitive evidence will be available for clinicians and experts to determine the most effective or least harmful treatments for patients with various cancers.
“Radiation is an important treatment modality for 60% of patients with cancer, and protons are another form of radiation,” senior report author Jeffrey Buchsbaum, MD, PhD, medical officer and program director of the radiation research program in the division of cancer treatment and diagnosis at NCI, told HemOnc Today. “Studying protons is needed so that physicians have data to make the best treatment choices with their patients. It is important to remember that radiation is a proven, life-saving modality.”
Proton therapy confers various benefits for patients with cancer, particularly due to its better toxicity profile compared with photon therapy.
“Protons may allow dose escalation for more cure or same dose use with lower side effects,” Buchsbaum said.
Still, trial researchers want to determine whether proton therapy might be associated with different adverse events when used to target cancers at different sites. Proton therapy also has more physical and biologic uncertainties than photon therapy, which can lead to higher radiation dose and damage to nearby healthy tissue.
The seven randomized clinical trials — spearheaded by NCI and Patient-Centered Outcomes Research Institute, or PCORI — seek to answer these questions by evaluating the benefits and harms of proton therapy for various cancers, including those of the breast, lung, prostate, esophagus and liver, as well as low-grade glioma and glioblastoma.
“We don’t know if protons are truly superior in the context of the hypotheses being tested in each trial,” Buchsbaum said.
Despite the importance of learning more about proton therapy through these clinical trials, enrollment has remained low. Barriers to enrollment have delayed the start of multiple trials that, if completed, stand to have life-saving implications.
“Centers need to accrue to the trials so that we can generate evidence,” Buchsbaum said.
Lack of coverage
A variety of obstacles have slowed enrollment for these trials.
“These are challenging trials to accrue to for a host of reasons, with no fault being cast on anyone or any party,” Buchsbaum said.
After consulting with clinicians, patient advocates and insurers involved in the clinical trials, Buchsbaum and colleagues found that restrictive insurance coverage is the primary barrier to enrollment.
In the report, researchers reviewed coverage policies among commercial insurers in health care markets of the proton centers involved in the trials. They found most insurers and state Medicaid plans did not cover proton therapy for the study indications; however, Medicare usually covers the treatment through local coverage determinations, which often require clinical trial participation.
Although it is FDA approved, most insurance carriers state it is unproven that proton therapy is a clinically more effective and less harmful treatment for the cancers under study.
Insurance carriers deny coverage to reduce inappropriate use of medical technologies, according to report author Justin E. Bekelman, MD, associate professor of radiation oncology and medical ethics and health policy and senior fellow in Leonard Davis Institute for Health Economics at University of Pennsylvania’s Perelman School of Medicine.
“A downside when applied to proton therapy is that patients cannot participate in randomized clinical trials designed to answer crucial questions about its benefits and harms,” Bekelman said in a press release.
In addition to the lack of proven superiority compared with other treatment modalities, the cost of proton therapy also can drive a lack of coverage. The average Medicare reimbursement for each treatment course is $10,000 to $20,000 greater for proton therapy than for photon-based intensity-modulated radiation therapy, according to the report authors.
Still, some insurance companies cover proton therapy for certain cancers involved in studies or have coverage established with study participation policies. Select proton therapy centers also offer discount or reference pricing with or without evidence development.
“Some success has been achieved when centers work with insurers directly for the development of evidence,” Buchsbaum said. “People have worked together to address this issue.”
A lack of insurance coverage may not only further delay enrollment, but also negatively affect applicability of results.
Buchsbaum and colleagues reported a number of clinicians no longer approach patients to participate in the proton arm of the clinical trial due to insurance restrictions.
Additional barriers
Other institutional barriers to enrollment include inadequate reimbursement for trial operational costs, time-consuming consideration by institutional review boards, time pressures in routine care that prevent trial discussions with patients, and lack of recognition of individual trial contributions for academic promotion.
Patients also may be deterred from wanting to participate due to personal costs and preference of treatment.
Travel and associated out-of-pocket expenses can preclude some patients from participating in trials, Buchsbaum said.
A survey of 59 eligible patients who declined to participate in the breast cancer trial cited the following reasons: personal preference for another treatment (53%); insurance coverage preference for another treatment (34%); or doctor preference for another treatment (15%).
Time to approval also can affect patient participation, Buchsbaum said.
“If covered, some insurance companies take quite a bit of time to approve protons, and patients get nervous about waiting for care,” he said.
Improving participation
Buchsbaum and colleagues proposed the following solutions to address enrollment barriers for proton therapy trials:
- A collaboration between commercial insurers, proton therapy centers, hospitals and patient advocates should establish coverage within the radiation therapy treatment trials;
- Radiation therapy centers need to strive for higher enrollment rates; and
- Clinicians and researchers should increase engagement with patients to promote enrollment and retention.
“Focusing on keeping the need to do the study front and center ... is one main way to encourage participation,” Buchsbaum said.
Radiation therapy manufacturers also are encouraged to become involved in this collaboration, because garnering more scientific evidence can expand indications for radiation treatment.
“Talking with the insurance companies is how we have started collaboration, and meeting with the insurance executives was our next step to learn from each other and try to move things forward,” Buchsbaum said. “Getting evidence ultimately helps everyone.”
Such collaboration stands to benefit future treatment modalities.
“To complete these trials, we need a coalition of patients, clinicians, payers, vendors, hospitals and funders,” Bekelman said. “If we are successful, our efforts could serve as a model to evaluate new advanced technologies in the future.” – by Melinda Stevens
Reference:
Bekelman JE, et al. J Clin Oncol. 2018;doi:10.1200/JCO.2018.77.7078.
For more information:
Jeffrey Buchsbaum, MD, PhD, can be reached at Radiation Research Program, Division of Cancer Treatment and Diagnosis, NCI, NIH, 9609 Medical Center Drive, MSC 9727, Bethesda, MD 20892-9727; email: jeff.buchsbaum@nih.gov.
Disclosures: The authors report no relevant financial disclosures.
Perspective
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The potential benefits of proton therapy depend on the disease site and the details of an individual patient, but examples can include reducing or eliminating certain side effects during therapy — such as gastrointestinal toxicities after treatment of spine or retroperitoneal tumors, or oral mucositis after head and neck radiation — and reducing risks and complications after treatment, such as cardiac toxicity or radiation pneumonitis in thoracic cancers, or secondary malignancy risks and many other late toxicities of treatment among pediatric and young adult cancer survivors.
In their report, the authors have outlined options and different approaches to improving patient access to clinical trials in proton therapy. I applaud their vision of a public-private partnership to develop a mechanism that supports the research infrastructure and treatment costs of patients enrolled in national cooperative clinical trials evaluating proton therapy. Although that is clearly a priority, I also hope to see broader insurance coverage for proton therapy in institutional and multi-institutional clinical trials that will generate credible and meaningful evidence to guide treatment decisions and to better inform evaluations of cost-effectiveness.
Because we need more high-quality outcomes data to inform the evaluation — including both immediate and long-term side effects of therapy and patient-reported outcomes — it is premature to make a judgment of the cost-effectiveness of proton therapy for the treatment of most disease sites. Generation of clinical evidence through research in national cooperative group randomized trials, institutional and industry research endeavors, and innovative and pragmatic approaches — such as the PCORI comparative prostate trial — should be the priority for all stakeholders in proton therapy.
Cancer treatment, detection and prevention continue to evolve in exciting new directions, but more than 100 years into the therapeutic application of radiation in treatment of malignancies, radiation treatment remains a cornerstone of curative treatment for a wide array of diseases. So much of the improvement in the therapeutic ratio that we have achieved with radiation is based around the fundamental goal to concentrate the radiation in the target, and reduce or eliminate radiation to normal tissues. Proton therapy can accomplish that in ways and to a degree that simply are not possible with X-ray therapy, based on the differences in the underlying physics of how protons and X-rays deposit radiation in the body.
Proton therapy is one very exciting tool that can unlock greater improvements in the therapeutic ratio of radiation treatment for some conditions. I do not believe that proton therapy is or will be an appropriate option for every indication or for every patient receiving radiation but, when you treat the right indications with proton therapy and you see the differences in toxicity among your own patients, it really leaves no doubt that this is a technology worthy of our attention, investment and research.
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