Does proton therapy have a role in the treatment of brain tumors?
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Proton therapy (PT) is a potentially important radiation modality for primary brain tumors due to its unique dose distributions. Unlike photon radiation, PT dose is characterized by a well-defined maximal range where the majority of the dose is deposited, followed by a rapid dose falloff to zero distally within a mere few millimeters.
This unique dosimetric profile is highly advantageous in the brain, where numerous critical organs at risk (OARs) are densely packed within a confined space. Thus, achievable radiation dose to the target often is limited by radiation dose constraints for adjacent OARs. For high-grade histology like glioblastoma, PT can allow for dose escalation by sparing OARs distal to the target in hopes of improving local control.
Unlike malignancies elsewhere in the human body, high-grade primary central nervous system malignancies typically do not metastasize; therefore, the mechanism for morbidity and mortality is predominantly local progression.
The ability to dose-escalate with PT is intriguing and is being studied in NRG BN-001, a phase 2 randomized trial exploring radiation dose escalation via PT or IMRT to 75 Gy vs. the standard dose of 60 Gy for patients with newly diagnosed glioblastoma receiving concurrent temozolomide. Interim results showed no statistically significant OS difference between the dose-escalated IMRT group and the standard-dose group; however, we are still awaiting results of the PT group.
In the age of immunotherapy, there is growing recognition of the important role our immune system may play in the battle against malignancies. As a result, radiation’s potential deleterious effect on the immune system via myelosuppression warrants scrutiny, and any immune-sparing approach should be considered.
A randomized phase 2 trial that compared PT vs. photon radiation for patients with glioblastoma receiving concurrent temozolomide demonstrated a statistically significant reduction in grade 3 lymphopenia with PT. In contrast to high-grade histology, the primary concern in treating patients with benign or low-grade lesions, which generally carry a good prognosis with expected long survival, is late-term sequelae such as neurocognitive decline. Due to the ability of PT to spare brain tissue distal to the target, it can spare not only specific subregions of the brain but also reduce total brain volume exposure to the “spill” of low-dose radiation. Both of these qualities could enhance the therapeutic ratio of radiation treatment.
The potential role of PT in cognitive preservation is being studied in NRG-BN005, a randomized phase 2 trial comparing PT vs. photon radiation in patients with IDH-mutant, low- to intermediate-grade gliomas.
In summary, PT holds promise in primary brain tumors by enabling dose escalation, improving radiation sequelae such as neurocognitive decline, and preserving the immune system. Multiple randomized clinical trials on these topics are ongoing, and we eagerly await the results.
- Gondi V, et al. Int J Radiat Oncol Biol Phys. 2020;doi:10.1016/j.ijrobp.2020.07.2109.
- Mohan R, et al. Neuro-Oncol. 2021;doi:10.1093/neuonc/noaa182.
Chenyang (Michael) Wang, MD, PhD, is assistant professor in the department of radiation oncology at The University of Texas MD Anderson Cancer Center. He can be reached at firstname.lastname@example.org.
Fractionated radiation therapy is associated with risk for late toxicity. The incidence and gravity of vascular damage, endocrine dysfunction, radiation-induced necrosis and cognitive decline depend on radiation dose and fractionation, as well as extent of radiation field and tumor location. In patients with a lower-grade glioma, who can live for decades after diagnosis, long-term adverse effects may substantially alter quality of life and functioning. Thus, attempts to limit late radiation effects are laudable.
Proton irradiation has gained increasing attention as a method to mitigate detrimental effects of radiotherapy. Protons allow for high-precision delivery of radiotherapy with a sharp decline after deposition of the energy in the target tissue and less or no radiation to surrounding normal tissue. However, high precision may not be logical nor warranted in a diffuse or infiltrative disease like glioma, and radiation planning encompasses up to a 2 cm border to account for infiltrative disease. Although proton fields undoubtedly will be smaller, this may be to the detriment of longer-term tumor control. Proton radiation has been associated with higher incidence of radiation necrosis and radiation-induced contrast uptake due to acute and chronic inflammation. These findings often are falsely considered tumor progression, leading to subsequent treatment with further inherent risks and toxicities.
Approval and acceptance of new drugs requires prospective, controlled trials to establish efficacy; however, novel technologies are being introduced without proper testing based on technical equivalence, safety and theoretical considerations, and without proof of efficacy or superiority. The literature is full of reports on presumed benefits of proton radiotherapy in brain tumors; these are largely case series and retrospective analyses of modest scientific value. Yet, a few high-impact studies on the extent of cognitive decline have been reported.
Klein and colleagues evaluated cognitive domains in 195 patients with low-grade glioma (53% previously irradiated) and compared them with those of 100 patients with low-grade hematologic malignancies and 100 healthy controls. They demonstrated inferior cognitive performance in all domains for patients with glioma due to the disease itself, even without radiotherapy. Yet, long-term follow-up (median, 12 years) demonstrated a progressive cognitive decline with an increase in attentional function.
Jalali and colleagues conducted a randomized trial among patients aged 25 years or younger with low-grade brain neoplasms, comparing a modern, highly conformal radiotherapy technique with a conventional radiotherapy encompassing somewhat larger radiation fields. The more conformational technology reduced late cognitive decline and neuroendocrine abnormalities. These results indicate a substantial risk reduction can be achieved with available technologies, and that the possible incremental benefit of protons may not justify the cost and effort. Results of a large, randomized trial that included patients with high-risk low-grade glioma who received either standard conformal radiotherapy or chemotherapy without radiation showed no difference in outcome after median follow-up of 4 years. Extensive longitudinal neurocognitive function tests performed on a subgroup of 98 patients showed no difference in outcome.
The NRG BN-005 and BN-001 trials will provide important insights into the benefits and limitations of proton beam radiotherapy for glioma.
Until additional evidence is demonstrated supporting a quantifiable benefit of proton irradiation in glioma — including its impact on long-term cognition and outcome, and careful evaluation and identification of yet-unknown long-term risks associated with proton radiotherapy — this modality should be strictly limited to a few established indications in very rare tumors and pediatric patients. In situations of equipoise, investigational treatments should only be offered within controlled clinical trials. This is the quickest way to make progress and, if innovation is proved beyond doubt as superior, it should be rapidly introduced into standard clinical practice.
- Baumert BG, et al. Lancet Oncol. 2016;doi:10.1016/S1470-2045(16)30313-8.
- Douw L, et al. Lancet Neurol. 2009;doi:10.1016/S1474-4422(09)70204-2.
- Jalali R, et al. JAMA Oncol. 2017;doi:10.1001/jamaoncol.2017.0997.
- Klein M, et al. Lancet. 2002;doi:10.1016/S0140-6736(02)11398-5.
- Klein M, et al. Neuro Oncol. 2021;doi:10.1093/neuonc/noaa252.
Roger Stupp, MD, is chief of neuro-oncology at Northwestern University Feinberg School of Medicine. He can be reached at email@example.com.