A review of proton therapy – Current status and future directions

Abstract

The original rationale for proton therapy was its highly conformal depth‐dose distributions compared to photons, which allow greater sparing of normal tissues and escalation of tumor doses, thus potentially improving outcomes. Additionally, recent research has revealed previously unrecognized advantages of proton therapy. For instance, the higher relative biological effectiveness (RBE) near the end of the proton range can be exploited to increase the difference in biologically effective dose in tumors versus normal tissues. Moreover, the smaller “dose bath,” that is, the compact nature of proton dose distributions, has been found to reduce the exposure of circulating lymphocytes and the immune organs at risk. There is emerging evidence that the resulting sparing of the immune system has the potential to improve outcomes. Protons accelerated to energies ranging from 70 to 250 MeV enter the treatment head mounted typically on a rotating gantry. Initially, the beams of protons are narrow and, to be suitable for treatments, must be spread laterally and longitudinally and shaped appropriately. Such spreading and shaping may be accomplished electro‐mechanically for the “passively scattered proton therapy” (PSPT) mode; or it may be achieved through magnetic scanning of thin “beamlets” of protons. Intensities of scanning beamlets are optimized to deliver intensity‐modulated proton therapy (IMPT), which optimally balances tumor dose and the sparing of normal tissues. IMPT is presumably the most powerful form of proton therapy. The planning and evaluation of proton dose distributions require substantially different techniques compared to photon therapy. This is mainly due to the fact that proton dose distributions are highly sensitive to inter‐ and intra‐fractional variations in anatomy. In addition, for the same physical dose, the biological effectiveness of protons is different from photons. In the current practice of proton therapy, the RBE is simplistically assumed to have a constant value of 1.1. In reality, the RBE is variable and a highly complex function of numerous variables including energy of protons, dose per fraction, tissue and its environment, cell type, end point, and possibly other factors. While the theoretical potential of proton therapy is high, the clinical evidence in support of its use has so far been mixed. The uncertainties and assumptions mentioned above and the limitations of the still evolving technology of proton therapy may have diminished its true clinical potential. Although promising results have been reported for many types of cancers, they are often based on small studies. At the same time, there have been reports of unforeseen toxicities. Furthermore, because of the high cost of proton therapy, questions are often raised about its value. The general consensus is that there is a need for continued improvement in the state of the art of proton therapy. There is also a need to generate high level evidence of the potential of protons. Fortuitously, such efforts are taking place curr...

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“…Several studies have also revealed previously unrecognized biological advantages of proton therapy (PT) specifically [ 177 ]. Moreover, the lower integral dose of PT and its dose sparing properties, have been found to reduce the exposure of circulating lymphocytes and the immune organs at risk compared to photon-based RT [ 178 ]. Preliminary findings of a study in NSCLC with underlying idiopathic pulmonary fibrosis showed a trend of non-statistically significant better OS compared to X-rays for patients treated with PT [ 179 ].…”

“…The higher RBE at the distal edge of the beam could potentially be problematic if this region is deposited in an organ at risk such as the heart. When one applies generous margins to circumvent the problem of tumour motion and tissue heterogeneity, this might counteract the dosimetric advantage and cause more normal tissue injury [ 178 ]. This adds an additional layer of complexity in the incorporation of proton therapy with RE seeing as microvascular heterogeneity is another important variable to consider due to its abundance in lung tissue [ 183 ], and its direct influence on the efficacy of anti-angiogenic therapy.…”

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“…The finite range and sharp distal fall-off characteristics of protons allow radiation dose to be delivered to a specific depth using the spread-out Bragg peak. The distant normal tissue receives a negligible radiation dose [16,30]. More conformal dose distributions can be achieved due to the ability of IMPT to control the beamlet energies and intensities.…”

“…Since protons have a larger penumbra, normal tissues near the target may receive a higher radiation dose [16]. Xu et al reported that compared to IMRT, proton therapy performed poorly in decreasing the irradiated volume of PBM in the high-dose region (33.9-42.9 Gy), and the PBM V 40 increased by 14.6%.…”

“…Only a few fields are needed to meet the dose coverage of the target. Proton therapy has great potential for BMS due to its physical dose deposition properties that can effectively protect normal tissues adjacent to the target [16,17]. Therefore, we used MR functional imaging to segment the PABM.…”