Proton SBRT is ready to move past uncertainties and towards improved clinical outcomes

Stereotactic body radiation therapy (SBRT) is adopted as an effective treatment option for most early stage and some locally advanced cancers [1-2], with treatment planning, delivery and quality assurance guidelines well established [3]. SBRT, as has historically been delivered with photon therapy, becomes increasingly difficult to deliver when tumor becomes more locally advanced in size (>5 cm) or centrally located near critical structures, especially for lung and liver tumors, as surrounding normal tissue toxicities can become prohibitive [4-5]. Toxicities from low dose (<5 Gy) irradiation during photon SBRT, including lymphopenia and loss of remaining liver or lung function, can often be completely eliminated with stereotactic body proton therapy (SBPT) [6-8] because of essentially zero exit dose for proton beams beyond a fixed depth, the practical range of maximum incoming proton energy. Limited proton range makes SBRT highly advantageous for some central lung and liver tumors when critical organs at risks (OARs) are located beyond proton range uncertainty. Such SBPT advantages make it the treatment of choice for reirradiation and for patients with significantly preexisting liver or lung dysfunction.

Technical procedures for motion management and related proton range uncertainties, patient immobilization, simulation imaging, treatment planning, image-guidance in the treatment room and delivery are established with original research [9-11] and clinic practice consensus [12-13]. Recently, 4D robust treatment planning [14] has been further developed to utilize intensity-modulated proton therapy (IMPT) and account for motion-related range uncertainties, which has further improved the therapeutic ratio over intensity-modulated photon therapy. Therefore, early literature predating the use of proton volumetric imaging [11] and utilizing double-scattering proton therapy that have excessive treatment margins in SBPT are not valid for modern IMPT-enabled SBPT.

Prospective phase II data for hypofractionation consistently show the benefits of proton therapy over what has been able to be safely achievable with photon therapy for lung [15-16] and liver tumors [17]. Now, comparative data for ultra-high dose stereotactic ablative radiation therapy is growing and similarly consistently shows a benefit to SBPT over SBRT, including randomized trial [18] and meta-analysis [4] data for non-small cell lung cancer and population-based [19] and institutional data [20] for hepatocellular carcinoma. Furthermore, SBPT has the added benefit that it can be optimized to linear energy transfer (LET) higher than 4 keV/µm for radiation resistant tumors or lower than 2.5 keV/µm for radiation sensitive OARs [21-22].

Previously hesitations to adopt the use of proton therapy for the delivery of SBRT, such as motion-related range uncertainties and 4D robust planning, are not specific to SBPT, and they have been largely resolved to a margin comparable with photon-related uncertainties. Our group and others have shown that the interplay effect of SBPT is not clinically relevant when avoiding single-fraction SBPT and instead delivering fractionated stereotactic and other treatments [23], especially when conforming to established clinical practice guidelines of mitigating motion to 5 mm or less [13]. Furthermore, additional computed tomography (CT) characterization for proton therapy application can be controlled within 2% with widely available multi-energy CT [24], which is smaller than a typical photon SBRT margin of 5 mm.

SBPT also typically has a larger shoulder (95% to 80% prescription) and dose gradient (80% to 20%), which is determined by robust treatment planning and inherent proton properties. Additionally, SBPT has a much smaller low dose bath (i.e. < 20% prescription) than SBRT. These properties together can allow for an up to 5 mm additional shoulder with more optimal target coverage and improved dose gradient for SBPT, while also better protecting patients with preexisting lung dysfunction (severe COPD, interstitial lung disease, prior thoracic surgeries or thoracic radiation therapy, etc) and preexisting liver dysfunction (hepatitis, advanced Child-Pugh Score, prior liver resections or local therapies) from developing fatal radiation pneumonitis and fatal radiation-induced liver disease, respectively. Furthermore, reducing the low-to-intermediate doses delivered to normal tissues with SBPT relative to SBRT and the resulting lymphodepletion sparing afforded by proton therapy is particularly beneficial when delivering treatment to oligometastatic and oligoprogressive patients receiving systemic therapy, and this may be increasingly important for early stage patients as immunotherapy is poised to become more integrated into the management of localized disease. As such, SBPT can make an even big difference in the era of immunotherapy for both tumor control through its high LET and its improvement in the therapeutic window at marginal volume, as well as through its improved OAR sparing by elimination of irrelevant low dose bath.

By applying elevated LET over the margins for parallel OARs and reducing LET for serial OARs, the desired therapeutic window between tumor and OARs can be widened with SBPT, whereas it cannot be similarly optimized or achieved using SBRT. These advantages of proton therapy extend to reirradiation, a scenario for which SBRT is increasingly used but for which toxicities can be considerable. Proton therapy can be the most optimal way to deliver reirradiation for both thoracic and gastrointestinal target volumes, allowing SBPT the potential to reduce toxicities [25] and better preserve quality of life [26] relative to SBRT, while not needing to compromise target coverage that is commonly necessary to meet dose constraints with SBRT [27].

Outcomes with photon therapy and current photon SBRT practices remain quite limited for tumors in central locations [28] and for more locally advanced disease [29] that needs concurrent chemoradiation and maintenance immunotherapy for thoracic targets and for tumors in central locations [30] for liver targets, and outcomes for these patients are poised to be improved with SBPT.

There are two notable development that could additionally benefit SBPT, but not in SBRT, in the future: (1) ultra-high dose rate FLASH-enabled SBPT [31-33] has the potential to further reduce toxicities from radiotherapy through the FLASH effect and may further provide for synergy with immunotherapy, and (2) Proton CT [34] can further reduce the proton range uncertainty below ~1%, making proton therapy a much more attractive approach for reducing not just low and intermediate doses but also high doses to critical organs at risk versus photon SBRT that typically employs 5 mm treatment margins.

With the preponderance of evidence showing the benefits of proton therapy over photon therapy for hypofractionated treatment of both lung and liver tumors, and the increasingly robust data showing the same for stereotactic treatments for these disease sites, it is time to move beyond the question of if we are ready for SBPT and to start increasing the delivering of this advanced modality to improve the outcomes for our patients.