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Proton therapy for hematologic malignancies
Introduction
As early as the 1970s, proton therapy was considered a promising treatment for hematologic malignancies, specifically for use in total nodal irradiation, the historic standard of care treatment for Hodgkin lymphoma (HL). In one report, it was recognized that patients treated with 4000 to 4400 rad to the mantle and inverted Y fields experienced considerable morbidity when treated with standard photons, including, but not limited to, nausea, vomiting, hair loss, and decreased blood counts. The authors suggested that this treatment could be delivered by using proton irradiation, which would not only decrease treatment toxicity but also treatment length because both fields could be treated simultaneously. They also recognized the value in sparing bone marrow, as lymphoma patients often depend on marrow reserves to tolerate chemotherapy. Interestingly, this publication focused on acute toxicities of treatment, as the authors admitted that the time required for documentation of late toxicities had not yet elapsed, although hepatic, cardiac, and pulmonary changes had been documented. They concluded that “the improved dose distribution should be manifested by increased local control of irradiated cancer, as well as by decreased patient morbidity.”
The treatment paradigm for HL and other hematologic malignancies has certainly evolved since those times, with chemotherapy replacing radiation as the primary therapy and the overall focus shifting to de-escalation of treatment, given the excellent treatment outcomes. Because such patients tend to receive treatment at a young age and long life expectancies are anticipated, they must be spared the late toxicities that can manifest decades later. Both chemotherapy and radiation therapy (RT) have been progressively deintensified and optimized; research efforts have focused on identifying the minimum treatment necessary to maintain these excellent outcomes. ,
Proton therapy has, in more recent years, been highlighted once again as a mode of radiation delivery ideal for this patient population. Radiation field sizes and doses have been decreased markedly from the days of total nodal irradiation, and the current standard of care uses a technique called involved-site RT, in which only initial sites of disease are treated, with no elective nodal irradiation performed. Some institutions with workflows that allow prechemotherapy positron emission tomography-computed tomography imaging while the patient is in the radiation treatment position can even achieve involved-node RT, a technique that results in the smallest treatment fields used thus far. With these decreased field sizes and decreased radiation doses, the acute toxicities of treatment are typically not the primary concern. The patient age at treatment, long life expectancy, and close proximity of critical structures (e.g., heart and lungs) necessitate careful consideration of late toxicities of radiation before treatment is prescribed. Therefore, it is imperative that techniques be used to reduce the dose to normal tissues as much as possible. Technology has improved dose distributions of photon treatment and spared normal tissue via implementation of inverse planning with intensity-modulated RT (IMRT). Other modifications of the treatment setup and delivery, including the use of deep inspiration breathhold (DIBH), have strikingly improved the total radiation dose delivered to the heart and lungs. Although these advances are notable, the distinct physical properties of photon treatment that result in exit dose to normal tissues cannot be modified, and many have pointed toward particle therapy with protons as a revolutionary method of radiation treatment delivery for this unique patient population. The unique absence of exit dose achieved with proton therapy (see Chapter 2 ) allows not only decreased dose to specific critical structures but also decreased total body radiation dose (integral dose), which is exceedingly important for patients in whom secondary malignancy is a primary concern.
Dosimetric advantage of protons compared with photon-based three-dimensional conformal and intensity-modulated radiation therapy
More recent investigations of the value of proton therapy for patients with lymphoma have compared the dosimetric advantages of delivering proton therapy versus more conventional RT techniques (e.g., three-dimensional [3D] conformal, IMRT). These reports have usually focused on patients with the most common disease site presentation, the mediastinum. Early comparisons of conventional photon RT with 3D proton treatment for patients with HL confirmed that proton therapy reduced the doses to the heart, lungs, esophagus, and coronary arteries. One report by Chera et al. reproduced treatment plans with 3D conformal RT (CRT), IMRT, and 3D proton therapy for nine patients with early-stage HL without disease involving or below the hila. They concluded that, although IMRT, produced the most conformal high-dose distributions, proton therapy afforded the lowest mean doses to nontarget tissues including breast, lung, and total body. In a similar study comparing 3D CRT, IMRT, and proton therapy for early-stage HL using involved-node techniques, Hoppe et al. concluded that the dose to cardiac substructures (chambers, valves, and vessels) was significantly decreased with proton therapy, and this should translate to a decrease in cardiac toxicity. Proton therapy, when used with involved-node techniques, has been shown to give less dose to the carotid arteries compared with volumetric-modulated arc therapy and mantle field radiation (but not 3D CRT), potential improvements in head and neck treatment delivery for some patients, and the lowest-risk estimates (based on dosimetry) of nearly all esophageal complications when compared with photon-based treatments. A study of pediatric patients with HL determined that proton therapy, when compared with 3D CRT, allowed the reduction of unnecessary breast dose by as much as 80%, and another comparison of passive scatter proton therapy to tomotherapy and 3D CRT also confirmed the advantage of proton therapy for better sparing breast tissue.
Advances in proton therapy, including pencil beam scanning, have allowed additional comparisons. Ten patients with mediastinal lymphoma had RT treatment plans designed for 3D CRT, IMRT, pencil beam scanning (PBS) proton therapy, and proton double-scattering techniques. Authors concluded that PBS significantly decreased the mean lung and mean heart doses compared with the other modalities. They also measured deviations from planned dose and determined that PBS plan robustness can be maintained with repainting or large spot sizes. Although these studies provided valuable information, they did not take advantage of treatment delivery techniques such as DIBH that are known to significantly reduce dose to critical structures such as the heart and lungs. , A more recent publication describing involved-node techniques compared IMRT to PBS proton therapy, each planned using both free-breathing and DIBH planning scans, and estimated the risk of late effects and life years lost for these young patients. Interestingly, IMRT free-breathing plans were inferior to all others, but IMRT DIBH plans were not significantly different from proton free-breathing plans. The lowest number of life-years lost was achieved with proton therapy DIBH plans, although the authors cautioned that this combination is rarely available, and the most likely treatment alternatives will be IMRT DIBH or free-breathing proton therapy. A report by Moreno et al. from MD Anderson similarly concluded that proton therapy is advantageous in the setting of DIBH. IMRT plans using breath hold were comparable in terms of dose to heart, breasts, and coronary arteries when compared with proton free-breathing plans.
Proton therapy for hematologic malignancies outside the mediastinum
In HL patients presenting with subdiaphragmatic disease, proton therapy has also been compared with 3D CRT and IMRT and found to provide significant reductions in dose to structures such as the stomach, liver, pancreas, bowel, and kidneys. For patients with central nervous system (CNS) involvement of leukemia and lymphoma, proton therapy has been implemented to deliver craniospinal irradiation (CSI) before stem cell transplantation. In that work, both photon and proton therapy offered excellent local control, and acute mucositis occurred less often with proton CSI.
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