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Charged Particle Radiotherapy
Over recent years, the interest and technologic advances in charged particle therapy have resulted in the opening of numerous charged particle radiation oncology centers across the globe. Interest in the use of charged particle radiotherapy derives from the superior dose distributions that can be achieved with these particles compared with those produced by standard photon therapy techniques, as well as the potential for higher biological effect in the tumor with heavier charged particles. Charged particles deposit energy in tissue through multiple interactions with electrons in the atoms of cells, although a small fraction of energy is also transferred to tissue through collisions with the nuclei of atoms. The energy loss per unit path length is initially relatively small and constant until near the end of the range where the residual energy is lost over a short distance, resulting in a steep rise in the absorbed dose (energy absorbed per unit mass). This portion of the particle track, where energy is rapidly lost over a short distance, is known as the Bragg peak ( Fig. 24.1 ).
Depth-dose distributions for a spread-out Bragg peak (SOBP, red ), its constituent pristine Bragg peaks (green), and a 10-MV photon beam (blue). The SOBP dose distribution is created by adding the contributions of individually modulated pristine Bragg peaks. The penetration depth, or range (measured as the depth of the distal 90% of the plateau dose), of the SOBP dose distribution is determined by the range of the most distal pristine peak. The dashed lines (black) indicate the clinically acceptable variation in the plateau dose of ±2%. The dot-dashed lines (red) indicate the 90% dose and the spatial, range, and modulation width intervals. The SOBP dose distribution of even a single field can provide complete target volume coverage in depth and lateral dimensions, in sharp contrast to a single photon dose distribution; only a composite set of photon fields can deliver an appropriate clinical target dose distribution. Note the absence of dose beyond the distal fall-off edge of the SOBP.
(Reprinted with permission from Levin WP, Kooy H, Loeffler JS, et al. Proton beam therapy. Br J Cancer. 2005;93:849–854.)
The initial low-dose region in the depth-dose curve, before the Bragg peak, which is referred to as the plateau of the dose distribution, delivers about 30% of the Bragg peak maximum dose. The Bragg peak is too narrow for practical clinical applications. For the irradiation of most tumors, the beam energy is modulated to achieve a uniform dose over a significant volume, which has traditionally been accomplished by superimposing several Bragg peaks of descending energies (ranges) and weights to create a region of uniform dose over the depth of the target; these extended regions of uniform dose are called spread-out Bragg peaks (SOBP; see Fig. 24.1 ). Although the SOBP beam modulation does increase the entrance dose, the proton dose distribution is still characterized by a lower-dose region in normal tissue proximal to the tumor, a uniform high-dose region in the tumor, and nearly zero dose beyond the tumor. The protons are distributed laterally through the target volumes by a passive scattering foil, collimated with brass apertures, and contoured distally with customized range compensators to compensate for proton range differences from variable proton absorption by tissues of different radiologic density.
Increasingly, however, charged particle therapy is being delivered by raster scanning a pencil beam of charged particles through the deepest slab of the target volume, then reducing the energy of the particle beam and repeating the process iteratively through the target volume. The pencil beam scanning technique delivers lower proximal dose than the traditional SOBP modulation with passive scattering; it can eliminate the need for machining customized apertures and range compensators and it provides greater flexibility in dose delivery, including dose painting and intensity modulation.
Charged particles are generally characterized as having either high or low linear energy transfer (LET), which is the rate of energy loss by the particle in tissue. The LET influences the biologic impact of the energy deposited in tissue. X and gamma ray photons, protons, and helium ions are considered to be forms of low LET radiation. Heavier charged particles (e.g., neon ions, carbon ions) are considered to be forms of high LET radiation. There is an initial increase in the relative biologic effectiveness (RBE) with an increase in LET. Carbon ions have an RBE of about 3, whereas the recommended RBE of protons is 1.1. Higher-LET radiation is less influenced by tissue oxygenation and less sensitive to variations in the cell cycle and DNA repair. For particle radiation, the gray (Gy) equivalent dose is calculated by multiplying the physical dose administered by the RBE for that particle; the recommended nomenclature for expressing the dose is Gy(RBE) = physical dose in Gy × RBE.
Proton Beam Radiotherapy
The overall favorable dose distribution of proton radiotherapy can result in decreased patient morbidity and opens the door for investigational studies evaluating radiation dose escalation. Given the clinical benefits and technologic advances of proton radiotherapy, there has been a rapid increase in the development of proton therapy centers. Specifically, there are currently 79 charged particle centers (68 proton and 11 carbon ion) ( Table 24.1 ) across the globe with another 46 under construction and 22 in planning. In addition, in recent years significant advances have been made in the basic, translational, clinical, and technologic research of proton and other charged particle therapy. This research is highlighted by the development of numerous comparative randomized clinical trials that will help clarify the clinical benefits of proton therapy for different cancers ( Table 24.2 ). In this chapter we focus primarily on a selection of the clinical advances of proton therapy by disease site. We also provide a brief overview of other charged particle therapies.
TABLE 24.1
Charged Particle Therapy Centers in Operation
Adapted with minor modifications from the Particle Therapy Co-Operative Group (PTCOG) website ( www.ptcog.ch )
| Country | Institution | Particle Type | Opened |
|---|---|---|---|
| Austria | MedAustron, Wiener Neustadt | Proton | 2017 |
| Austria | MedAustron, Wiener Neustadt | Carbon | 2017 |
| Canada | TRIUMF, Vancouver | Proton | 1995 |
| Czech Republic | PTC Czech r.s.o., Prague | Proton | 2012 |
| China | WPTC, Wanjie, Zi-Bo | Proton | 2004 |
| China | IMP-CAS, Lanzhou | Carbon | 2006 |
| China | SPHIC, Shanghai | Proton | 2014 |
| China | SPHIC, Shanghai | Carbon | 2014 |
| England | Clatterbridge | Proton | 1989 |
| France | CAL/IMPT, Nice | Proton | 1991, 2016 |
| France | CPO, Orsay | Proton | 1991, 2014 |
| Germany | HZB, Berlin | Proton | 1998 |
| Germany | RPTC, Munich | Proton | 2009 |
| Germany | HIT, Heidelberg | Proton | 2009, 2012 |
| Germany | HIT, Heidelberg | Carbon | 2009, 2012 |
| Germany | WPE, Essen | Proton | 2013 |
| Germany | UPTD, Dresden | Proton | 2014 |
| Germany | MIT, Marburg | Proton | 2015 |
| Germany | MIT, Marburg | Carbon | 2015 |
| Italy | INFN-LNS, Catania | Proton | 2002 |
| Italy | CNAO, Pavia | Proton | 2011 |
| Italy | CNAO, Pavia | Carbon | 2012 |
| Italy | APSS, Trento | Proton | 2014 |
| Japan | HIMAC, Chiba | Carbon | 1994, 2017 |
| Japan | NCC, Kashiwa | Proton | 1998 |
| Japan | HIBMC, Hyogo | Proton | 2001 |
| Japan | HIBMC, Hyogo | Carbon | 2002 |
| Japan | PMRC 2, Tsukuba | Proton | 2001 |
| Japan | Shizuoka Cancer Center | Proton | 2003 |
| Japan | STPTC, Koriyama-City | Proton | 2008 |
| Japan | GHMC, Gunma | Carbon | 2010 |
| Japan | MPTRC, Ibusuki | Proton | 2011 |
| Japan | Fukui Prefectural Hospital PTC, Fukui City | Proton | 2011 |
| Japan | Nagoya PTC, Nagoya City, Aichi | Proton | 2013 |
| Japan | SAGA-HIMAT, Tosu | Carbon | 2013 |
| Japan | Hokkaido Univ. Hospital PBTC, Hokkaido | Proton | 2014 |
| Japan | Aizawa Hospital PTC, Nagano | Proton | 2014 |
| Japan | i-Rock Kanagawa Cancer Center, Yokohama | Carbon | 2015 |
| Japan | Tsuyama Chuo Hospital, Okayama | Proton | 2016 |
| Japan | Hakuhokai Group Osaka PT Clinic, Osaka | Proton | 2017 |
| Japan | Kobe Proton Centre, Kobe | Proton | 2017 |
| Poland | IFJ PAN, Krakow | Proton | 2011, 2016 |
| Russia | ITEP, Moscow | Proton | 1969 |
| Russia | JINR 2, Dubna | Proton | 1999 |
| Russia | MIBS, Saint-Petersburg | Proton | 2018 |
| South Africa | NRF - iThemba Labs | Proton | 1993 |
| South Korea | KNCC, IIsan | Proton | 2007 |
| South Korea | Samsung PTC, Seoul | Proton | 2015 |
| Sweden | The Skandion Clinic, Uppsala | Proton | 2015 |
| Switzerland | CPT, PSI, Villigen | Proton | 1984, 1996, 2013 |
| Taiwan | Chang Gung Memorial Hospital, Taipei | Proton | 2015 |
| The Netherlands | UMC PTC, Groningen | Proton | 2018 |
| USA | J. Slater PTC, Loma Linda | Proton | 1990 |
| USA | UCSF-CNL, San Francisco | Proton | 1994 |
| USA | MGH Francis H. Burr PTC, Boston | Proton | 2001 |
| USA | MD Anderson Cancer Center, Houston | Proton | 2006 |
| USA | UFHPTI, Jacksonville | Proton | 2006 |
| USA | ProCure PTC, Oklahoma City | Proton | 2009 |
| USA | Roberts PTC, U Penn, Philadelphia | Proton | 2010 |
| USA | Chicago Proton Center, Warrenville | Proton | 2010 |
| USA | HUPTI, Hampton | Proton | 2010 |
| USA | ProCure Proton Therapy Center, Somerset | Proton | 2012 |
| USA | SCCA ProCure Proton Therapy Center, Seattle | Proton | 2013 |
| USA | S. Lee Kling PTC, Barnes Jewish Hospital, St. Louis | Proton | 2013 |
| USA | ProVision Cancer Cares Proton Therapy Center, Knoxville | Proton | 2014 |
| USA | California Protons Cancer Therapy Center, San Diego | Proton | 2014 |
| USA | Willis Knighton Proton Therapy Cancer Center, Shreveport | Proton | 2014 |
| USA | Ackerman Cancer Center, Jacksonville | Proton | 2015 |
| USA | Mayo Clinic Proton Beam Therapy Center, Rochester | Proton | 2015 |
| USA | Laurie Proton Center of Robert Wood Johnson University Hospital, New Brunswick | Proton | 2015 |
| USA | Texas Center for Proton Therapy, Irving | Proton | 2015 |
| USA | St. Jude Red Frog Events Proton Therapy Center, Memphis | Proton | 2015 |
| USA | Mayo Clinic Proton Therapy Center, Phoenix | Proton | 2016 |
| USA | Maryland Proton Treatment Center, Baltimore | Proton | 2016 |
| USA | Orlando Health PTC, Orlando | Proton | 2016 |
| USA | UH Sideman CC, Cleveland | Proton | 2016 |
| USA | Cincinnati Children's Proton Therapy Center, Cincinnati | Proton | 2016 |
| USA | Beaumont Health Proton Therapy Center, Detroit | Proton | 2017 |
| USA | Baptist Hospital's Cancer Institute PTC, Miami | Proton | 2017 |
Accessed April 2018.
TABLE 24.2
Randomized Clinical Trials Comparing Proton and Photon Radiation
| Malignancy | Primary Endpoint | Phase | Clinical Trial Identifier |
|---|---|---|---|
| Head and Neck Cancer (unilateral neck radiation) | Grade ≥2 Mucositis | II | NCT02923570 |
| Oropharyngeal Cancer | Late Grade 3–5 Toxicity | II/III | NCT01893307 |
| Non–Small-Cell Lung Cancer (Locally Advanced) | Time to Treatment Failure | II | NCT00915005 |
| Non–Small-Cell Lung Cancer (Locally Advanced) | Overall Survival | III | NCT01993810 |
| Grade II/III Gliomas | Cognitive Changes | II | NCT03180502 |
| Glioblastoma a | Overall Survival | II | NCT02179086 |
| Glioblastoma | Time to Cognitive Failure | II | NCT01854554 |
| Esophageal Cancer | Progression Free Survival | II/III | NCT01512589 |
| Hepatocellular Carcinoma | Overall Survival | III | NCT03186898 |
| Breast Cancer (partial breast) | Rate of Adverse Cosmesis | II | NCT02453737 |
| Breast Cancer | Cardiac Events | III | NCT02603341 |
| Prostate Cancer | 2-year EPIC Bowel Score | III | NCT01617161 |
a The primary endpoint of this trial is overall survival between dose escalated and standard dose radiation. Within the dose escalated arm, patients will receive protons or intensity-modulated radiation therapy (IMRT) and the overall survival between these groups is a secondary endpoint.
Central Nervous System and Skull Base Malignancies
Gliomas
Increasing evidence indicates that a portion of patients with low-grade gliomas benefit from adjuvant radiotherapy. However, survivors may suffer chronic toxicity, including neurocognitive toxicity and endocrine imbalances, among others. By reducing dose to critical normal structures and uninvolved brain tissue, proton therapy can enormously impact the long-term outcomes for these patients. Accordingly, dosimetric comparisons of photon versus proton plans for patients with low-grade gliomas show a clear benefit to proton therapy when assessing a variety of neural subsites and structures, as well as integral dose to the brain as a whole. These dosimetric advantages appear to translate into a more tolerable treatment. A review of a multi-institutional prospective database of patients with low-grade gliomas treated with protons demonstrated a favorable acute toxicity profile with no patients experiencing grade 3 toxicities. Furthermore, Shih et al. published a 20-patient prospective trial of proton radiotherapy for low-grade gliomas. With 5.1 years of follow-up, no significant neurocognitive decline or overall quality of life decrement occurred. Endocrine abnormalities were found in 30% of patients; however, all but one of these patients had direct radiation to the hypothalamus-pituitary axis. Comparative sparing of brain function in IDH mutant grade 2 or 3 glioma patients is being assessed in an ongoing randomized phase II study (NRG Oncology Clinical Trial BN0005, Clinical Trials.gov Identifier NCT03180502) or IMRT versus protons.
Patients with high-grade gliomas primarily relapse in the high-dose region. However, increasing evidence indicates that dose escalation may improve local control, and utilizing proton therapy may allow for safe dose escalation in this sensitive anatomic location. The question of dose escalation and the utility of protons in this setting is being evaluated in NRG Oncology Clinical Trial BN0001, where patients with glioblastoma will be randomized to the standard dose of 60 Gy using photons (intensity modulated radiation therapy (IMRT) or 3D conformal) or 75 Gy using either IMRT or protons (ClinicalTrials.gov Identifier NCT02179086).
Meningioma
Meningiomas are the most common intracranial primary brain tumor. Although, the majority are classified as World Health Organization (WHO) grade 1 and considered benign, WHO grade 2 and WHO grade 3 tumors act more aggressively with a higher rate of local relapse. Proton therapy may be beneficial in treating larger WHO 1 meningiomas that are not resectable or too large for stereotactic radiosurgery by sparing integral low dose to large portions of the brain, which could lead to less long-term neurocognitive toxicity and decrease the risk of a secondary malignancy, In addition, depending on the location of the meningioma, protons could spare certain critical organs at risk. Furthermore, high doses of radiation (≥ 60 Gy) appear necessary to treat high-grade meningiomas to maximize local control. Proton therapy permits safer dose escalation and sparing of critical organs at risk. The Paul Scherrer Institute recently published their series of 96 patients with meningiomas treated with definitive or adjuvant pencil beam scanning proton therapy. Their results indicate that proton therapy is safe and effective, particularly in the context that these patients were often referred specifically for protons because of the referring physician’s concern about the risks of treating with photons.
Head and Neck Malignancies
Patients with head and neck malignancies may suffer from a plethora of acute and chronic toxicities related to their radiation treatments. Dosimetric comparisons of IMRT and proton plans in a variety of clinical settings (postoperative, definitive, unilateral neck radiation) reveal that protons have the ability to spare many critical normal structures, which may translate into less toxicity ( Fig. 24.2 ). When analyzing matched patient cohorts of patients with oropharyngeal cancers treated with intensity modulated proton therapy (IMPT) versus IMRT, patients treated with protons had a lower risk of grade 3 weight loss and gastrostomy tube placement. Moreover, patient-reported outcomes suggest that IMPT can reduce the morbidity of the subacute phase of treatment. A common fear with proton therapy is that given the sharp dose gradient, patients will be at increased risk of a marginal failure. Importantly, no differences were seen in overall or progression-free survival in the two groups and no increase in marginal failures. The benefit of proton therapy as definitive treatment for oropharyngeal squamous cell carcinoma is being evaluated with a muti-institutional randomized Phase II/III trial comparing IMPT and IMRT with the primary outcome being late toxicity ( ClinicalTrials.gov Identifier NCT01893307).
In a variety of head and neck malignancies it is appropriate to limit the treatment volume to include only the unilateral draining lymph nodes in the neck, while avoiding the opposite side of the neck. In these instances, dosimetric comparisons show a significant benefit of proton therapy to spare both contralateral and midline structures that may contribute to significant patient morbidity. Accordingly, a retrospective comparison of patients treated with protons versus IMRT to the ipsilateral neck suggests that these dosimetric advantages translate into less patient morbidity with lower rates of dysguesia, mucositis, and nausea in the patients who received proton therapy. The benefit of protons in unilateral neck radiation is being further evaluated in a randomized trial ( ClinicalTrials.gov Identifier NCT02923570).
Proton therapy has also been evaluated in the setting of reirradiation for head and neck cancers. Reirradiation of the head and neck is potentially very toxic, and protons may significantly lower the morbidity of treatment by minimizing dose to surrounding tissues that have already been radiated. The largest series of pooled prospective proton registries demonstrates that, although still toxic and associated with a risk of significant treatment-related morbidity, including death, this modality appears favorable compared with historic reirradiation data using photons.
Thoracic Malignancies
Lung Cancer
Locally advanced non–small-cell lung cancer (NSCLC) is often treated with definitive chemoradiation that can lead to significant acute and chronic toxicity. In particular, excessive dose to the lungs and heart can lead to significant morbidity and mortality. For example, it is well established that the lung V20 and mean dose are predictive for radiation pneumonitis, which can be fatal. In addition, recent data suggest the importance of cardiac dose to survival after chemoradiation. Given the favorable dosimetry of protons, this modality may improve the therapeutic ratio in locally advanced NSCLC. In support of the benefit of protons, a longitudinal study collecting patient-reported outcomes demonstrated less severe symptoms in patients who received proton therapy compared with IMRT or 3D conformal radiation. Furthermore, a recent open label Phase II trial of dose-escalated proton passive scattered radiation (74 Gy) with concurrent chemotherapy demonstrated favorable survival and toxicity outcomes. Similarly, proton therapy has demonstrated promising outcomes in prospective studies in small cell lung cancer and when utilized in the postoperative setting. However, a recent randomized Phase II trial comparing passive scattering proton therapy and IMRT for locally advanced NSCLC did not reveal any significant advantage to proton therapy. In particular, no difference was found in local control or radiation pneumonitis. Proton therapy did improve the cardiac dose, but also resulted in an increase in the lung V20. However, this trial was conducted utilizing passive scattering proton therapy, and the dose distribution should be improved using the more advanced technique of IMPT. Such a trial comparing IMPT and IMRT with a simultaneous integrated boost for locally advanced NSCLC is in process (NCT01629498). This trial treats the entire volume to 60 Gy with a dose-escalating simultaneous boost to the gross tumor volume. The Phase I portion of this trial was recently reported, and in the IMPT group, the boost dose of 78 Gy resulted in excessive toxicity in the form of grade 3 or greater pneumonitis. As a result, the final randomized portion will escalate to 72 Gy. NRG Oncology is also conducting a randomized Phase III study of photons versus protons in the chemoradiation treatment of locally advanced non–small-cell lung cancer; the study endpoint is overall survival (NCT01993810).
Local failure in patients with NSCLC remains a significant problem, but well-selected patients can be salvaged with reirradiation. Protons may mitigate the morbidity of such treatment by minimizing overlap with prior radiation fields. A multi-institutional prospective reirradiation trial for NSCLC demonstrated that even with double scatter protons, reirradiation can be very toxic with 6/57 grade 5 toxicities. Importantly, toxicity was correlated with higher overlap to the central airway, mean esophageal and cardiac doses, as well as concurrent chemotherapy. However, reirradiation with IMPT, which often results in improved dose distribution compared with double scatter proton therapy, had a much safer toxicity profile.
Thymoma
Thymomas are the most common malignancy of the anterior mediastinum. Radiation is an important part of the treatment of patients who present with nonresectable disease or with certain pathologic features after surgical resection. Given the location of thymomas, proton therapy can substantially reduce dose to the heart, lungs, esophagus, and breast, which can prevent both acute and long-term toxicity. Prospective data confirm that protons have a favorable toxicity profile with good tumor control outcomes. In addition, given the overall favorable tumor control outcomes of thymomas, mitigating the risk of a radiation-induced malignancy is an important consideration. Research using models of second malignancy risk predict that in this setting, proton therapy can prevent 5 excess second cancers per 100 patients compared with IMRT.
Mesothelioma
Malignant pleural mesothelioma is an aggressive malignancy of the pleural cavity. After treatment with pleurectomy and decortication, these tumors are especially difficult to radiate because of the circumferential nature of the treatment volume and the need to spare mediastinal structures, liver, and the contralateral lung. Although data are limited, IMPT following pleurectomy and decortication is feasible; it lowers the dose to the contralateral lung, heart, esophagus, kidney, and liver compared with IMRT. Similar advantages to IMPT are evident after patients are treated with an extrapleural pneumonectomy.
Breast Cancer
Radiotherapy plays an integral role in the treatment of patients with localized breast cancer after breast conservation therapy and in certain instances after mastectomy. Because many patients exhibit excellent cancer control, it is increasingly important to mitigate the long-term toxicity of radiotherapy. In particular, long-term cardiac morbidity is an important consideration when treating left-sided breast cancers. Darby et al. identified the mean heart dose as a predictor of cardiac toxicity with an increased risk of 7.4% of a major cardiac event per Gy increase in the mean heart dose. Not only is the mean heart dose a critical parameter, it is becoming increasingly clear that dose to the left anterior descending artery, which often is included in tangent fields of left-sided cancers, can lead to stenosis and coronary artery disease. For many patients, when only the breasts are targeted, dose to the heart can be reduced with simple techniques such as treating with deep inspiration breath hold. However, cardiac sparing becomes increasingly challenging when treating regional draining lymph nodes, particularly the internal mammary chain. Dosimetric comparisons in the setting of regional node irradiation have demonstrated significant reduction in heart and lung doses when comparing protons with photon plans. The clinical implications of cardiac sparing with proton therapy is being investigated with the prospective multisite RADCOMP (Radiotherapy Comparative Effectiveness) clinical trial comparing proton and photon regional node irradiation for breast cancer (NCT02603341) with the primary outcome of major cardiac events.
Proton therapy has also been investigated as an option for accelerated partial breast irradiation. In certain respects, protons seem like the ideal modality for partial breast radiation. Unlike brachytherapy, it is noninvasive and can spare more heart, lung, and uninvolved breast than photons. However, results from a Phase I/II trial demonstrated that those treated with passively scattered proton partial breast irradiation had worse acute and long-term skin toxicity compared with those receiving photon treatments. This resulted in worse physician-rated cosmesis, although patient-reported cosmesis was similar. On the basis of this initial experience, if protons were to be used in the setting of accelerated partial breast irradiation, the authors of the study recommended the use of multiple fields and treatment of all fields per treatment session or the use of scanning or IMPT techniques to minimize skin toxicity.
Gastrointestinal Malignancies
Esophageal and Gastric Carcinoma
In many instances the standard management of resectable locally advanced esophageal cancer is neoadjuvant chemoradiation followed by surgical resection. Several reports have described a dose to critical organs, namely the lung dose, as a strong predictor of perioperative complications that can sometimes be fatal. Proton therapy can significantly decrease dose to the lungs and heart ( Fig. 24.3 ), which could translate into reduced perioperative morbidity. A multi-institutional retrospective analysis of postoperative complications demonstrated that proton therapy or IMRT compared with 3D conformal radiation resulted in significantly fewer cardiac and pulmonary complications. Compared with IMRT, proton therapy had less wound complications and resulted in a shorter hospital stay postoperatively. Furthermore, when chemoradiation is the definitive treatment for esophageal cancer, proton therapy can be delivered safely with encouraging clinical results. Interestingly, in a large retrospective analysis, despite clear dosimetric advantages in dose to the lung and heart, protons did not reduce the toxicity of therapy, but did improve survival. This survival advantage needs to be confirmed in prospective trials, but could be related to lower cardiopulmonary doses, similar to locally advanced NSCLC.
The role of radiation therapy in the management of gastric cancer is controversial, but in the United States, it is often used in the adjuvant setting. Although, minimal data exist for the utility of proton therapy in gastric cancer, dosimetric studies demonstrate reduced small bowel, heart, liver, kidney, and overall integral dose when comparing double scatter proton therapy with IMRT. An important consideration when irradiating the stomach is that variability in bowel gas patterns could have a significant impact on the dose distributions. However, verification scans during treatment show that the protons plan are very robust with no more than 2% variability.
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