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Proton Radiation Therapy
C H A P T E R
9 Proton Radiation Therapy Recently, Proton therapy (PT) has emerged as an important tool for cancer treatments. More and more commercially available proton canters are now available for clinical use. This chapter will discuss the rationale, clinical indications, techniques, and toxicity of proton radiotherapy.
PROTON BEAM DEPTH DOSE Protons are heavy charged particles, have mass, and possess a positive charge, as such interact differently with matter than do photons. Protons do not change direction appreciably while traveling through matter but generally interact with matter by undergoing inelastic collisions with atomic electrons. In this process, they give up a portion of their energy with each collision (without changing direction appreciably). Hence, a monoenergetic proton beam continues to lose its energy while traveling through tissue, and the rate of energy loss increases with decreasing proton energy, resulting in most of the dose deposition occurring at the end of the range in a sharp Bragg peak. Proton beam absorbed dose beyond the Bragg peak is negligible [1e3]. The depth of the Bragg peak is dependent on the incident proton beam energy. To deliver a uniform dose to a target volume, the proton energy is tuned and varied to superimpose multiple Bragg peaks across the target, resulting in a region of relatively uniform dose called the spread out Bragg peak (SOBP). Proximal to the target, the SOBP delivers less of a dose than that given at the target dose (low entrance dose). Distal to the target, the SOBP delivers negligible dose (minimum exit dose). A single photon beam, on the other hand, delivers a higher dose proximal to the target and lower, but nonnegligible dose distal to the target. Protons therefore have a dosimetric advantage over photons, delivering less integral dose to normal tissues for the same tumor dose. Furthermore, most proton treatment plans require only one to three beams. Proton and photon beam depth dose characteristics are illustrated in Fig. 9.1.
PROTON RELATIVE BIOLOGICAL EFFECTIVENESS The relative biologic effectiveness (RBE) of protons is similar to megavoltage photons that are used in radiation therapy. The RBE of therapeutic energy protons (up to Copyright © 2019 Elsevier Inc. All rights reserved.
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FIGURE 9.1 In a typical treatment plan for proton therapy, the spread out Bragg peak (SOBP, dashed blue line) is the therapeutic radiation distribution. The SOBP is the sum of several individual Bragg peaks (thin blue lines) at staggered depths. The depthedose plot of an X-ray beam (red line) is provided for comparison. The pink area represents additional doses of X-ray radiotherapydwhich can damage normal tissues and cause secondary cancers, especially of the skin. Ref 4. Reproduced from Wikipedia, the free encyclopedia. Proton therapy, page 1: Wikimedia Foundation, Inc.; 2008.
250 MeV) is around 1.1; however, the RBE increases from 1.1 to 1.7 in the Bragg peak where slow protons have higher biologic effectiveness [5e8]. Thus, lower doses to normal structures at the entrance and along the protons’ pathway and with no exit dose improves the therapeutic ratio of PT compared with photon therapy. Nevertheless, sensitive normal tissues should not be positioned immediately distal to the dose falloff. As small changes in the penetration of the beam resulting from uncertainty, for example, the treatment planning CT, can cause the sensitive structure receiving the full physical dose because of the increased RBE.
BEAM PRODUCTION, DELIVERY, TREATMENT PLANNING, AND QUALITY ASSURANCE Proton generation: High-voltage electric current is applied to hydrogen gas, stripping electrons from the hydrogen atoms, leaving positively charged proton particles. Proton acceleration: Protons are accelerated by either a cyclotron or a synchrotron. A cyclotron produces a monoenergetic proton beam, typically 250 MeV. The proton energy of a synchrotron can be selected within a designed range.
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FIGURE 9.2
Proton therapy system with cyclotron, energy selection system, beam line, gantry, and nozzle. Scattering is illustrated in the nozzle on the left and scanning in the nozzle on the right. Modified from Mendenhall NL, et al. Proton Therapy; July 2, 2016, Posted by admin in
Oncology. https://oncohemakey.com/proton-therapy-2.
Proton beam transport: A series of large bending and focusing magnets along with diagnostic measuring tools guides the proton beam from the cyclotron or synchrotron to the patient treatment rooms, Fig. 9.2. Proton beam delivery: The pencil-shaped proton beam has to be modified for clinical use by the following techniques: Fig. 9.3. • Scattering beam technique: The pencil beam passes through a range modulator followed by first and second scatterer then through a compensator to treat the patient. The variable thickness range modulator spins in front of the pencil beam creating a flat top Bragg peak. By using the two scatterers and the compensator, the pencil beameshaped proton beam is spread laterally for clinical use. The scatterers and the compensator are custom-made for each proton beam. • Scanning beam technique: Multiple variable strength magnets scan the pencil beameshaped proton beam laterally to conform to the tumor/target volume. The scanning beam technique does not require patient-specific hardware. Treatment planning: A CT simulation of the patient is performed for imaging data collection. The CT values are converted to proton stopping power (as opposed to electron densities for photon treatment planning). This is followed by delineation of the target volume. Finally, selection of beam direction and plan optimization is performed. A field patching technique to match multiple beams at the 50% isodose lines laterally and at the distal level produces the desired treatment plan. The planning system designs the aperture and the compensator for each single field. Pencil beam algorithms are used for the dose calculation and the radiation dose unit is cobalt Gray equivalent (CGE).
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FIGURE 9.3 The protons emerging from a cyclotron or synchrotron form a narrow pencil beam. To cover a treatment field of practical size, the pencil beam must be either scattered by a foil or scanned. Passive scattering is by far the simplest technique but suffers the disadvantage of increased total-body effective dose to the patient. From Hall EJ. Intensity-modulated radiation therapy, protons, and the risk of second cancers. Int J Radiat Oncol Biol May 1, 2006;65(1):1e7.
Currently, intensity-modulated proton therapy (IMPT) is in use in the clinical environment. With this technique, Bragg peaks of pencil beams are distributed around the target volume and beam weights are optimized by inverse planning. Finally, several magnets are used to deflect and focus the pencil beams to the target to treat the patient. Using the IMPT technique can dramatically reduce the proton treatment time because of its complexity and labor-intensity in making the 3D compensators. PT quality assurance: Daily, monthly, and annual quality assurance (QA) for mechanical and X-ray system is needed for the PT machine and the proton radiation beam. QA includes constancy of radiation field dose/MU, distal range, SOBP width and flatness and symmetry, range uniformity check, constancy of output versus gantry angle, gantry mechanical isocentricity check, treatment able translational motion accuracy and mechanical isocentricity checks, snout horizontal motion accuracy check, patient positioning system accuracy check, X-rays, and proton field coincidence check. In addition, the patient-specific QA procedures, such as MU verification measurement and dosimetric tolerance are usually set at less than 3% difference from calculation. The QA items include, but are not limited to, items such as compensator apertures must match the treatment plan: compensator thickness tolerance <0.5 mm, point dose measurement in phantom for the treatment, depth dose measurement in solid phantoms, 2D dose verification at three to five different depths for each field, QA tolerance for point dose is within 2% or 2 mm of calculation, 2D dose distribution verification, and the tolerance is 90% that of the pixels have the passing gamma with 2% dose or 2 mm distance agreement criteria.
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FIGURE 9.4 Comparative dose painting treatment plans using intensity-modulated radiotherapy (IMRT), intensity-modulated proton therapy (IMPT). (A) A 56-year-old woman with T1N1 left-sided nasopharyngeal carcinoma (four nodes in left levels IIa, IIb, III, and Va). (B) A 47-year-old woman with T4N0 adenoid cystic carcinoma of the hard palate (surgery followed by adjuvant radiotherapy). Ref 11. Modified from Blanchard P, et al. Proton therapy for head and neck cancers. Semin Radiat Oncol January 2018;28(1):53e63.
CLINICAL EXPERIENCE OF PROTON RADIOTHERAPY Head and Neck Cancer PT is well established for paranasal sinus cancer treatments. A metaanalysis from Mayo Clinic reported that PT provides better disease-free survival 72% versus 50%, at 5 years, (P ¼ 0.045) and tumor control of 81% versus 64% at the longest follow-up, for PT versus photon treatments, respectively, (P ¼ 0.011) [9]. With the development of active scanning PT and the multifield optimization IMPT technique reduces radiation dose compared with photon beam intensity-modulated radiotherapy (IMRT). Frank et al., have demonstrated that gastrostomy tubes decrease by more than 50% with IMPT during the treatment of patients with oropharyngeal cancer [10]. A current ongoing randomized phase II/III clinical trial NCT01893307 is comparing the side effects of 2 radiation treatments for head and neck cancer. The 2 treatments are intensity modulated photon therapy (IMRT) and intensity modulated proton therapy (IMPT). The RT dose is 70 Gy, and chemotherapy is at the discretion of the physician. The primary end point of the trial is rate of grade 3e5 late toxicities. Fig. 9.4 shows photon versus proton treatments for a nasopharyngeal and adenoid cystic carcinoma of patients with hard palate cancer, IMPT significantly reduces radiation dose to the critical normal structures.
Lung Cancer For medically inoperable early-stage lung cancer patients, stereotactic body radiation therapy (SBRT) is now considered the standard of care. A systematic review by Chi et al., demonstrated that PT was associated with improved overall survival and progression-free survival relative to SBRT for early-stage lung cancer [12]. In several clinical trials, it has been demonstrated that small peripheral tumors could be treated effectively by PT or photons; however, large and central tumors are good candidates
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FIGURE 9.5 Typical dose distributions achieved with three-dimensional conformal radiotherapy (3DCRT), intensity-modulated radiotherapy (IMRT), and protons for a patient with stage III nonesmall cell lung cancer. Reprinted with permission from Nichols RC, Huh SN, Henderson RH, Mendenhall NP, Flampouri S, Li Z, D’Agostino HJ, Cury JD, Pham DC, Hoppe BS. Proton radiation therapy provides reduced normal lung and bone marrow exposure for patients receiving dose-escalated radiation therapy for unresectable stage III non-small-cell lung cancer: A dosimetric study. Clin Lung Cancer July 2011;12(4):252e7. https:// doi.org/10.1016/j.cllc.2011.03.027. Epub 2011 April 27.
for PT [13e18]. For locally advanced lung cancers, several trials have shown promising results [19,20]. The first randomized trial comparing passively scattered proton therapy (PSPT) and IMRT did not show a significant difference between the groups [21]. The ongoing clinical trial RTOG 1308 is currently enrolling patients with stage IIeIIIB none small cell lung cancer, which is randomized with respect to image-guided, and motionmanaged photon radiotherapy (Arm 1) versus image guided, motion-managed proton radiotherapy (Arm 2), both given with concurrent platinum-based chemotherapy. The primary end of the study is overall survival, and the secondary end point is toxicity, QoL, and cost-effectiveness. Fig. 9.5 is a comparison between plans for three-dimensional conformal radiotherapy (3DCRT)/IMRT and proton treatments for a lung cancer patient.
Prostate Cancer A randomized trial by Shipley et al. [22] did not show any differences between photon IMRT and PT; however, PT was only used as a boost in this study. In a more recent study, PT provided superior rectal sparing at low-to-higher doses and bladder sparing
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FIGURE 9.6
Comparison of single-field uniform dose, VMAT, and intensitymodulated proton therapy (IMPT) treatment plans for one prostate cancer patient. Here, SFUD represents a two-beam IMPT single-field uniform dose distribution plan. This plan is used to treat patients at our institution. VMAT represents a photon volumetric-modulated arc therapy plan, and IMPT-BAO is a class IIIeangle IMPT plan, where BAO interprets beam angle optimization. Chao W et al. Improved beam angle arrangement in
intensity modulated proton therapy treatment planning for localized prostate cancer. Cancers (Basel) March 30, 2015;7(2):574e84. https://doi.org/10.3390/cancers7020574.
at low-to-medium doses compared with sliding window and rapid arc techniques [23]. In addition, the latest trial data report less toxicity with prostate cancer proton treatments [24,25]. A current ongoing phase III clinical trial NCT01617161 (PartiQOL) is comparing Proton Beam or Intensity-Modulated Radiation Therapy in Treating Patients with Low or Low-Intermediate Risk Prostate Cancer. Patients are randomized to either ARM I: IMRT 5 days a week for 9 weeks vs ARM II: PBT 5 days a week for 9 weeks. The primary objective of the trial is to compare the reduction in mean Expanded Prostate Cancer Index Composite (EPIC) bowel scores for men with low or intermediate risk prostate cancer (PCa) treated with PBT versus IMRT at 24 months following radiation. Fig. 9.6 is a comparison between three-field IMPT and volumetric-modulated arc therapy for a prostate cancer patient.
Pediatric Cancer Modeling studies suggest there is a significant reduction in the risk of second malignancies with PT for pediatric patients [26,27]. Miralbell et al., showed improved dose distribution with PT compared with 3D conformal photon radiation and intensitymodulated photon beam radiation regarding second malignancies [26]. Recently an update from the Pediatric Proton Consortium Registry by Hess CB et al (2018), reported that a total of 1,854 patients have consented and enrolled in the PPCR from October 2012 until September 2017. The most tumors treated are the central nervous system (CNS) tumors comprising 61% of the cohort. The most common CNS histologies are: medulloblastoma (n ¼ 276), ependymoma (n ¼ 214), glioma/astrocytoma (n ¼ 195),
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FIGURE 9.7
Pencil-beam scanning proton dose distribution for a 17-year-old patient with an unresectable pilocytic astrocytoma centered on the left thalamus. The teal line denotes the GTV, whereas the red line denotes the CTV (5-mm isotropic margin). The maximum dose point on this slice is 100.7% (54 Gy prescription). Color wash represents 95% isodose line (left) and 10% isodose line (right). Courtesy of Derek Tsang
MD. Radiation Oncology: University of Toronto, Princess Margaret Cancer Centre, Toronto, ON, Canada.
FIGURE 9.8 In this pediatric patient with mediastinal Hodgkin’s lymphoma, the target is shown in red and the color wash represents 10% isodoses and higher. Intensity-modulated proton therapy was planned using robust planning, to account for the presence of breathing motion and heterogeneous tissues. The posterior oblique beams are able to spare breast tissue. Courtesy of Derek Tsang MD. Radiation Oncology: University of Toronto, Princess Margaret Cancer Centre, Toronto, ON, Canada.
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craniopharyngioma (n ¼ 153), and germ cell tumors (n ¼ 108). The most common nonCNS tumors diagnoses are: rhabdomyosarcoma (n ¼ 191), Ewing sarcoma (n ¼ 105), Hodgkin lymphoma (n ¼ 66), and neuroblastoma (n ¼ 55). The median follow-up of the registry is 1.5 years with a range of 0.14 to 4.6 years. The authors concluded that the PPCR’s prospective cohort of children irradiated with modern proton therapy has reached critical mass for long-awaited clinical outcomes research through use of the cohort’s open access partnership design [28]. As such varius CNS and non-CNS pediatric patients now treated with PT with lower morbidity compared with photon treatment as shown below (Figs. 9.7 and 9.8). Proton technology is improving and is very promising for the future of radiation therapy. Randomized phase II and III trials with PT are ongoing. In the adult population, cost-effectiveness is still a debate because of the lack of comparative clinical trials. Among the pediatric population, however, PT has established its presence, and it is already standard of treatment for many pediatric cancers.
References Ref 1. Mendenhall, et al. Proton therapy: principles and practice of radiation oncology. 6th ed. New York: Lippincott Willimas & Wilkins publishing; 2013. p. 379e92. Ref 2. Levin, et al. Charged particle radiotherapy: clinical radiation oncology. 4th ed. New York: Elsivier publishing; 2016. p. 358e72. Ref 3. Lomax T. Intensity-modulated proton therapy: treatment planning in radiation therapy. 4th ed. Wolters Kluwer Publishing; 2016. p. 150e67. Ref 4. Wikipedia, the free encyclopedia. Proton therapy, page 1. Wikimedia Foundation, Inc; 2008. Ref 5. Paganetti H, Niemierko A, Ancukiewicz M, et al. Relative biological effectiveness (RBE) values for proton beam therapy. Int J Radiat Oncol Biol Phys 2002;53:407e21. Ref 6. Gerweck LE, Kozin SV. Relative biological effectiveness of proton beams in clinical therapy. Radiother Oncol 1999;50:135e42. Ref 7. Britten RA, Nazaryan V, Davis LK, et al. Variations in the RBE for cell killing along the depth-dose profile of a modulated proton therapy beam. Radiat Res 2013;179:21e8. Ref 8. Matsumoto Y, Matsuura T, Wada M, et al. Enhanced radiobiological effects at the distal end of a clinical proton beam: in vitro study. J Radiat Res 2014;55:816e22. Ref 9. Patel SH, Wang Z, Zong WW, et al. Charged particle therapy versus photon therapy for paranasal sinus and nasal cavity malignant disease: a systematic review and meta-analysis. Lancet Oncol 2014;15:1027e38. Ref 10. Frank SJ, Rosenthal DI, Ang K, et al. Gastrostomy tubes decrease by over 50% with intensity modulated proton therapy during the treatment of oropharyngeal cancer patients. A case control study (abstract). Int J Radiat Oncol Biol Phys 2013;87(Suppl 2):S144. Ref 11. Blanchard P, et al. Proton therapy for head and neck cancers. Semin Radiat Oncol January 2018;28(1):53e63.
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Ref 12. Chi A, Chen H, Wen S, Yan H, Liao Z. Comparison of particle beam therapy and stereotactic body radiotherapy for early stage non-small cell lung cancer: a systematic review and hypothesis-generating meta-analysis. Radiother Oncol 2017;123(3):346e54. Ref 13. Koto M, Takai Y, Ogawa Y, et al. A phase II study on stereotactic body radiotherapy for stage I non-small cell lung cancer. Radiother Oncol 2007;85(3):429e34. Ref 14. Iwata H, Demizu Y, Fujii O, et al. Long term outcome of proton therapy and carbonion therapy for large (T2a-T2bN0M0) non-small cell lung cancer. J Thorac Oncol 2013;8(6):726e35. Ref 15. Timmerman R, McGarry R, Yiannoutsos C, et al. Excessive toxicity when treating central tumors in a phase II study of stereotactic body radiation therapy for medically inoperable early-stage lung cancer. J Clin Oncol 2006;24(30):4833e9. Ref 16. Register SP, Zhang X, Mohan R, Chang JY. Proton stereotactic body radiation therapy for clinically challenging cases of centrally and superiorly located stage I non-small-cell lung cancer. Int J Radiat Oncol Biol Phys 2011;80(4):1015e22. Ref 17. Kanemoto A, Okumura T, Ishikawa H, et al. Outcomes and prognostic factors for recurrence after high-dose proton beam therapy for centrally and peripherally located stage I nondsmall-cell lung cancer. Clin Lung Cancer 2014;15(2):e7e12. Ref 18. Makita C, Nakamura T, Takada A, et al. High-dose proton beam therapy for stage I nonesmall cell lung cancer: clinical outcomes and prognostic factors. Acta Oncol 2015;54(3):307e14. Ref 19. Oshiro Y, Okumura T, Kurishima K, et al. High-dose concurrent chemo-proton therapy for Stage III NSCLC: preliminary results of a phase II study. J Radiat Res 2014;55(5):959e65. Ref 20. Chang JY, Komaki R, Lu C, et al. Phase 2 study of high-dose proton therapy with concurrent chemotherapy for unresectable stage III non-small cell lung cancer. Cancer 2011;117(20):4707e13. Ref 21. Liao ZX, Lee JJ, Komaki R, et al. Bayesian randomized trial comparing intensity modulated radiation therapy versus PSPT for locally advanced non-small cell lung cancer. J Clin Oncol 2016;34(Suppl. 15):abstr 8500. Ref 22. Shipley WU, Verhey LJ, Munzenrider JE, et al. Advanced prostate cancer: the results of a randomized comparative trial of high dose irradiation boosting with conformal protons compared with conventional dose irradiation using photons alone. Int J Radiat Oncol Biol Phys 1995;32:3e12. Ref 23. Scobiola S, Kittel C, Wismann N, et al. A treatment planning study comparing tomotherapy, volumetric modulated arc therapy, Sliding Window and proton therapy fpr low-risk prostate carcinoma. Radiat Oncol 2016;11(1):128. Ref 24. Mendenhall NP, Li Z, Hoppe BS, et al. Early outcomes from three prospective trials of image-guided proton theray for prostate cancer. Int J Radiat Oncol Biol Phys 2012;82:213e21. Ref 25. Hoppe BS, Nichols RC, Henderson RH, et al. Erectile function, incontinence, and other quality of life outcomes following proton therapy for prostate cancer in men 60 years old and younger. Cancer 2012;118:4619e26.
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Ref 26. Miralbell R, Lomax A, Cella L, Schneider U. Potential reduction of the incidence of radiation-induced second cancers by using proton beams in the treatment of pediatric tumors. Int J Radiat Oncol Biol Phys 2002;54(3):824e9. Ref 27. Paganetti H, Athar BS, Moteabbed M, et al. Assesment of radiation induced second cancer risks in proton therapy and IMRT for organ inside the primary radiation fields. Phys Med Biol 2012;57(19):6047e61. Ref 28. Hess CB, et al. An Update From the Pediatric Proton Consortium Registry. Front Oncol 2018;8:165.
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9 Proton Radiation Therapy Recently, Proton therapy (PT) has emerged as an important tool for cancer treatments. More and more commercially available proton canters are now available for clinical use. This chapter will discuss the rationale, clinical indications, techniques, and toxicity of proton radiotherapy.
PROTON BEAM DEPTH DOSE Protons are heavy charged particles, have mass, and possess a positive charge, as such interact differently with matter than do photons. Protons do not change direction appreciably while traveling through matter but generally interact with matter by undergoing inelastic collisions with atomic electrons. In this process, they give up a portion of their energy with each collision (without changing direction appreciably). Hence, a monoenergetic proton beam continues to lose its energy while traveling through tissue, and the rate of energy loss increases with decreasing proton energy, resulting in most of the dose deposition occurring at the end of the range in a sharp Bragg peak. Proton beam absorbed dose beyond the Bragg peak is negligible [1e3]. The depth of the Bragg peak is dependent on the incident proton beam energy. To deliver a uniform dose to a target volume, the proton energy is tuned and varied to superimpose multiple Bragg peaks across the target, resulting in a region of relatively uniform dose called the spread out Bragg peak (SOBP). Proximal to the target, the SOBP delivers less of a dose than that given at the target dose (low entrance dose). Distal to the target, the SOBP delivers negligible dose (minimum exit dose). A single photon beam, on the other hand, delivers a higher dose proximal to the target and lower, but nonnegligible dose distal to the target. Protons therefore have a dosimetric advantage over photons, delivering less integral dose to normal tissues for the same tumor dose. Furthermore, most proton treatment plans require only one to three beams. Proton and photon beam depth dose characteristics are illustrated in Fig. 9.1.
PROTON RELATIVE BIOLOGICAL EFFECTIVENESS The relative biologic effectiveness (RBE) of protons is similar to megavoltage photons that are used in radiation therapy. The RBE of therapeutic energy protons (up to Copyright © 2019 Elsevier Inc. All rights reserved.
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FIGURE 9.1 In a typical treatment plan for proton therapy, the spread out Bragg peak (SOBP, dashed blue line) is the therapeutic radiation distribution. The SOBP is the sum of several individual Bragg peaks (thin blue lines) at staggered depths. The depthedose plot of an X-ray beam (red line) is provided for comparison. The pink area represents additional doses of X-ray radiotherapydwhich can damage normal tissues and cause secondary cancers, especially of the skin. Ref 4. Reproduced from Wikipedia, the free encyclopedia. Proton therapy, page 1: Wikimedia Foundation, Inc.; 2008.
250 MeV) is around 1.1; however, the RBE increases from 1.1 to 1.7 in the Bragg peak where slow protons have higher biologic effectiveness [5e8]. Thus, lower doses to normal structures at the entrance and along the protons’ pathway and with no exit dose improves the therapeutic ratio of PT compared with photon therapy. Nevertheless, sensitive normal tissues should not be positioned immediately distal to the dose falloff. As small changes in the penetration of the beam resulting from uncertainty, for example, the treatment planning CT, can cause the sensitive structure receiving the full physical dose because of the increased RBE.
BEAM PRODUCTION, DELIVERY, TREATMENT PLANNING, AND QUALITY ASSURANCE Proton generation: High-voltage electric current is applied to hydrogen gas, stripping electrons from the hydrogen atoms, leaving positively charged proton particles. Proton acceleration: Protons are accelerated by either a cyclotron or a synchrotron. A cyclotron produces a monoenergetic proton beam, typically 250 MeV. The proton energy of a synchrotron can be selected within a designed range.
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FIGURE 9.2
Proton therapy system with cyclotron, energy selection system, beam line, gantry, and nozzle. Scattering is illustrated in the nozzle on the left and scanning in the nozzle on the right. Modified from Mendenhall NL, et al. Proton Therapy; July 2, 2016, Posted by admin in
Oncology. https://oncohemakey.com/proton-therapy-2.
Proton beam transport: A series of large bending and focusing magnets along with diagnostic measuring tools guides the proton beam from the cyclotron or synchrotron to the patient treatment rooms, Fig. 9.2. Proton beam delivery: The pencil-shaped proton beam has to be modified for clinical use by the following techniques: Fig. 9.3. • Scattering beam technique: The pencil beam passes through a range modulator followed by first and second scatterer then through a compensator to treat the patient. The variable thickness range modulator spins in front of the pencil beam creating a flat top Bragg peak. By using the two scatterers and the compensator, the pencil beameshaped proton beam is spread laterally for clinical use. The scatterers and the compensator are custom-made for each proton beam. • Scanning beam technique: Multiple variable strength magnets scan the pencil beameshaped proton beam laterally to conform to the tumor/target volume. The scanning beam technique does not require patient-specific hardware. Treatment planning: A CT simulation of the patient is performed for imaging data collection. The CT values are converted to proton stopping power (as opposed to electron densities for photon treatment planning). This is followed by delineation of the target volume. Finally, selection of beam direction and plan optimization is performed. A field patching technique to match multiple beams at the 50% isodose lines laterally and at the distal level produces the desired treatment plan. The planning system designs the aperture and the compensator for each single field. Pencil beam algorithms are used for the dose calculation and the radiation dose unit is cobalt Gray equivalent (CGE).
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FIGURE 9.3 The protons emerging from a cyclotron or synchrotron form a narrow pencil beam. To cover a treatment field of practical size, the pencil beam must be either scattered by a foil or scanned. Passive scattering is by far the simplest technique but suffers the disadvantage of increased total-body effective dose to the patient. From Hall EJ. Intensity-modulated radiation therapy, protons, and the risk of second cancers. Int J Radiat Oncol Biol May 1, 2006;65(1):1e7.
Currently, intensity-modulated proton therapy (IMPT) is in use in the clinical environment. With this technique, Bragg peaks of pencil beams are distributed around the target volume and beam weights are optimized by inverse planning. Finally, several magnets are used to deflect and focus the pencil beams to the target to treat the patient. Using the IMPT technique can dramatically reduce the proton treatment time because of its complexity and labor-intensity in making the 3D compensators. PT quality assurance: Daily, monthly, and annual quality assurance (QA) for mechanical and X-ray system is needed for the PT machine and the proton radiation beam. QA includes constancy of radiation field dose/MU, distal range, SOBP width and flatness and symmetry, range uniformity check, constancy of output versus gantry angle, gantry mechanical isocentricity check, treatment able translational motion accuracy and mechanical isocentricity checks, snout horizontal motion accuracy check, patient positioning system accuracy check, X-rays, and proton field coincidence check. In addition, the patient-specific QA procedures, such as MU verification measurement and dosimetric tolerance are usually set at less than 3% difference from calculation. The QA items include, but are not limited to, items such as compensator apertures must match the treatment plan: compensator thickness tolerance <0.5 mm, point dose measurement in phantom for the treatment, depth dose measurement in solid phantoms, 2D dose verification at three to five different depths for each field, QA tolerance for point dose is within 2% or 2 mm of calculation, 2D dose distribution verification, and the tolerance is 90% that of the pixels have the passing gamma with 2% dose or 2 mm distance agreement criteria.
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FIGURE 9.4 Comparative dose painting treatment plans using intensity-modulated radiotherapy (IMRT), intensity-modulated proton therapy (IMPT). (A) A 56-year-old woman with T1N1 left-sided nasopharyngeal carcinoma (four nodes in left levels IIa, IIb, III, and Va). (B) A 47-year-old woman with T4N0 adenoid cystic carcinoma of the hard palate (surgery followed by adjuvant radiotherapy). Ref 11. Modified from Blanchard P, et al. Proton therapy for head and neck cancers. Semin Radiat Oncol January 2018;28(1):53e63.
CLINICAL EXPERIENCE OF PROTON RADIOTHERAPY Head and Neck Cancer PT is well established for paranasal sinus cancer treatments. A metaanalysis from Mayo Clinic reported that PT provides better disease-free survival 72% versus 50%, at 5 years, (P ¼ 0.045) and tumor control of 81% versus 64% at the longest follow-up, for PT versus photon treatments, respectively, (P ¼ 0.011) [9]. With the development of active scanning PT and the multifield optimization IMPT technique reduces radiation dose compared with photon beam intensity-modulated radiotherapy (IMRT). Frank et al., have demonstrated that gastrostomy tubes decrease by more than 50% with IMPT during the treatment of patients with oropharyngeal cancer [10]. A current ongoing randomized phase II/III clinical trial NCT01893307 is comparing the side effects of 2 radiation treatments for head and neck cancer. The 2 treatments are intensity modulated photon therapy (IMRT) and intensity modulated proton therapy (IMPT). The RT dose is 70 Gy, and chemotherapy is at the discretion of the physician. The primary end point of the trial is rate of grade 3e5 late toxicities. Fig. 9.4 shows photon versus proton treatments for a nasopharyngeal and adenoid cystic carcinoma of patients with hard palate cancer, IMPT significantly reduces radiation dose to the critical normal structures.
Lung Cancer For medically inoperable early-stage lung cancer patients, stereotactic body radiation therapy (SBRT) is now considered the standard of care. A systematic review by Chi et al., demonstrated that PT was associated with improved overall survival and progression-free survival relative to SBRT for early-stage lung cancer [12]. In several clinical trials, it has been demonstrated that small peripheral tumors could be treated effectively by PT or photons; however, large and central tumors are good candidates
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FIGURE 9.5 Typical dose distributions achieved with three-dimensional conformal radiotherapy (3DCRT), intensity-modulated radiotherapy (IMRT), and protons for a patient with stage III nonesmall cell lung cancer. Reprinted with permission from Nichols RC, Huh SN, Henderson RH, Mendenhall NP, Flampouri S, Li Z, D’Agostino HJ, Cury JD, Pham DC, Hoppe BS. Proton radiation therapy provides reduced normal lung and bone marrow exposure for patients receiving dose-escalated radiation therapy for unresectable stage III non-small-cell lung cancer: A dosimetric study. Clin Lung Cancer July 2011;12(4):252e7. https:// doi.org/10.1016/j.cllc.2011.03.027. Epub 2011 April 27.
for PT [13e18]. For locally advanced lung cancers, several trials have shown promising results [19,20]. The first randomized trial comparing passively scattered proton therapy (PSPT) and IMRT did not show a significant difference between the groups [21]. The ongoing clinical trial RTOG 1308 is currently enrolling patients with stage IIeIIIB none small cell lung cancer, which is randomized with respect to image-guided, and motionmanaged photon radiotherapy (Arm 1) versus image guided, motion-managed proton radiotherapy (Arm 2), both given with concurrent platinum-based chemotherapy. The primary end of the study is overall survival, and the secondary end point is toxicity, QoL, and cost-effectiveness. Fig. 9.5 is a comparison between plans for three-dimensional conformal radiotherapy (3DCRT)/IMRT and proton treatments for a lung cancer patient.
Prostate Cancer A randomized trial by Shipley et al. [22] did not show any differences between photon IMRT and PT; however, PT was only used as a boost in this study. In a more recent study, PT provided superior rectal sparing at low-to-higher doses and bladder sparing
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FIGURE 9.6
Comparison of single-field uniform dose, VMAT, and intensitymodulated proton therapy (IMPT) treatment plans for one prostate cancer patient. Here, SFUD represents a two-beam IMPT single-field uniform dose distribution plan. This plan is used to treat patients at our institution. VMAT represents a photon volumetric-modulated arc therapy plan, and IMPT-BAO is a class IIIeangle IMPT plan, where BAO interprets beam angle optimization. Chao W et al. Improved beam angle arrangement in
intensity modulated proton therapy treatment planning for localized prostate cancer. Cancers (Basel) March 30, 2015;7(2):574e84. https://doi.org/10.3390/cancers7020574.
at low-to-medium doses compared with sliding window and rapid arc techniques [23]. In addition, the latest trial data report less toxicity with prostate cancer proton treatments [24,25]. A current ongoing phase III clinical trial NCT01617161 (PartiQOL) is comparing Proton Beam or Intensity-Modulated Radiation Therapy in Treating Patients with Low or Low-Intermediate Risk Prostate Cancer. Patients are randomized to either ARM I: IMRT 5 days a week for 9 weeks vs ARM II: PBT 5 days a week for 9 weeks. The primary objective of the trial is to compare the reduction in mean Expanded Prostate Cancer Index Composite (EPIC) bowel scores for men with low or intermediate risk prostate cancer (PCa) treated with PBT versus IMRT at 24 months following radiation. Fig. 9.6 is a comparison between three-field IMPT and volumetric-modulated arc therapy for a prostate cancer patient.
Pediatric Cancer Modeling studies suggest there is a significant reduction in the risk of second malignancies with PT for pediatric patients [26,27]. Miralbell et al., showed improved dose distribution with PT compared with 3D conformal photon radiation and intensitymodulated photon beam radiation regarding second malignancies [26]. Recently an update from the Pediatric Proton Consortium Registry by Hess CB et al (2018), reported that a total of 1,854 patients have consented and enrolled in the PPCR from October 2012 until September 2017. The most tumors treated are the central nervous system (CNS) tumors comprising 61% of the cohort. The most common CNS histologies are: medulloblastoma (n ¼ 276), ependymoma (n ¼ 214), glioma/astrocytoma (n ¼ 195),
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FIGURE 9.7
Pencil-beam scanning proton dose distribution for a 17-year-old patient with an unresectable pilocytic astrocytoma centered on the left thalamus. The teal line denotes the GTV, whereas the red line denotes the CTV (5-mm isotropic margin). The maximum dose point on this slice is 100.7% (54 Gy prescription). Color wash represents 95% isodose line (left) and 10% isodose line (right). Courtesy of Derek Tsang
MD. Radiation Oncology: University of Toronto, Princess Margaret Cancer Centre, Toronto, ON, Canada.
FIGURE 9.8 In this pediatric patient with mediastinal Hodgkin’s lymphoma, the target is shown in red and the color wash represents 10% isodoses and higher. Intensity-modulated proton therapy was planned using robust planning, to account for the presence of breathing motion and heterogeneous tissues. The posterior oblique beams are able to spare breast tissue. Courtesy of Derek Tsang MD. Radiation Oncology: University of Toronto, Princess Margaret Cancer Centre, Toronto, ON, Canada.
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craniopharyngioma (n ¼ 153), and germ cell tumors (n ¼ 108). The most common nonCNS tumors diagnoses are: rhabdomyosarcoma (n ¼ 191), Ewing sarcoma (n ¼ 105), Hodgkin lymphoma (n ¼ 66), and neuroblastoma (n ¼ 55). The median follow-up of the registry is 1.5 years with a range of 0.14 to 4.6 years. The authors concluded that the PPCR’s prospective cohort of children irradiated with modern proton therapy has reached critical mass for long-awaited clinical outcomes research through use of the cohort’s open access partnership design [28]. As such varius CNS and non-CNS pediatric patients now treated with PT with lower morbidity compared with photon treatment as shown below (Figs. 9.7 and 9.8). Proton technology is improving and is very promising for the future of radiation therapy. Randomized phase II and III trials with PT are ongoing. In the adult population, cost-effectiveness is still a debate because of the lack of comparative clinical trials. Among the pediatric population, however, PT has established its presence, and it is already standard of treatment for many pediatric cancers.
References Ref 1. Mendenhall, et al. Proton therapy: principles and practice of radiation oncology. 6th ed. New York: Lippincott Willimas & Wilkins publishing; 2013. p. 379e92. Ref 2. Levin, et al. Charged particle radiotherapy: clinical radiation oncology. 4th ed. New York: Elsivier publishing; 2016. p. 358e72. Ref 3. Lomax T. Intensity-modulated proton therapy: treatment planning in radiation therapy. 4th ed. Wolters Kluwer Publishing; 2016. p. 150e67. Ref 4. Wikipedia, the free encyclopedia. Proton therapy, page 1. Wikimedia Foundation, Inc; 2008. Ref 5. Paganetti H, Niemierko A, Ancukiewicz M, et al. Relative biological effectiveness (RBE) values for proton beam therapy. Int J Radiat Oncol Biol Phys 2002;53:407e21. Ref 6. Gerweck LE, Kozin SV. Relative biological effectiveness of proton beams in clinical therapy. Radiother Oncol 1999;50:135e42. Ref 7. Britten RA, Nazaryan V, Davis LK, et al. Variations in the RBE for cell killing along the depth-dose profile of a modulated proton therapy beam. Radiat Res 2013;179:21e8. Ref 8. Matsumoto Y, Matsuura T, Wada M, et al. Enhanced radiobiological effects at the distal end of a clinical proton beam: in vitro study. J Radiat Res 2014;55:816e22. Ref 9. Patel SH, Wang Z, Zong WW, et al. Charged particle therapy versus photon therapy for paranasal sinus and nasal cavity malignant disease: a systematic review and meta-analysis. Lancet Oncol 2014;15:1027e38. Ref 10. Frank SJ, Rosenthal DI, Ang K, et al. Gastrostomy tubes decrease by over 50% with intensity modulated proton therapy during the treatment of oropharyngeal cancer patients. A case control study (abstract). Int J Radiat Oncol Biol Phys 2013;87(Suppl 2):S144. Ref 11. Blanchard P, et al. Proton therapy for head and neck cancers. Semin Radiat Oncol January 2018;28(1):53e63.
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9. PROTON RADIATION THERAPY
Ref 12. Chi A, Chen H, Wen S, Yan H, Liao Z. Comparison of particle beam therapy and stereotactic body radiotherapy for early stage non-small cell lung cancer: a systematic review and hypothesis-generating meta-analysis. Radiother Oncol 2017;123(3):346e54. Ref 13. Koto M, Takai Y, Ogawa Y, et al. A phase II study on stereotactic body radiotherapy for stage I non-small cell lung cancer. Radiother Oncol 2007;85(3):429e34. Ref 14. Iwata H, Demizu Y, Fujii O, et al. Long term outcome of proton therapy and carbonion therapy for large (T2a-T2bN0M0) non-small cell lung cancer. J Thorac Oncol 2013;8(6):726e35. Ref 15. Timmerman R, McGarry R, Yiannoutsos C, et al. Excessive toxicity when treating central tumors in a phase II study of stereotactic body radiation therapy for medically inoperable early-stage lung cancer. J Clin Oncol 2006;24(30):4833e9. Ref 16. Register SP, Zhang X, Mohan R, Chang JY. Proton stereotactic body radiation therapy for clinically challenging cases of centrally and superiorly located stage I non-small-cell lung cancer. Int J Radiat Oncol Biol Phys 2011;80(4):1015e22. Ref 17. Kanemoto A, Okumura T, Ishikawa H, et al. Outcomes and prognostic factors for recurrence after high-dose proton beam therapy for centrally and peripherally located stage I nondsmall-cell lung cancer. Clin Lung Cancer 2014;15(2):e7e12. Ref 18. Makita C, Nakamura T, Takada A, et al. High-dose proton beam therapy for stage I nonesmall cell lung cancer: clinical outcomes and prognostic factors. Acta Oncol 2015;54(3):307e14. Ref 19. Oshiro Y, Okumura T, Kurishima K, et al. High-dose concurrent chemo-proton therapy for Stage III NSCLC: preliminary results of a phase II study. J Radiat Res 2014;55(5):959e65. Ref 20. Chang JY, Komaki R, Lu C, et al. Phase 2 study of high-dose proton therapy with concurrent chemotherapy for unresectable stage III non-small cell lung cancer. Cancer 2011;117(20):4707e13. Ref 21. Liao ZX, Lee JJ, Komaki R, et al. Bayesian randomized trial comparing intensity modulated radiation therapy versus PSPT for locally advanced non-small cell lung cancer. J Clin Oncol 2016;34(Suppl. 15):abstr 8500. Ref 22. Shipley WU, Verhey LJ, Munzenrider JE, et al. Advanced prostate cancer: the results of a randomized comparative trial of high dose irradiation boosting with conformal protons compared with conventional dose irradiation using photons alone. Int J Radiat Oncol Biol Phys 1995;32:3e12. Ref 23. Scobiola S, Kittel C, Wismann N, et al. A treatment planning study comparing tomotherapy, volumetric modulated arc therapy, Sliding Window and proton therapy fpr low-risk prostate carcinoma. Radiat Oncol 2016;11(1):128. Ref 24. Mendenhall NP, Li Z, Hoppe BS, et al. Early outcomes from three prospective trials of image-guided proton theray for prostate cancer. Int J Radiat Oncol Biol Phys 2012;82:213e21. Ref 25. Hoppe BS, Nichols RC, Henderson RH, et al. Erectile function, incontinence, and other quality of life outcomes following proton therapy for prostate cancer in men 60 years old and younger. Cancer 2012;118:4619e26.
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REFERENCES
171
Ref 26. Miralbell R, Lomax A, Cella L, Schneider U. Potential reduction of the incidence of radiation-induced second cancers by using proton beams in the treatment of pediatric tumors. Int J Radiat Oncol Biol Phys 2002;54(3):824e9. Ref 27. Paganetti H, Athar BS, Moteabbed M, et al. Assesment of radiation induced second cancer risks in proton therapy and IMRT for organ inside the primary radiation fields. Phys Med Biol 2012;57(19):6047e61. Ref 28. Hess CB, et al. An Update From the Pediatric Proton Consortium Registry. Front Oncol 2018;8:165.
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