International Journal of
Radiation Oncology biology
physics
www.redjournal.org
EDITORIAL
Advancing (Proton) Radiation Therapy Harald Paganetti, PhD Department of Radiation Oncology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts Received Jul 26, 2013, and in revised form Aug 20, 2013. Accepted for publication Aug 23, 2013. In 2013, the number of radiation therapy patients treated with protons reached the milestone of 100,000. Even though this is only a small fraction of radiation therapy patients, proton therapy draws disproportional attention based on assessments of costeffectiveness. The controversy goes beyond attaching a price tag to improved patient care. It is questioned whether protons offer improved outcome at all. The future will see more randomized clinical trials, of which currently only a few are ongoing (eg, prostate and lung). Technological advances improving treatment accuracy or precision (eg, intensity modulated radiation therapy) were often not tested in clinical trials owing to equipoise (1). Further, technology assessments by clinical trials are often hampered by the fact that treatment techniques are constantly evolving. Proton therapy is currently in transition because of the deployment of in-room imaging techniques that are already standard in photon therapy and the move to beam scanning (including intensity modulated proton therapy [IMPT]). At the same time, the advent of lower-cost solutions will expand availability and further proliferate proton usage. Biophysics research contributes to the assessment of proton therapy and mainly focuses on understanding the clinical relevance and on proper utilization of proton beam characteristics. Three aspects are most prominent: (1) understanding doseeresponse relationships to predict treatment outcome; (2) reducing planning and delivery uncertainties; and (3) utilizing the clinical potential of IMPT.
DoseeResponse Relationships Assuming identical target dose conformity and target volumes, proton therapy reduces the total energy deposited in the patient manifold compared with any type of external beam photon treatments, independent of any photon planning or delivery technique. This integral dose advantage is what makes proton therapy attractive. It has been argued that proton and photon Reprint requests to: Harald Paganetti, PhD, Massachusetts General Hospital, Harvard Medical School, Department of Radiation Oncology, 30
Int J Radiation Oncol Biol Phys, Vol. 87, No. 5, pp. 871e873, 2013 0360-3016/$ - see front matter Ó 2013 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.ijrobp.2013.08.030
plans can be assessed by dosimetric comparisons alone, but are we overstating the predictive power and significance of dosimetric indices? If the total reduced dose to critical structures were all that mattered, there would be no need for clinical trials comparing photons and protons. For the pediatric patient population, clinical trials are judged to be unethical because they would deliver significant excess dose to healthy structures in the photon arm (2). Matters are not as clear for adults because the clinical consequences of the reduced integral dose is not fully understood. We need to identify those patients who benefit most from proton therapy and prioritize accordingly (ie, those patients for whom a dosimetric advantage translates most likely into a clinical benefit), potentially with the use of appropriate biomarkers. Assessing clinical impact can be difficult because proton dose distributions in critical structures are typically more heterogeneous compared with photon therapy. Yet most organ dose constraints are defined according to mean dose, neglecting the difference between a small volume of high dose and a large volume of low dose. Proton therapy dose constraints need to be defined differently (eg, with the use of equivalent uniform dose). Ideally, we would not prescribe dose but tumor control probability and normal tissue complication probabilities. The difference in dose distribution between proton and photon therapy could have even more complex consequences. When interpreting side effects we might have to investigate physiologic interactions of different organs (3). Future research will give insight into such systemic reactions from radiation therapy. Lower normal tissue doses should positively affect (1) cognitive endpoints in pediatric patients; (2) the potential for dose escalation; (3) the potential for integration with systemic chemotherapy; and/or (4) toxicity when treating large volumes. Imaging to assess treatment response has largely focused on imaging radiation effects on tumors. To understand the integral dose effects we need to focus more on functional imaging of irradiated critical structures. Fruit St, Boston, MA 02114. Tel: (617) 726-5847; E-mail: hpaganetti@ partners.org Conflict of interest: none.
872
Paganetti
Although there is the potential for hypofractionation when using photons, the reduced dose bath with proton therapy allows a revision of current standard fractionation regimens for many more sites because of the reduced normal tissue dose. When evaluating fractionation regimens, we have to be aware of the difference in dose distribution between photon and proton treatments (4). Here we should assess normal tissue effects by considering voxelized local doseeresponse because of dose gradients and inhomogeneous organ distributions. The relative biological effectiveness (RBE) of proton beams is not well understood and subscribes to a value of 1.1 on the basis of evidence that this presents the average value in the center of the target (5). As long as we continue to use photon doseeresponse curves as a reference, RBE uncertainties will affect the interpretation of proton dose distributions. The RBE depends on the local linear energy transfer, the dose, and the tissue a/b. In particular, the latter is often not known accurately. Consequently we might not only miss opportunities of utilizing variable effect distributions but also misinterpret trials comparing proton and photon treatments, in particular for low a/b endpoints. It is also possible that mechanistic effects of radiation action on cells are different between protons and photons (6). Note that the high-dose volumes in photon and proton treatments often differ. For instance, for large depths the penumbra of proton fields can be wider than the one for photon fields. More important, there are considerable uncertainties in predicting the exact range of proton beams, resulting in a nonsymmetric planning target volume (PTV) expansion and thus differences in target volume between modalities. Because of our lack of understanding with respect to localizing cancerous tissues, it is possible that the reduction of treatment volumes or margins can potentially worsen outcome.
Planning and Delivery Uncertainties In proton therapy, the common PTV expansion is applicable only when considering lateral uncertainties. Range uncertainties require a separate expansion along the beam direction. This can cause a larger “PTV” volume in proton therapy as compared with photon therapy. Range uncertainties depend on the specific patient geometry and beam angle. Clinically, most centers apply a distal uncertainty margin on the order of 2.5%-3.5% of the range plus an additional 1-3 mm, resulting in significant overshoot and irradiation of healthy tissues. Avoiding beams pointing toward critical structures can minimize the impact of uncertainties, but it negates one of the key benefits of proton therapy (ie, the finite beam range). Treatment plans can be designed to be more robust in terms of the clinical consequences of range uncertainties, a method particularly promising in IMPT (7). Robustness toward range uncertainty might reduce conformity. Note that when using beam scanning, range uncertainties not only affect the distal part of the dose distribution but also the homogeneity of the target dose. Range uncertainty margins for scanning are not yet well defined. Uncertainties can be related to beam delivery (ie, to patient setup or intra- and interfractional anatomic changes). However, more significant uncertainties are introduced by dose calculations owing to approximations in algorithms and to imperfections in diagnostic imaging information on which the dose calculation is based (eg, CT resolution and conversion algorithms to translate Hounsfield units to relative stopping powers). Dual-energy CT or even proton CT might help reducing range uncertainties. Dose
International Journal of Radiation Oncology Biology Physics calculation algorithms are often optimized for calculation speed and not necessarily accuracy (ie, dose calculation using Monte Carlo will reduce uncertainties considerably) (8). One can expect that range uncertainties will decrease to approximately 1% of the range for nonmoving geometries in the short term. Note that changes in patient anatomy are less forgiving in proton therapy compared with photon therapy and cannot easily be corrected for without online imaging and potential replanning. Reducing range uncertainties can have clinical consequences beyond reducing margins. Currently, certain beam angles are not considered because of concerns regarding overshoot into critical structures. For example, anterioreposterior fields in prostate radiation therapy are being avoided because range uncertainty margins would require significant dose to the rectum. Thus, one uses the lateral beam penumbra to spare the rectum, with no expected dosimetric advantage compared with photon beams. It is feasible to verify the range in the patient by using in vivo dosimeters or by using imaging systems utilizing protons that undergo nuclear interactions. This can produce b-emitters or cause the emission of high-energy photons; both techniques are being developed for in vivo range verification (9). Proton therapy offers unique dose verification opportunities we need to utilize.
Clinical Potential of IMPT Compared with intensity modulated radiation therapy, protons have an additional degree of freedom when optimizing dose (ie, the potential to change the Bragg peak position in depth). The resulting advanced dose-shaping capability allows dose conformity in particular for complex targets not achievable using photon beams, this in particular when applying IMPT. Scanning systems delivering IMPT can differ significantly, and we can expect future developments to change the performance of these systems. In the meantime, passive scattering systems still offer a dosimetric benefit compared with conventional radiation therapy. The superior dose-painting capabilities of IMPT can be used on the basis of future advances in tumor imaging. Furthermore, there are efforts toward adaptive radiation therapy not only with respect to frequent reimaging and replanning but also toward online motion compensation. Although there are various imaging and dose calculation issues still to be solved, proton beam scanning is clearly an ideal tool to pursue such efforts. Magnetically changing the beam position can be done much faster than beam adaptation using a multileaf collimator. The use of IMPT also opens the door for biological dose painting and biological optimization in which the distribution of linear energy transfer can be influenced in treatment planning (10).
Summary In summary, current research efforts focus on assessing the clinical significance of the reduced dose bath when using proton beams. Further, a significant reduction of the current planning and delivery uncertainties limiting the potential of protons can be expected in the short term. Most importantly, the potential for technical advancements leading to improved treatments is by far greater in proton therapy compared with conventional therapies, in particular with the advent of IMPT. This will affect the design of clinical trials (which could be biophysics driven) and will advance the field of radiation therapy as a whole.
Volume 87 Number 5 2013
References 1. Sakurai H, Lee WR, Orton CG. We do not need randomized clinical trials to demonstrate the superiority of proton therapy. Point/Counterpoint. Med Phys 2012;39:1685-1687. 2. Johnstone PA, McMullen KP, Buchsbaum JC, et al. Pediatric craniospinal irradiation: Are protons the only ethical approach?. Int J Radiat Oncol Biol Phys 2013;87:228-230. 3. Paganetti H, van Luijk P. Biological considerations when comparing proton therapy with photon therapy. Semin Radiat Oncol 2013;23: 77-87. 4. Unkelbach J, Craft D, Salari E, et al. The dependence of optimal fractionation schemes on the spatial dose distribution. Phys Med Biol 2013;58:159-167.
Advancing (proton) radiation therapy
873
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;53:407-421. 6. Girdhani S, Sachs R, Hlatky L. Biological effects of proton radiation: What we know and don’t know. Radiat Res 2013;179:257-272. 7. Unkelbach J, Bortfeld T, Martin BC, et al. Reducing the sensitivity of IMPT treatment plans to setup errors and range uncertainties via probabilistic treatment planning. Med Phys 2009;36:149-163. 8. Paganetti H. Range uncertainties in proton therapy and the role of Monte Carlo simulations. Phys Med Biol 2012;57:R99-R117. 9. Knopf AC, Lomax A. In vivo proton range verification: A review. Phys Med Biol 2013;58:R131-R160. 10. Giantsoudi D, Grassberger C, Craft D, et al. LET-guided optimization in intensity modulated proton therapy: Feasibility study and clinical potential. Int J Radiat Oncol Biol Phys 2013;87:216-222.
Radiation Oncology biology
physics
www.redjournal.org
EDITORIAL
Advancing (Proton) Radiation Therapy Harald Paganetti, PhD Department of Radiation Oncology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts Received Jul 26, 2013, and in revised form Aug 20, 2013. Accepted for publication Aug 23, 2013. In 2013, the number of radiation therapy patients treated with protons reached the milestone of 100,000. Even though this is only a small fraction of radiation therapy patients, proton therapy draws disproportional attention based on assessments of costeffectiveness. The controversy goes beyond attaching a price tag to improved patient care. It is questioned whether protons offer improved outcome at all. The future will see more randomized clinical trials, of which currently only a few are ongoing (eg, prostate and lung). Technological advances improving treatment accuracy or precision (eg, intensity modulated radiation therapy) were often not tested in clinical trials owing to equipoise (1). Further, technology assessments by clinical trials are often hampered by the fact that treatment techniques are constantly evolving. Proton therapy is currently in transition because of the deployment of in-room imaging techniques that are already standard in photon therapy and the move to beam scanning (including intensity modulated proton therapy [IMPT]). At the same time, the advent of lower-cost solutions will expand availability and further proliferate proton usage. Biophysics research contributes to the assessment of proton therapy and mainly focuses on understanding the clinical relevance and on proper utilization of proton beam characteristics. Three aspects are most prominent: (1) understanding doseeresponse relationships to predict treatment outcome; (2) reducing planning and delivery uncertainties; and (3) utilizing the clinical potential of IMPT.
DoseeResponse Relationships Assuming identical target dose conformity and target volumes, proton therapy reduces the total energy deposited in the patient manifold compared with any type of external beam photon treatments, independent of any photon planning or delivery technique. This integral dose advantage is what makes proton therapy attractive. It has been argued that proton and photon Reprint requests to: Harald Paganetti, PhD, Massachusetts General Hospital, Harvard Medical School, Department of Radiation Oncology, 30
Int J Radiation Oncol Biol Phys, Vol. 87, No. 5, pp. 871e873, 2013 0360-3016/$ - see front matter Ó 2013 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.ijrobp.2013.08.030
plans can be assessed by dosimetric comparisons alone, but are we overstating the predictive power and significance of dosimetric indices? If the total reduced dose to critical structures were all that mattered, there would be no need for clinical trials comparing photons and protons. For the pediatric patient population, clinical trials are judged to be unethical because they would deliver significant excess dose to healthy structures in the photon arm (2). Matters are not as clear for adults because the clinical consequences of the reduced integral dose is not fully understood. We need to identify those patients who benefit most from proton therapy and prioritize accordingly (ie, those patients for whom a dosimetric advantage translates most likely into a clinical benefit), potentially with the use of appropriate biomarkers. Assessing clinical impact can be difficult because proton dose distributions in critical structures are typically more heterogeneous compared with photon therapy. Yet most organ dose constraints are defined according to mean dose, neglecting the difference between a small volume of high dose and a large volume of low dose. Proton therapy dose constraints need to be defined differently (eg, with the use of equivalent uniform dose). Ideally, we would not prescribe dose but tumor control probability and normal tissue complication probabilities. The difference in dose distribution between proton and photon therapy could have even more complex consequences. When interpreting side effects we might have to investigate physiologic interactions of different organs (3). Future research will give insight into such systemic reactions from radiation therapy. Lower normal tissue doses should positively affect (1) cognitive endpoints in pediatric patients; (2) the potential for dose escalation; (3) the potential for integration with systemic chemotherapy; and/or (4) toxicity when treating large volumes. Imaging to assess treatment response has largely focused on imaging radiation effects on tumors. To understand the integral dose effects we need to focus more on functional imaging of irradiated critical structures. Fruit St, Boston, MA 02114. Tel: (617) 726-5847; E-mail: hpaganetti@ partners.org Conflict of interest: none.
872
Paganetti
Although there is the potential for hypofractionation when using photons, the reduced dose bath with proton therapy allows a revision of current standard fractionation regimens for many more sites because of the reduced normal tissue dose. When evaluating fractionation regimens, we have to be aware of the difference in dose distribution between photon and proton treatments (4). Here we should assess normal tissue effects by considering voxelized local doseeresponse because of dose gradients and inhomogeneous organ distributions. The relative biological effectiveness (RBE) of proton beams is not well understood and subscribes to a value of 1.1 on the basis of evidence that this presents the average value in the center of the target (5). As long as we continue to use photon doseeresponse curves as a reference, RBE uncertainties will affect the interpretation of proton dose distributions. The RBE depends on the local linear energy transfer, the dose, and the tissue a/b. In particular, the latter is often not known accurately. Consequently we might not only miss opportunities of utilizing variable effect distributions but also misinterpret trials comparing proton and photon treatments, in particular for low a/b endpoints. It is also possible that mechanistic effects of radiation action on cells are different between protons and photons (6). Note that the high-dose volumes in photon and proton treatments often differ. For instance, for large depths the penumbra of proton fields can be wider than the one for photon fields. More important, there are considerable uncertainties in predicting the exact range of proton beams, resulting in a nonsymmetric planning target volume (PTV) expansion and thus differences in target volume between modalities. Because of our lack of understanding with respect to localizing cancerous tissues, it is possible that the reduction of treatment volumes or margins can potentially worsen outcome.
Planning and Delivery Uncertainties In proton therapy, the common PTV expansion is applicable only when considering lateral uncertainties. Range uncertainties require a separate expansion along the beam direction. This can cause a larger “PTV” volume in proton therapy as compared with photon therapy. Range uncertainties depend on the specific patient geometry and beam angle. Clinically, most centers apply a distal uncertainty margin on the order of 2.5%-3.5% of the range plus an additional 1-3 mm, resulting in significant overshoot and irradiation of healthy tissues. Avoiding beams pointing toward critical structures can minimize the impact of uncertainties, but it negates one of the key benefits of proton therapy (ie, the finite beam range). Treatment plans can be designed to be more robust in terms of the clinical consequences of range uncertainties, a method particularly promising in IMPT (7). Robustness toward range uncertainty might reduce conformity. Note that when using beam scanning, range uncertainties not only affect the distal part of the dose distribution but also the homogeneity of the target dose. Range uncertainty margins for scanning are not yet well defined. Uncertainties can be related to beam delivery (ie, to patient setup or intra- and interfractional anatomic changes). However, more significant uncertainties are introduced by dose calculations owing to approximations in algorithms and to imperfections in diagnostic imaging information on which the dose calculation is based (eg, CT resolution and conversion algorithms to translate Hounsfield units to relative stopping powers). Dual-energy CT or even proton CT might help reducing range uncertainties. Dose
International Journal of Radiation Oncology Biology Physics calculation algorithms are often optimized for calculation speed and not necessarily accuracy (ie, dose calculation using Monte Carlo will reduce uncertainties considerably) (8). One can expect that range uncertainties will decrease to approximately 1% of the range for nonmoving geometries in the short term. Note that changes in patient anatomy are less forgiving in proton therapy compared with photon therapy and cannot easily be corrected for without online imaging and potential replanning. Reducing range uncertainties can have clinical consequences beyond reducing margins. Currently, certain beam angles are not considered because of concerns regarding overshoot into critical structures. For example, anterioreposterior fields in prostate radiation therapy are being avoided because range uncertainty margins would require significant dose to the rectum. Thus, one uses the lateral beam penumbra to spare the rectum, with no expected dosimetric advantage compared with photon beams. It is feasible to verify the range in the patient by using in vivo dosimeters or by using imaging systems utilizing protons that undergo nuclear interactions. This can produce b-emitters or cause the emission of high-energy photons; both techniques are being developed for in vivo range verification (9). Proton therapy offers unique dose verification opportunities we need to utilize.
Clinical Potential of IMPT Compared with intensity modulated radiation therapy, protons have an additional degree of freedom when optimizing dose (ie, the potential to change the Bragg peak position in depth). The resulting advanced dose-shaping capability allows dose conformity in particular for complex targets not achievable using photon beams, this in particular when applying IMPT. Scanning systems delivering IMPT can differ significantly, and we can expect future developments to change the performance of these systems. In the meantime, passive scattering systems still offer a dosimetric benefit compared with conventional radiation therapy. The superior dose-painting capabilities of IMPT can be used on the basis of future advances in tumor imaging. Furthermore, there are efforts toward adaptive radiation therapy not only with respect to frequent reimaging and replanning but also toward online motion compensation. Although there are various imaging and dose calculation issues still to be solved, proton beam scanning is clearly an ideal tool to pursue such efforts. Magnetically changing the beam position can be done much faster than beam adaptation using a multileaf collimator. The use of IMPT also opens the door for biological dose painting and biological optimization in which the distribution of linear energy transfer can be influenced in treatment planning (10).
Summary In summary, current research efforts focus on assessing the clinical significance of the reduced dose bath when using proton beams. Further, a significant reduction of the current planning and delivery uncertainties limiting the potential of protons can be expected in the short term. Most importantly, the potential for technical advancements leading to improved treatments is by far greater in proton therapy compared with conventional therapies, in particular with the advent of IMPT. This will affect the design of clinical trials (which could be biophysics driven) and will advance the field of radiation therapy as a whole.
Volume 87 Number 5 2013
References 1. Sakurai H, Lee WR, Orton CG. We do not need randomized clinical trials to demonstrate the superiority of proton therapy. Point/Counterpoint. Med Phys 2012;39:1685-1687. 2. Johnstone PA, McMullen KP, Buchsbaum JC, et al. Pediatric craniospinal irradiation: Are protons the only ethical approach?. Int J Radiat Oncol Biol Phys 2013;87:228-230. 3. Paganetti H, van Luijk P. Biological considerations when comparing proton therapy with photon therapy. Semin Radiat Oncol 2013;23: 77-87. 4. Unkelbach J, Craft D, Salari E, et al. The dependence of optimal fractionation schemes on the spatial dose distribution. Phys Med Biol 2013;58:159-167.
Advancing (proton) radiation therapy
873
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;53:407-421. 6. Girdhani S, Sachs R, Hlatky L. Biological effects of proton radiation: What we know and don’t know. Radiat Res 2013;179:257-272. 7. Unkelbach J, Bortfeld T, Martin BC, et al. Reducing the sensitivity of IMPT treatment plans to setup errors and range uncertainties via probabilistic treatment planning. Med Phys 2009;36:149-163. 8. Paganetti H. Range uncertainties in proton therapy and the role of Monte Carlo simulations. Phys Med Biol 2012;57:R99-R117. 9. Knopf AC, Lomax A. In vivo proton range verification: A review. Phys Med Biol 2013;58:R131-R160. 10. Giantsoudi D, Grassberger C, Craft D, et al. LET-guided optimization in intensity modulated proton therapy: Feasibility study and clinical potential. Int J Radiat Oncol Biol Phys 2013;87:216-222.
