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Policy Implications of Proton Radiation Therapy: Toward an Evidence-Based Approach for Implementing Novel Oncologic Technologies
International Journal of
Radiation Oncology biology
physics
www.redjournal.org
COMMENTS Policy Implications of Proton Radiation Therapy: Toward an Evidence-Based Approach for Implementing Novel Oncologic Technologies To the Editor: Despite the potential clinical advantages, some proton treatments cost 3 to 4 times their analogous photon-based approaches, placing additional pressure on our healthcare system (1). Consequently, the optimal allocation of this advanced technology represents an emerging challenge, because although theoretically superior, protons suffer from limited level 1 evidence (2) and considerable economic hurdles. As protons gain traction, we propose 2 parallel research and policy endeavors that hinge on developing high-level evidence, for although cohort studies can demonstrate the feasibility of protons, they cannot alone be used to shift the standard of care. Leaders in the field have cited profound resistance to the initiation of randomized controlled trials, owing to the widely accepted physical benefits of protons (3). However, it remains economically difficult to justify the expense of protonbased radiation therapy solely on the basis of theoretical or modeled benefits. Therefore, we propose the following baseline approach: (1) where clinicians feel there is not equipoise, for example in pediatric malignancies, expert consensus should guide policy; and (2) among equivocal disease sites, phase 2 studies should lay the groundwork for major phase 3 trials. Indeed, inherent cost considerations along with the established utilization and availability of photons necessarily place the burden on protons to demonstrate superiority. Although many trials are underway, several years will elapse before definitive data are available. In the interim, utilization should be limited to cases with compelling clinical evidence or to robust trials where such evidence is being generated. Historically, the US government has used the idea of coverage with evidence development (4). In this model, a novel technology is conditionally covered only in the context of a clinical study. This approach successfully expanded coverage for FDG-PET scans through the establishment of the National Oncology PET
Int J Radiation Oncol Biol Phys, Vol. 95, No. 1, pp. 560e561, 2016 0360-3016/$ - see front matter Ó 2016 Elsevier Inc. All rights reserved.
Registry, which resulted in the generation of significant data in a relatively short time (5). The science of proton radiation therapy stands to benefit similarly from coverage with evidence development. Accordingly, a researchbased incentive should be implemented, whereby centers demonstrating rigorous investigational standards and monitoring are reimbursed more generously than those that merely supplant conventional approaches without oversight. The mechanism for such monitoring could mimic current US Food and Drug Administration strategies for regulation of investigational drugs or devices, though with the aim of incentivizing and funding promising research. Conversely, off-protocol proton treatments administered in the absence of compelling clinical evidence should be reimbursed commensurate with the analogous photon therapy. This reference pricing approach will undoubtedly limit the viability of certain centers that were financially dependent on the price premium of protons. Unfortunately, however, the current cost of off-protocol proton therapy is unsustainable. To enhance efficiency, critical studies should be driven by an overarching cooperative group with clinical, governmental, and industrial input. Data generated by each center would accrue to a central registry for interval monitoring and comprehensive analysis. This design would allow these expansive studies to be maximally powered and, occasionally, for early closure based on interim evidence of either superiority or futility. As the costs of oncologic care accelerate in this era of precision medicine, it behooves us as a radiation oncology community to adopt responsible approaches to the implementation of our most promising technologies. Via broad-based endeavors through our cooperative groups, we would be well served to seize such initiatives rather than awaiting their imposition by external stakeholders, as has happened, rather memorably, in the recent past. Lior Z. Braunstein, MD Laura E.G. Warren, MD, EdM Harvard Radiation Oncology Program Boston, Massachusetts http://dx.doi.org/10.1016/j.ijrobp.2015.11.001
Volume 95 Number 1 2016
References 1. Peeters A, Grutters JP, Pijls-Johannesma M, et al. How costly is particle therapy? Cost analysis of external beam radiotherapy with carbon-ions, protons and photons. Radiother Oncol 2010;95:45-53. 2. Trikalinos TA, Terasawa T, Ip S, et al. Particle Beam Radiaton Therapies for Cancer. Rockville, MD: Agency for Healthcare Research and Quality, 2009. 3. Goitein M, Cox JD. Should randomized clinical trials be required for proton radiotherapy? J Clin Oncol 2008;26:175-176. 4. Centers for Medicare & Medicaid Services. Guidance for the Public, Industry, and CMS Staff: National Coverage Determinations with Data Collection as a Condition of Coverage: Coverage with Evidence Development. Baltimore, MD: CMS, 2006. 5. Tunis S, Whicher D. The National Oncologic PET Registry: Lessons learned for coverage with evidence development. J Am Coll Radiol 2009;6:360-365.
Carbon-Ion Therapy: One More Step in the Endless Quest for the Ideal Dose Distribution An overriding paradigm of radiation therapy since its inception has been the optimization of dose distributions (ie, maximizing the tumor dose while minimizing the dose to organs at risk). To this end, highly effective technologies such as x-rayebased intensity modulated radiation therapy and stereotactic body radiation therapy, as well as proton beam therapy (PBT) are now part of our repertoire. For the past 10 or more years, our European and Asian colleagues have been testing beams of high-energy carbon ions primarily because their dose distributions exceed even those of PBT. Currently some of the more intrepid among us argue that the United States is falling behind in the radiation therapy “arms race,” and that to catch up we should be planning a state of the art carbon-ion therapy (CIT) facility. However, with an unremarkable clinical track record, and a staggering $200-$300 million price tag, we cannot help but ask, “To what end?” Because radiation therapy is mainly available to those living within a 30- to 40-mile radius of a treatment center, and assuming very significant improvements in CIT outcomes, many billions of dollars would have to be invested over the next decades before supply could start meeting demand. During this period, it is likely that new drugs will reduce the number of patients needing radiation therapy. Such drugs, albeit expensive, can in most cases be made readily available to all in need, and unlike CIT, they require no major construction projects. Additionally, when drug A is superseded by drug B, only drug A’s production facility is affected, and in most cases it can be used to make drug B. Given the biases of patient selection and the subjective evaluations of toxicity implicit in the current European and Asian phase 2 clinical reports, it would be imprudent to
Comments
561
proceed with a project on the scale of a CIT facility without first having objective determinations that show significantly improved clinical outcomes. To obtain these kinds of data, it would seem reasonable to set up cooperative randomized, controlled trials with our European and Asian colleagues. Although such undertakings would extend the timeline of a CIT project, should we be willing to rush in and “bet the farm” that a bigger and more energetic machine will improve the lives of cancer patients? Carbon ions are not magic bullets. Despite the hype of its proponents, CIT is still about little more than dose distributions and its ability to provide therapeutic ratios only marginally higher than those provided by PBT. Additionally, and like PBT, a successful treatment is contingent on the precise implementation of the treatment plan, this being a far from trivial issue for a radiation whose positioning is not amenable to portal imaging. With CIT and PBT, the seemingly endless quest to enhance the therapeutic ratio has reached a point of diminishing returns in terms of mortality and morbidity. Until proven otherwise, there can be little doubt that the cost/benefit ratios of modern x-rayebased systems will remain significantly lower, mainly because of equivalent benefits and far lower costs. Significant advances in our understanding of cancer and the development of new treatments proceed apace. In radiation oncology there is, among others, research on the abscopal effects of localized irradiation due to stimulation of the patient’s immune system, as well as the concurrent, as opposed to sequential, use of radiation and chemotherapy (1-3). These kinds of research show imagination and promise far beyond that offered by the adoption of ever more complicated radiation machines, and are far more likely to ensure a role for radiation oncology in the conquest of cancer. Robert J. Schulz, PhD Department of Therapeutic Radiology Yale University New Haven, Connecticut A. Robert Kagan, MD Radiation Oncology Department Southern California Permanente Medical Group Los Angeles, California http://dx.doi.org/10.1016/j.ijrobp.2016.01.011
References 1. Golden EB, Apetoh L. Radiotherapy and immunogenic cell death. Semin Radiat Oncol 2015;25:11-17. 2. Crittenden M, Kohrt H, Levy R, et al. Current clinical trials testing combinations of immunotherapy and radiation. Semin Radiat Oncol 2015;25:54-64. 3. Schaue D, McBride WH. Opportunities and challenges of radiotherapy for treating cancer. Nat Rev Clin Oncol 2015;12:527-539.
Radiation Oncology biology
physics
www.redjournal.org
COMMENTS Policy Implications of Proton Radiation Therapy: Toward an Evidence-Based Approach for Implementing Novel Oncologic Technologies To the Editor: Despite the potential clinical advantages, some proton treatments cost 3 to 4 times their analogous photon-based approaches, placing additional pressure on our healthcare system (1). Consequently, the optimal allocation of this advanced technology represents an emerging challenge, because although theoretically superior, protons suffer from limited level 1 evidence (2) and considerable economic hurdles. As protons gain traction, we propose 2 parallel research and policy endeavors that hinge on developing high-level evidence, for although cohort studies can demonstrate the feasibility of protons, they cannot alone be used to shift the standard of care. Leaders in the field have cited profound resistance to the initiation of randomized controlled trials, owing to the widely accepted physical benefits of protons (3). However, it remains economically difficult to justify the expense of protonbased radiation therapy solely on the basis of theoretical or modeled benefits. Therefore, we propose the following baseline approach: (1) where clinicians feel there is not equipoise, for example in pediatric malignancies, expert consensus should guide policy; and (2) among equivocal disease sites, phase 2 studies should lay the groundwork for major phase 3 trials. Indeed, inherent cost considerations along with the established utilization and availability of photons necessarily place the burden on protons to demonstrate superiority. Although many trials are underway, several years will elapse before definitive data are available. In the interim, utilization should be limited to cases with compelling clinical evidence or to robust trials where such evidence is being generated. Historically, the US government has used the idea of coverage with evidence development (4). In this model, a novel technology is conditionally covered only in the context of a clinical study. This approach successfully expanded coverage for FDG-PET scans through the establishment of the National Oncology PET
Int J Radiation Oncol Biol Phys, Vol. 95, No. 1, pp. 560e561, 2016 0360-3016/$ - see front matter Ó 2016 Elsevier Inc. All rights reserved.
Registry, which resulted in the generation of significant data in a relatively short time (5). The science of proton radiation therapy stands to benefit similarly from coverage with evidence development. Accordingly, a researchbased incentive should be implemented, whereby centers demonstrating rigorous investigational standards and monitoring are reimbursed more generously than those that merely supplant conventional approaches without oversight. The mechanism for such monitoring could mimic current US Food and Drug Administration strategies for regulation of investigational drugs or devices, though with the aim of incentivizing and funding promising research. Conversely, off-protocol proton treatments administered in the absence of compelling clinical evidence should be reimbursed commensurate with the analogous photon therapy. This reference pricing approach will undoubtedly limit the viability of certain centers that were financially dependent on the price premium of protons. Unfortunately, however, the current cost of off-protocol proton therapy is unsustainable. To enhance efficiency, critical studies should be driven by an overarching cooperative group with clinical, governmental, and industrial input. Data generated by each center would accrue to a central registry for interval monitoring and comprehensive analysis. This design would allow these expansive studies to be maximally powered and, occasionally, for early closure based on interim evidence of either superiority or futility. As the costs of oncologic care accelerate in this era of precision medicine, it behooves us as a radiation oncology community to adopt responsible approaches to the implementation of our most promising technologies. Via broad-based endeavors through our cooperative groups, we would be well served to seize such initiatives rather than awaiting their imposition by external stakeholders, as has happened, rather memorably, in the recent past. Lior Z. Braunstein, MD Laura E.G. Warren, MD, EdM Harvard Radiation Oncology Program Boston, Massachusetts http://dx.doi.org/10.1016/j.ijrobp.2015.11.001
Volume 95 Number 1 2016
References 1. Peeters A, Grutters JP, Pijls-Johannesma M, et al. How costly is particle therapy? Cost analysis of external beam radiotherapy with carbon-ions, protons and photons. Radiother Oncol 2010;95:45-53. 2. Trikalinos TA, Terasawa T, Ip S, et al. Particle Beam Radiaton Therapies for Cancer. Rockville, MD: Agency for Healthcare Research and Quality, 2009. 3. Goitein M, Cox JD. Should randomized clinical trials be required for proton radiotherapy? J Clin Oncol 2008;26:175-176. 4. Centers for Medicare & Medicaid Services. Guidance for the Public, Industry, and CMS Staff: National Coverage Determinations with Data Collection as a Condition of Coverage: Coverage with Evidence Development. Baltimore, MD: CMS, 2006. 5. Tunis S, Whicher D. The National Oncologic PET Registry: Lessons learned for coverage with evidence development. J Am Coll Radiol 2009;6:360-365.
Carbon-Ion Therapy: One More Step in the Endless Quest for the Ideal Dose Distribution An overriding paradigm of radiation therapy since its inception has been the optimization of dose distributions (ie, maximizing the tumor dose while minimizing the dose to organs at risk). To this end, highly effective technologies such as x-rayebased intensity modulated radiation therapy and stereotactic body radiation therapy, as well as proton beam therapy (PBT) are now part of our repertoire. For the past 10 or more years, our European and Asian colleagues have been testing beams of high-energy carbon ions primarily because their dose distributions exceed even those of PBT. Currently some of the more intrepid among us argue that the United States is falling behind in the radiation therapy “arms race,” and that to catch up we should be planning a state of the art carbon-ion therapy (CIT) facility. However, with an unremarkable clinical track record, and a staggering $200-$300 million price tag, we cannot help but ask, “To what end?” Because radiation therapy is mainly available to those living within a 30- to 40-mile radius of a treatment center, and assuming very significant improvements in CIT outcomes, many billions of dollars would have to be invested over the next decades before supply could start meeting demand. During this period, it is likely that new drugs will reduce the number of patients needing radiation therapy. Such drugs, albeit expensive, can in most cases be made readily available to all in need, and unlike CIT, they require no major construction projects. Additionally, when drug A is superseded by drug B, only drug A’s production facility is affected, and in most cases it can be used to make drug B. Given the biases of patient selection and the subjective evaluations of toxicity implicit in the current European and Asian phase 2 clinical reports, it would be imprudent to
Comments
561
proceed with a project on the scale of a CIT facility without first having objective determinations that show significantly improved clinical outcomes. To obtain these kinds of data, it would seem reasonable to set up cooperative randomized, controlled trials with our European and Asian colleagues. Although such undertakings would extend the timeline of a CIT project, should we be willing to rush in and “bet the farm” that a bigger and more energetic machine will improve the lives of cancer patients? Carbon ions are not magic bullets. Despite the hype of its proponents, CIT is still about little more than dose distributions and its ability to provide therapeutic ratios only marginally higher than those provided by PBT. Additionally, and like PBT, a successful treatment is contingent on the precise implementation of the treatment plan, this being a far from trivial issue for a radiation whose positioning is not amenable to portal imaging. With CIT and PBT, the seemingly endless quest to enhance the therapeutic ratio has reached a point of diminishing returns in terms of mortality and morbidity. Until proven otherwise, there can be little doubt that the cost/benefit ratios of modern x-rayebased systems will remain significantly lower, mainly because of equivalent benefits and far lower costs. Significant advances in our understanding of cancer and the development of new treatments proceed apace. In radiation oncology there is, among others, research on the abscopal effects of localized irradiation due to stimulation of the patient’s immune system, as well as the concurrent, as opposed to sequential, use of radiation and chemotherapy (1-3). These kinds of research show imagination and promise far beyond that offered by the adoption of ever more complicated radiation machines, and are far more likely to ensure a role for radiation oncology in the conquest of cancer. Robert J. Schulz, PhD Department of Therapeutic Radiology Yale University New Haven, Connecticut A. Robert Kagan, MD Radiation Oncology Department Southern California Permanente Medical Group Los Angeles, California http://dx.doi.org/10.1016/j.ijrobp.2016.01.011
References 1. Golden EB, Apetoh L. Radiotherapy and immunogenic cell death. Semin Radiat Oncol 2015;25:11-17. 2. Crittenden M, Kohrt H, Levy R, et al. Current clinical trials testing combinations of immunotherapy and radiation. Semin Radiat Oncol 2015;25:54-64. 3. Schaue D, McBride WH. Opportunities and challenges of radiotherapy for treating cancer. Nat Rev Clin Oncol 2015;12:527-539.