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The model-based approach to clinical studies in particle radiotherapy – A new concept in evidence based radiation oncology?
Radiotherapy and Oncology 107 (2013) 265–266
Contents lists available at SciVerse ScienceDirect
Radiotherapy and Oncology journal homepage: www.thegreenjournal.com
Editorial
The model-based approach to clinical studies in particle radiotherapy – A new concept in evidence based radiation oncology? Cai Grau ⇑ Department of Oncology, Aarhus University Hospital, Aarhus C, Denmark
The current issue of Radiotherapy & Oncology contains a comprehensive report and recommendation from a Dutch national consortium on Particle Radiotherapy, describing how a modelbased approach may alleviate a long-standing critical problem in the employment of evidence-based particle beam radiotherapy [1]. The precision and conformity of megavoltage radiotherapy has been refined and improved significantly over the years, but is inherently limited by the inferior depth-dose characteristics of Xrays compared to charged particle beams. Protons or heavier charged particles deposit a large proportion of their energy in a well-defined volume whose depth within the patient can be defined by the energy of the particle beam. The result is substantially less radiation dose to the surrounding tissue, holding the potential for greatly reduced side effects [2–10]. There are three main potential benefits from proton radiotherapy compared to photon radiotherapy: (a) Protons result in less late side effects compared to photons; (b) The reduced side effects may be utilized for dose escalation resulting in improved disease control; and (c) protons reduce the risk for secondary malignancy. Despite the fact that 100,000 patients have been treated with protons, the current level of published clinical evidence for proton therapy is still low. There are relatively few prospective observational studies and no randomized controlled trial comparing protons to photons, as reviewed by several authors over the last decade [11–16]. Since evidence-based medicine is a cornerstone in radiation oncology and randomized controlled phase III trials remain the gold standard for assessing differential benefits in clinical outcome, it has been argued that for proton therapy to have an impact on clinical practice it will require rigorous clinical trials comparing proton with best photon therapy, and that only the results of such prospective studies will define the role of protons [17,18]. The underlying reasons for the low level of clinical evidence are probably multiple. First of all, the vast majority of the existing facilities are built for physics research purposes and not for patient care. It is only in recent years that hospital-based particle therapy facilities are emerging, and many of the new centers have a commercial basis rather than scientific focus, resulting in less room or incentive for academic research. It has also been argued, by leading experts in the field, that it is unnecessary or ⇑ Address: Department of Oncology, Aarhus University Hospital, Nørrebrogade 44, Bld. 5, DK-8000 Aarhus C, Denmark. E-mail address: [email protected] 0167-8140/$ - see front matter Ó 2013 Elsevier Ireland Ltd. All rights reserved. http://dx.doi.org/10.1016/j.radonc.2013.06.031
even unethical to conduct randomized trials in particle therapy because of the well-established biological and clinical knowledge of the dose-relationships, showing clear advantages for protons over conventional radiotherapy [19–21]. No patients would, if fully informed, consent to participate in such studies, many professionals claim, and such a situation is inconsistent with the principle of clinical equipoise, which requires a genuine uncertainty in the expert medical community over whether a treatment will be beneficial. This is particularly true in situations, where the predictable difference in toxicity is relatively large, as also described in the Dutch report [1]. The cost of protons is higher than photons, and especially the initial capital costs are a limiting factor. A clinical facility with two or three treatment rooms costs around 100 million EUR. Goitein and Jermann have estimated the relative costs of proton beam therapy to high-technology X-ray therapy to be a factor of 1.7 [22], and several reports have analyzed the relative cost-effectiveness of the novel technology [23–25]. Although it is likely that the costs of proton therapy equipment will drop due to competition and development of less expensive facilities, the capital investment will most likely remain a limiting factor for many years ahead [24]. The high initial capital costs involved in establishing a proton facility have resulted in a ‘‘Catch-22’’ dilemma of particle therapy: evidence is required before the key decision makers and stakeholders (national health services, insurance companies) are willing to invest and reimburse – and clinical evidence can only be created if research-based facilities are being built. The approach presented in the current issue of Radiotherapy & Oncology by the Dutch particle radiotherapy consortium may provide a practical and politically acceptable solution to this dilemma [1]. Considering that randomized trials may not always be feasible for validating proton radiotherapy, the authors suggest an approach which can individually tailor the indication criteria in order to select patients who are expected to benefit from protons, and at the same time provide a valid methodology for clinical validation of the predicted benefit without always requiring a randomized trial. The model-based approach presents a scientific and innovative way of combining existing evidence (‘‘historical controls’’) with clinical decision making and prospective trials, which will in turn generate new insights. The already well-established radiotherapy (photon) dose–response information is used to group potential candidates for proton therapy in three categories depending on
266
Editorial / Radiotherapy and Oncology 107 (2013) 265–266
advantage of protons over photons. It builds on a multistep method utilizing normal tissue complication probability models (NTCP) which are based on experience in dose–volume relationships derived from photon therapy. Planning studies can then estimate the added benefit associated with protons rather than photons. The three patient categories and associated criteria for selection are as follows: in the first category, treatment with protons is obviously advantageous based on a favorable NTCP of protons compared to photons. Randomized trials are not justified in this group of patients. Almost all radiotherapy for cancer in children and young adolescents belong to this category. The next category includes the significant number of clinical cases where the advantage of proton radiotherapy is not yet documented, but may still be beneficial judged from comparative treatment planning studies with improvements in NTCP. Clinical trials, preferable (but not only) randomized trials comparing protons to photon radiotherapy need to be conducted in this category of patients. The clinically relevant toxicity-reduction depends on the shape of the NTCP-curve and on the initial value of the dose distribution parameter. Finally, the last category are situations where the comparisons reveal very small or no difference between photon and proton therapy or the expected robustness of proton therapy plans is poor. In this case photon radiotherapy is preferred. There are a few critical issues related to the suggested methodology. First of all, despite the fancy and useful wrapping, the approach is essentially a modeling exercise, and like all models, the output will never be better than the quality of the underlying data. Although we have a relatively broad knowledge base in radiation oncology with morbidity data from clinical trials and institutional series, the model-based approach will require a continued effort to collect and update clinical radiobiology data for e.g. new combined modality approaches, including routine morbidity assessments and collection of radiotherapy dose-plans both for photon and protons. Secondly, the number of patients who will be selected for proton therapy in the model-based approach will depend critically on the chosen threshold for NTCP-value reductions of the side effects in question. It is not completely clear how these thresholds will be developed and validated. The risk is that each institution, or even each clinician, will have their own set of thresholds. This will introduce unnecessary heterogeneity in the clinical trials, and in the worst case also jeopardize our professional credibility. The model-based approach was developed and promoted by a national consortium of leading Dutch radiation oncology experts, and is an excellent example of the huge potential influence experts can have on decision-making on a national level. The principle has already been adopted by the Dutch Health Council and the Dutch Health Care Insurance Board, so Dutch patients will be eligible for proton treatment if validated NTCP models predict clinically relevant less toxicity; method and results will be validated using sequential prospective cohort studies. By presenting a scientifically sound, yet still very practical solution to implementation of novel technology without relying on randomized trials only, the concept may very well in turn result in a paradigm shift within evidence based radiation oncology. The current paper by Langendijk and coworkers will without doubt have important implications for the particle therapy community and for many countries in Europe
and abroad where the introduction of proton therapy is currently being discussed and planned. References [1] Langendijk JA, Lambin P, De Ruysscher D, Widder J, Bos M, Verheij M. Selection of patients for radiotherapy with protons aiming at reduction of side effects: the model-based approach. Radiother Oncol 2013;107:267–73. [2] Jimenez RB, Goma C, Nyamwanda J, et al. Intensity modulated proton therapy for postmastectomy radiation of bilateral implant reconstructed breasts: a treatment planning study. Radiother Oncol 2013;107:213–7. [3] Fellin F, Azzeroni R, Maggio A, et al. Helical tomotherapy and intensity modulated proton therapy in the treatment of dominant intraprostatic lesion: a treatment planning comparison. Radiother Oncol 2013;107:207–12. [4] Efstathiou JA, Paly JJ, Lu HM, et al. Adjuvant radiation therapy for early stage seminoma: proton versus photon planning comparison and modeling of second cancer risk. Radiother Oncol 2012;103:12–7. [5] Sugahara S, Kamada T, Imai R, et al. Carbon ion radiotherapy for localized primary sarcoma of the extremities: Results of a phase I/II trial. Radiother Oncol 2012;105:226–31. [6] Simone 2nd CB, Ly D, Dan TD, et al. Comparison of intensity-modulated radiotherapy, adaptive radiotherapy, proton radiotherapy, and adaptive proton radiotherapy for treatment of locally advanced head and neck cancer. Radiother Oncol 2011;101:376–82. [7] Kim S, Min BJ, Yoon M, et al. Secondary radiation doses of intensity-modulated radiotherapy and proton beam therapy in patients with lung and liver cancer. Radiother Oncol 2011;98:335–9. [8] Stuschke M, Kaiser A, Pöttgen C, Lübcke W, Farr J. Potentials of robust intensity modulated scanning proton plans for locally advanced lung cancer in comparison to intensity modulated photon plans. Radiother Oncol 2012;104: 45–51. [9] Wolff HA, Wagner DM, Conradi L-C, et al. Irradiation with protons for the individualized treatment of patients with locally advanced rectal cancer: a planning study with clinical implications. Radiother Oncol 2012;102:30–7. [10] Schwarz M, Pierelli A, Fiorino C, et al. Helical tomotherapy and intensity modulated proton therapy in the treatment of early stage prostate cancer: a treatment planning comparison. Radiother Oncol 2011;98:74–80. [11] Miller RC, Lodge M, Murad MH, Jones B. Controversies in clinical trials in proton radiotherapy: the present and the future. Semin Radiat Oncol 2013;23: 127–33. [12] De Ruysscher D, Lodge MM, Jones B, et al. Charged particles in radiotherapy: a 5-year update of a systematic review. Radiother Oncol 2012;103:5–7. [13] Lodge M, Pijls-Johannesma M, Stirk L, Munro AJ, De Ruysscher D, Jefferson T. A systematic literature review of the clinical and cost-effectiveness of hadron therapy in cancer. Radiother Oncol 2007;83:110–22. [14] Olsen DR, Bruland OS, Frykholm G, Norderhaug IN. Proton therapy – a systematic review of clinical effectiveness. Radiother Oncol 2007;83:123–32. [15] Allen AM, Pawlicki T, Dong L, et al. An evidence based review of proton beam therapy: the report of ASTRO’s emerging technology committee. Radiother Oncol 2012;103:8–11. [16] Goitein M. Trials and tribulations in charged particle radiotherapy. Radiother Oncol 2010;95:23–31. [17] Zips D, Baumann M. Place of proton radiotherapy in future radiotherapy practice. Semin Radiat Oncol 2013;23:149–53. [18] Brada M, De Pijls-Johannesma M, Ruysscher D. Proton therapy in clinical practice: current clinical evidence. J Clin Oncol 2007;25:965–70. [19] Suit H, Kooy H, Trofimov A, et al. Should positive phase III clinical trial data be required before proton beam therapy is more widely adopted? Radiother Oncol 2008;86:148–53. [20] Goitein M, Cox JD. Should randomized clinical trials be required for proton radiotherapy? J Clin Oncol 2008;26:175–6. [21] Bentzen SM. Randomized controlled trials in health technology assessment: overkill or overdue? Radiother Oncol 2008;86:142–7. [22] Goitein M, Jermann M. The relative costs of proton and X-ray radiation therapy. Clin Oncol (R Coll Radiol) 2003;15:S37–50. [23] Pijls-Johannesma M, Pommier P, Lievens Y. Cost-effectiveness of particle therapy: current evidence and future needs. Radiother Oncol 2008;89:127–34. [24] Van den Lievens Y, Bogaert W. Proton beam therapy: too expensive to become true? Radiother Oncol 2005;75:131–3. [25] Van Loon J, Grutters J, Macbeth F. Evaluation of novel radiotherapy technologies: what evidence is needed to assess their clinical and cost effectiveness, and how should we get it? Lancet Oncol 2012;13:e169–77.
Contents lists available at SciVerse ScienceDirect
Radiotherapy and Oncology journal homepage: www.thegreenjournal.com
Editorial
The model-based approach to clinical studies in particle radiotherapy – A new concept in evidence based radiation oncology? Cai Grau ⇑ Department of Oncology, Aarhus University Hospital, Aarhus C, Denmark
The current issue of Radiotherapy & Oncology contains a comprehensive report and recommendation from a Dutch national consortium on Particle Radiotherapy, describing how a modelbased approach may alleviate a long-standing critical problem in the employment of evidence-based particle beam radiotherapy [1]. The precision and conformity of megavoltage radiotherapy has been refined and improved significantly over the years, but is inherently limited by the inferior depth-dose characteristics of Xrays compared to charged particle beams. Protons or heavier charged particles deposit a large proportion of their energy in a well-defined volume whose depth within the patient can be defined by the energy of the particle beam. The result is substantially less radiation dose to the surrounding tissue, holding the potential for greatly reduced side effects [2–10]. There are three main potential benefits from proton radiotherapy compared to photon radiotherapy: (a) Protons result in less late side effects compared to photons; (b) The reduced side effects may be utilized for dose escalation resulting in improved disease control; and (c) protons reduce the risk for secondary malignancy. Despite the fact that 100,000 patients have been treated with protons, the current level of published clinical evidence for proton therapy is still low. There are relatively few prospective observational studies and no randomized controlled trial comparing protons to photons, as reviewed by several authors over the last decade [11–16]. Since evidence-based medicine is a cornerstone in radiation oncology and randomized controlled phase III trials remain the gold standard for assessing differential benefits in clinical outcome, it has been argued that for proton therapy to have an impact on clinical practice it will require rigorous clinical trials comparing proton with best photon therapy, and that only the results of such prospective studies will define the role of protons [17,18]. The underlying reasons for the low level of clinical evidence are probably multiple. First of all, the vast majority of the existing facilities are built for physics research purposes and not for patient care. It is only in recent years that hospital-based particle therapy facilities are emerging, and many of the new centers have a commercial basis rather than scientific focus, resulting in less room or incentive for academic research. It has also been argued, by leading experts in the field, that it is unnecessary or ⇑ Address: Department of Oncology, Aarhus University Hospital, Nørrebrogade 44, Bld. 5, DK-8000 Aarhus C, Denmark. E-mail address: [email protected] 0167-8140/$ - see front matter Ó 2013 Elsevier Ireland Ltd. All rights reserved. http://dx.doi.org/10.1016/j.radonc.2013.06.031
even unethical to conduct randomized trials in particle therapy because of the well-established biological and clinical knowledge of the dose-relationships, showing clear advantages for protons over conventional radiotherapy [19–21]. No patients would, if fully informed, consent to participate in such studies, many professionals claim, and such a situation is inconsistent with the principle of clinical equipoise, which requires a genuine uncertainty in the expert medical community over whether a treatment will be beneficial. This is particularly true in situations, where the predictable difference in toxicity is relatively large, as also described in the Dutch report [1]. The cost of protons is higher than photons, and especially the initial capital costs are a limiting factor. A clinical facility with two or three treatment rooms costs around 100 million EUR. Goitein and Jermann have estimated the relative costs of proton beam therapy to high-technology X-ray therapy to be a factor of 1.7 [22], and several reports have analyzed the relative cost-effectiveness of the novel technology [23–25]. Although it is likely that the costs of proton therapy equipment will drop due to competition and development of less expensive facilities, the capital investment will most likely remain a limiting factor for many years ahead [24]. The high initial capital costs involved in establishing a proton facility have resulted in a ‘‘Catch-22’’ dilemma of particle therapy: evidence is required before the key decision makers and stakeholders (national health services, insurance companies) are willing to invest and reimburse – and clinical evidence can only be created if research-based facilities are being built. The approach presented in the current issue of Radiotherapy & Oncology by the Dutch particle radiotherapy consortium may provide a practical and politically acceptable solution to this dilemma [1]. Considering that randomized trials may not always be feasible for validating proton radiotherapy, the authors suggest an approach which can individually tailor the indication criteria in order to select patients who are expected to benefit from protons, and at the same time provide a valid methodology for clinical validation of the predicted benefit without always requiring a randomized trial. The model-based approach presents a scientific and innovative way of combining existing evidence (‘‘historical controls’’) with clinical decision making and prospective trials, which will in turn generate new insights. The already well-established radiotherapy (photon) dose–response information is used to group potential candidates for proton therapy in three categories depending on
266
Editorial / Radiotherapy and Oncology 107 (2013) 265–266
advantage of protons over photons. It builds on a multistep method utilizing normal tissue complication probability models (NTCP) which are based on experience in dose–volume relationships derived from photon therapy. Planning studies can then estimate the added benefit associated with protons rather than photons. The three patient categories and associated criteria for selection are as follows: in the first category, treatment with protons is obviously advantageous based on a favorable NTCP of protons compared to photons. Randomized trials are not justified in this group of patients. Almost all radiotherapy for cancer in children and young adolescents belong to this category. The next category includes the significant number of clinical cases where the advantage of proton radiotherapy is not yet documented, but may still be beneficial judged from comparative treatment planning studies with improvements in NTCP. Clinical trials, preferable (but not only) randomized trials comparing protons to photon radiotherapy need to be conducted in this category of patients. The clinically relevant toxicity-reduction depends on the shape of the NTCP-curve and on the initial value of the dose distribution parameter. Finally, the last category are situations where the comparisons reveal very small or no difference between photon and proton therapy or the expected robustness of proton therapy plans is poor. In this case photon radiotherapy is preferred. There are a few critical issues related to the suggested methodology. First of all, despite the fancy and useful wrapping, the approach is essentially a modeling exercise, and like all models, the output will never be better than the quality of the underlying data. Although we have a relatively broad knowledge base in radiation oncology with morbidity data from clinical trials and institutional series, the model-based approach will require a continued effort to collect and update clinical radiobiology data for e.g. new combined modality approaches, including routine morbidity assessments and collection of radiotherapy dose-plans both for photon and protons. Secondly, the number of patients who will be selected for proton therapy in the model-based approach will depend critically on the chosen threshold for NTCP-value reductions of the side effects in question. It is not completely clear how these thresholds will be developed and validated. The risk is that each institution, or even each clinician, will have their own set of thresholds. This will introduce unnecessary heterogeneity in the clinical trials, and in the worst case also jeopardize our professional credibility. The model-based approach was developed and promoted by a national consortium of leading Dutch radiation oncology experts, and is an excellent example of the huge potential influence experts can have on decision-making on a national level. The principle has already been adopted by the Dutch Health Council and the Dutch Health Care Insurance Board, so Dutch patients will be eligible for proton treatment if validated NTCP models predict clinically relevant less toxicity; method and results will be validated using sequential prospective cohort studies. By presenting a scientifically sound, yet still very practical solution to implementation of novel technology without relying on randomized trials only, the concept may very well in turn result in a paradigm shift within evidence based radiation oncology. The current paper by Langendijk and coworkers will without doubt have important implications for the particle therapy community and for many countries in Europe
and abroad where the introduction of proton therapy is currently being discussed and planned. References [1] Langendijk JA, Lambin P, De Ruysscher D, Widder J, Bos M, Verheij M. Selection of patients for radiotherapy with protons aiming at reduction of side effects: the model-based approach. Radiother Oncol 2013;107:267–73. [2] Jimenez RB, Goma C, Nyamwanda J, et al. Intensity modulated proton therapy for postmastectomy radiation of bilateral implant reconstructed breasts: a treatment planning study. Radiother Oncol 2013;107:213–7. [3] Fellin F, Azzeroni R, Maggio A, et al. Helical tomotherapy and intensity modulated proton therapy in the treatment of dominant intraprostatic lesion: a treatment planning comparison. Radiother Oncol 2013;107:207–12. [4] Efstathiou JA, Paly JJ, Lu HM, et al. Adjuvant radiation therapy for early stage seminoma: proton versus photon planning comparison and modeling of second cancer risk. Radiother Oncol 2012;103:12–7. [5] Sugahara S, Kamada T, Imai R, et al. Carbon ion radiotherapy for localized primary sarcoma of the extremities: Results of a phase I/II trial. Radiother Oncol 2012;105:226–31. [6] Simone 2nd CB, Ly D, Dan TD, et al. Comparison of intensity-modulated radiotherapy, adaptive radiotherapy, proton radiotherapy, and adaptive proton radiotherapy for treatment of locally advanced head and neck cancer. Radiother Oncol 2011;101:376–82. [7] Kim S, Min BJ, Yoon M, et al. Secondary radiation doses of intensity-modulated radiotherapy and proton beam therapy in patients with lung and liver cancer. Radiother Oncol 2011;98:335–9. [8] Stuschke M, Kaiser A, Pöttgen C, Lübcke W, Farr J. Potentials of robust intensity modulated scanning proton plans for locally advanced lung cancer in comparison to intensity modulated photon plans. Radiother Oncol 2012;104: 45–51. [9] Wolff HA, Wagner DM, Conradi L-C, et al. Irradiation with protons for the individualized treatment of patients with locally advanced rectal cancer: a planning study with clinical implications. Radiother Oncol 2012;102:30–7. [10] Schwarz M, Pierelli A, Fiorino C, et al. Helical tomotherapy and intensity modulated proton therapy in the treatment of early stage prostate cancer: a treatment planning comparison. Radiother Oncol 2011;98:74–80. [11] Miller RC, Lodge M, Murad MH, Jones B. Controversies in clinical trials in proton radiotherapy: the present and the future. Semin Radiat Oncol 2013;23: 127–33. [12] De Ruysscher D, Lodge MM, Jones B, et al. Charged particles in radiotherapy: a 5-year update of a systematic review. Radiother Oncol 2012;103:5–7. [13] Lodge M, Pijls-Johannesma M, Stirk L, Munro AJ, De Ruysscher D, Jefferson T. A systematic literature review of the clinical and cost-effectiveness of hadron therapy in cancer. Radiother Oncol 2007;83:110–22. [14] Olsen DR, Bruland OS, Frykholm G, Norderhaug IN. Proton therapy – a systematic review of clinical effectiveness. Radiother Oncol 2007;83:123–32. [15] Allen AM, Pawlicki T, Dong L, et al. An evidence based review of proton beam therapy: the report of ASTRO’s emerging technology committee. Radiother Oncol 2012;103:8–11. [16] Goitein M. Trials and tribulations in charged particle radiotherapy. Radiother Oncol 2010;95:23–31. [17] Zips D, Baumann M. Place of proton radiotherapy in future radiotherapy practice. Semin Radiat Oncol 2013;23:149–53. [18] Brada M, De Pijls-Johannesma M, Ruysscher D. Proton therapy in clinical practice: current clinical evidence. J Clin Oncol 2007;25:965–70. [19] Suit H, Kooy H, Trofimov A, et al. Should positive phase III clinical trial data be required before proton beam therapy is more widely adopted? Radiother Oncol 2008;86:148–53. [20] Goitein M, Cox JD. Should randomized clinical trials be required for proton radiotherapy? J Clin Oncol 2008;26:175–6. [21] Bentzen SM. Randomized controlled trials in health technology assessment: overkill or overdue? Radiother Oncol 2008;86:142–7. [22] Goitein M, Jermann M. The relative costs of proton and X-ray radiation therapy. Clin Oncol (R Coll Radiol) 2003;15:S37–50. [23] Pijls-Johannesma M, Pommier P, Lievens Y. Cost-effectiveness of particle therapy: current evidence and future needs. Radiother Oncol 2008;89:127–34. [24] Van den Lievens Y, Bogaert W. Proton beam therapy: too expensive to become true? Radiother Oncol 2005;75:131–3. [25] Van Loon J, Grutters J, Macbeth F. Evaluation of novel radiotherapy technologies: what evidence is needed to assess their clinical and cost effectiveness, and how should we get it? Lancet Oncol 2012;13:e169–77.