Radiotherapy and Oncology xxx (2015) xxx–xxx
Contents lists available at ScienceDirect
Radiotherapy and Oncology journal homepage: www.thegreenjournal.com
Editorial
SABR in NSCLC – The beginning of the end or the end of the beginning? Michael Brada a,b,⇑, Anthony Pope b, Michael Baumann c,d,e,f a
Department of Molecular and Clinical Cancer Medicine, University of Liverpool; b Department of Radiation Oncology, Clatterbridge Cancer Centre NHS Foundation Trust, Wirral, UK; Department of Radiation Oncology, Faculty of Medicine and University Hospital Carl Gustav Carus, Technische Universität, Dresden; d OncoRay – National Center for Radiation Research in Oncology, Dresden; e Helmholtz-Zentrum Dresden – Rossendorf, Institute of Radiooncology; and f German Cancer Consortium (DKTK) partner sites Dresden and German Cancer Research Center (DKFZ), Heidelberg, Germany
c
Stereotactic ablative body radiotherapy (SABR) has gained considerable momentum, with ever increasing popularity as a potentially curative treatment for localized non-small cell lung cancer (NSCLC) and treatment of oligometastatic disease. The current state of the art in localized NSCLC is described in this issue of Radiotherapy and Oncology by Louie et al. [1] and provides an excellent, comprehensive summary for the radiation oncology community. SABR in the context of modern radiotherapy SABR can be considered in the range of radiotherapy techniques as hypofractionated high precision conformal radiotherapy to small targets. SABR employs all the current high end spectrum of technological options available to achieve precision including motion management, image guidance and various forms of conformal delivery aiming for steep dose gradients between the target and normal tissues [2]. However, it should be recognized that SABR is a misnomer as ‘‘stereotaxy’’ is no longer employed. The term ‘‘ablative’’, representing a biologically effective (BED) threshold dose leading to death of all cancer cells, is radiobiologically not sound, clinically largely not defined and may simply be wishful thinking. While the terminology remains an effective branding, the mystique it generates is not necessarily helpful either for objective assessment of the technique’s comparative value or wider cost effective application outside the current indications; the terminology also potentially leads to restrictive practices. SABR in the context of management of stage I and II NSCLC SABR is one of the available options for treating localized NSCLC. It is currently employed largely in patients with significant comorbidity, considered medically inoperable. Although the apparent efficacy would argue for extending its use to patients with operable disease, SABR is not alone in this aspiration. Newer surgical techniques of thoracoscopy assisted sublobar resections [3,4] ⇑ Corresponding author at: University of Liverpool, Department of Molecular and Clinical Cancer Medicine, and Department of Radiation Oncology, Clatterbridge Cancer Centre NHS Foundation Trust, Bebington, Wirral CH63 4JY, UK. E-mail address: [email protected] (M. Brada).
and image guided radiofrequency/thermal ablation (RFA) [5,6] provide single session minimally invasive alternatives. The latter, although less publicized within the radiotherapy community, may on the currently available evidence provide equivalent tumour control to that achieved with SABR [5,6]. Conventionally fractionated conformal radiotherapy has largely been discounted as a viable alternative. While there is little doubt that short hypofractionated regimens provide from the patients’ perspective a more convenient treatment, in terms of efficacy and cost effectiveness the chapter may not yet be closed [4]. SABR unresolved issues The popular perception of SABR is of a highly effective, potentially curative treatment for localized NSCLC and a possible alternative to surgery. Whilst this may indeed be the case this conviction ignores a number of unresolved issues and some potentially worrying outcome data. Tumour control The perception of outstanding tumour control is largely based on investigator evaluated endpoint, recognized to be difficult to assess in the setting of associated radiation changes [7]. Even as series with longer follow-up of individual lesions become increasingly available, thereby easing doubts about underreported local failures, the preoccupation with local disease control is not necessarily appropriate. While of clear value in terms of assessing the efficacy of a local treatment modality, albeit somewhat subjective and prone to statistical uncertainty in the context of limited survival, local control is of questionable relevance to the patient unless also offering survival or quality of life benefit. Survival In the absence of appropriately powered randomized studies the attempts at comparing surgery with SABR show that when corrected for prognostic factors the efficacy in terms of tumour control and survival is equivalent [3,8,9]. This is supportive evidence as far as it goes but disguises the fact that patients with small localized NSCLC and significant comorbidity treated with SABR have a rela-
http://dx.doi.org/10.1016/j.radonc.2015.01.012 0167-8140/Ó 2015 Elsevier Ireland Ltd. All rights reserved.
Please cite this article in press as: Brada M et al. SABR in NSCLC – The beginning of the end or the end of the beginning?. Radiother Oncol (2015), http:// dx.doi.org/10.1016/j.radonc.2015.01.012
2
SABR in NSCLC – The beginning of the end or the end of the beginning?
tively poor outcome, with a 2 year survival in the region of 60–70% and in some studies considerably less [8–10]. While ascribed to comorbidity, which may well be the principal cause (although a somewhat circular argument), the causes of death are unfortunately poorly documented. Such data are key to address the question whether local tumour control achieved with SABR in patients with small localized NSCLC and significant comorbidity alters life expectancy. With limited life expectancy it is important to assess the competing risks of NSCLC and comorbidity on survival, as well as their potential interactions. While it may sound provocative, it remains unclear whether the use of SABR could alter the natural history of comorbid conditions as patients with high comorbidity scores have the worst outcome [11] and survival in SABR cohorts is related to ‘‘operability’’ [9] which is a likely surrogate for comorbidity. Studies of the causes of death in this group of patients combined with known prognostic factors [12] and detailed comorbidity scores may provide prognostic and ideally predictive factors for survival. This information is essential in identifying patients who may benefit from SABR and avoid treating patients with limited life expectancy from comorbid conditions such as severe chronic obstructive pulmonary disease (COPD) and ischaemic heart disease [11]. Comparing the expected and actual survival for comorbid conditions may also reveal potential interactions of SABR and underlying non-malignant disease. Such research is timely as initial evidence from radiation treatment of lung or oesophageal cancer suggests that for example early cardiovascular side effects may have to date been underestimated [13–17].
SABR dose fractionation The technical ability of high precision irradiation to deliver localized doses has led to ever increasing biologically effective doses using hypofractionated regimens. Yet the data on dose response with primary focus on local disease control are mostly from retrospective studies confounded by patient selection [18– 21] with limited regard given to other parameters affecting local control such as tumour volume, motion and invasiveness [22]. Dose response data with survival as the principal endpoint, also affected by patient selection bias, are limited [19,20], with some studies suggesting that high BED (P100 Gy) may not be necessary [23]. Based on the information available, the possibility that the current trend to deliver very high BED may be detrimental for survival, or quality of life, in the population of patients currently treated has not been excluded. The limitations of SABR and the future Judged by the exponential increase in publications and their positive tone, radiation oncology should be wary of overconfidence and self congratulation around SABR. It is undoubtedly an effective treatment at controlling small lesions. However, despite the suggestion of improved survival of the elderly early stage NSCLC patient population associated with increasing use of SABR [24], the impact of SABR as currently administered on the outcome of the totality of patients with NSCLC is likely to be limited. While the technique as practiced is only safely deliverable to small lesions in restricted locations, it carries a not insignificant morbidity, particularly in larger tumours [25], in central locations [26,27] and lesions close to the chest wall [28,29]. The interaction with respiratory and cardiac co-morbidity is not defined and bears further scrutiny. The development and wide implementation of SABR undoubtedly signifies progress in the delivery of radiotherapy, providing novel solutions to motion management, conformal delivery, image
guidance and hypofractionation. However, despite the apparently successful use in patients with poor lung function [21] and the theoretical benefit suggested in elderly patients [30], it remains to be shown that SABR in elderly patients with early stage NSCLC and multiple comorbidities improves survival. Careful evaluation of causes of death and the development of prognostic and predictive indices should allow for better patient selection reserving SABR for those most likely to benefit from it. There is a need for prospective dose finding studies not only for patients with central tumours (as in RTOG 0813 study [31]) but also for peripheral tumours with survival and QOL as primary endpoints as the current high BED approach may not be optimal. This is likely to need increased focus on morbidity, which should include all causes and not only what is assumed to be radiation related damage. The most testing challenge is how to transfer the current technical expertise in targeting early stage disease to locally advanced disease. The aim should be not only to improve the technological application of radiotherapy, but to translate it into improved survival in what is a far more commonly encountered indication for radical radiotherapy. Conclusion The introduction and wide implementation of SABR is undoubtedly an advance in radiotherapy. However this does not mean we can rest on our laurels. While SABR can be used for localized NSCLC achieving good disease control, it remains wanting in terms of survival, is only suitable for a limited proportion of patients and is not without morbidity. As the challenge of photon technology has been largely solved (image guided hypofractionated high dose particle therapy yet to be investigated), the time has come to ensure we do no harm and make it available to larger proportion of NSCLC patients as a more effective and safe treatment. This means prospective clinical studies with survival and toxicity/QOL endpoints moving away from the restrictive focus on local tumour control. This should be the end of the beginning for high precision hypofractionated conformal radiotherapy in NSCLC. Call it SABR if you will. . .. References [1] Louie AV, Palma DA, Dahele M, Rodrigues GB, Sensn S. Management of earlystage non-small cell lung cancer using stereotactic ablative radiotherapy: controversies, insights, and changing horizons. Radiat Oncol 2015. [2] De Ruysscher D, Faivre-Finn C, Nestle U, et al. European Organisation for Research and Treatment of Cancer recommendations for planning and delivery of high-dose, high-precision radiotherapy for lung cancer. J Clin Oncol 2010;28:5301–10. [3] Matsuo Y, Chen F, Hamaji M, et al. Comparison of long-term survival outcomes between stereotactic body radiotherapy and sublobar resection for stage I nonsmall-cell lung cancer in patients at high risk for lobectomy: a propensity score matching analysis. Eur J Cancer 2014;50:2932–8. [4] Shirvani SM, Jiang J, Chang JY, et al. Comparative effectiveness of 5 treatment strategies for early-stage non-small cell lung cancer in the elderly. Int J Radiat Oncol Biol Phys 2012;84:1060–70. [5] Renaud S, Falcoz PE, Olland A, Massard G. Is radiofrequency ablation or stereotactic ablative radiotherapy the best treatment for radically treatable primary lung cancer unfit for surgery? Interact Cardiovasc Thorac Surg 2013;16:68–73. [6] Simon TG, Beland MD, Machan JT, Dipetrillo T, Dupuy DE. Charlson Comorbidity Index predicts patient outcome, in cases of inoperable nonsmall cell lung cancer treated with radiofrequency ablation. Eur J Radiol 2012;81:4167–72. [7] Huang K, Dahele M, Senan S, et al. Radiographic changes after lung stereotactic ablative radiotherapy (SABR)–can we distinguish recurrence from fibrosis? A systematic review of the literature. Radiother Oncol 2012;102:335–42. [8] Solda F, Lodge M, Ashley S. Stereotactic radiotherapy (SABR) for the treatment of primary non-small cell lung cancer; systematic review and comparison with a surgical cohort. Radiother Oncol 2013;109:1. [9] Zheng X, Schipper M, Kidwell K, et al. Survival outcome after stereotactic body radiation therapy and surgery for stage I non-small cell lung cancer: a metaanalysis. Int J Radiat Oncol Biol Phys 2014;90:603–11.
Please cite this article in press as: Brada M et al. SABR in NSCLC – The beginning of the end or the end of the beginning?. Radiother Oncol (2015), http:// dx.doi.org/10.1016/j.radonc.2015.01.012
M. Brada et al. / Radiotherapy and Oncology xxx (2015) xxx–xxx [10] Timmerman R, Paulus R, Galvin J, et al. Stereotactic body radiation therapy for inoperable early stage lung cancer. JAMA 2010;303:1070–6. [11] Kopek N, Paludan M, Petersen J, et al. Co-morbidity index predicts for mortality after stereotactic body radiotherapy for medically inoperable earlystage non-small cell lung cancer. Radiother Oncol 2009;93:402–7. [12] Matsuo Y, Shibuya K, Nagata Y, et al. Prognostic factors in stereotactic body radiotherapy for non-small-cell lung cancer. Int J Radiat Oncol Biol Phys 2011;79:1104–11. [13] Evans JD, Gomez DR, Chang JY, et al. Cardiac (1)(8)F-fluorodeoxyglucose uptake on positron emission tomography after thoracic stereotactic body radiation therapy. Radiother Oncol 2013;109:82–8. [14] Basu S, Borde C, Kand P. Increasing cardiac (18)F-fluorodeoxyglucose (FDG) uptake on PET-CT as a biomarker for cardiotoxicity of chemo-radiotherapy in cancer: A myth or a reality? Radiother Oncol 2014;112:451–2. [15] Lutkenhaus LJ, Kamphuis M, van Wieringen N, Hulshof MC, Bel A. Reduction in cardiac volume during chemoradiotherapy for patients with esophageal cancer. Radiother Oncol 2013;109:200–3. [16] Nalbantov G, Kietselaer B, Vandecasteele K, et al. Cardiac comorbidity is an independent risk factor for radiation-induced lung toxicity in lung cancer patients. Radiother Oncol 2013;109:100–6. [17] Edmunds K, Brooks C, Hansen VN, Harris V, Tait DM. Cardiac volume effects during chemoradiotherapy for esophageal cancer (Regarding Lutkenhaus et al. reduction in cardiac volume during chemoradiotherapy for patients with esophageal cancer). Radiother Oncol 2014. [18] Kestin L, Grills I, Guckenberger M, et al. Dose-response relationship with clinical outcome for lung stereotactic body radiotherapy (SBRT) delivered via online image guidance. Radiother Oncol 2014;110:499–504. [19] Onishi H, Shirato H, Nagata Y, et al. Hypofractionated stereotactic radiotherapy (HypoFXSRT) for stage I non-small cell lung cancer: updated results of 257 patients in a Japanese multi-institutional study. J Thorac Oncol 2007;2:S94–S100. [20] Olsen JR, Robinson CG, El Naqa I, et al. Dose-response for stereotactic body radiotherapy in early-stage non-small-cell lung cancer. Int J Radiat Oncol Biol Phys 2011;81:e299–303. [21] Guckenberger M, Kestin LL, Hope AJ, et al. Is there a lower limit of pretreatment pulmonary function for safe and effective stereotactic body
[22]
[23]
[24]
[25]
[26]
[27]
[28]
[29]
[30]
[31]
3
radiotherapy for early-stage non-small cell lung cancer? J Thorac Oncol 2012;7:542–51. Salguero FJ, Belderbos JS, Rossi MM, et al. Microscopic disease extensions as a risk factor for loco-regional recurrence of NSCLC after SBRT. Radiother Oncol 2013;109:26–31. van Baardwijk A, Tome WA, van Elmpt W. Is high-dose stereotactic body radiotherapy (SBRT) for stage I non-small cell lung cancer (NSCLC) overkill? A systematic review. Radiother Oncol 2012. Haasbeek CJ, Palma D, Visser O, et al. Early-stage lung cancer in elderly patients: a population-based study of changes in treatment patterns and survival in The Netherlands. Ann Oncol 2012;23:2743–7. Bongers EM, Botticella A, Palma DA, et al. Predictive parameters of symptomatic radiation pneumonitis following stereotactic or hypofractionated radiotherapy delivered using volumetric modulated arcs. Radiother Oncol 2013;109:95–9. Senthi S, Haasbeek CJ, Slotman BJ, Senan S. Outcomes of stereotactic ablative radiotherapy for central lung tumours: a systematic review. Radiother Oncol 2013;106:276–82. 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;24:4833–9. Andolino DL, Forquer JA, Henderson MA, et al. Chest wall toxicity after stereotactic body radiotherapy for malignant lesions of the lung and liver. Int J Radiat Oncol Biol Phys 2011;80:692–7. Stephans KL, Djemil T, Tendulkar RD, et al. Prediction of chest wall toxicity from lung stereotactic body radiotherapy (SBRT). Int J Radiat Oncol Biol Phys 2012;82:974–80. Louie AV, Rodrigues G, Hannouf M, et al. Withholding stereotactic radiotherapy in elderly patients with stage I non-small cell lung cancer and co-existing COPD is not justified: outcomes of a Markov model analysis. Radiother Oncol 2011;99:161–5. RTOG0813, http://www.rtog.org/ClinicalTrials/ProtocolTable/StudyDetails. aspx?study=0813.
Please cite this article in press as: Brada M et al. SABR in NSCLC – The beginning of the end or the end of the beginning?. Radiother Oncol (2015), http:// dx.doi.org/10.1016/j.radonc.2015.01.012
Contents lists available at ScienceDirect
Radiotherapy and Oncology journal homepage: www.thegreenjournal.com
Editorial
SABR in NSCLC – The beginning of the end or the end of the beginning? Michael Brada a,b,⇑, Anthony Pope b, Michael Baumann c,d,e,f a
Department of Molecular and Clinical Cancer Medicine, University of Liverpool; b Department of Radiation Oncology, Clatterbridge Cancer Centre NHS Foundation Trust, Wirral, UK; Department of Radiation Oncology, Faculty of Medicine and University Hospital Carl Gustav Carus, Technische Universität, Dresden; d OncoRay – National Center for Radiation Research in Oncology, Dresden; e Helmholtz-Zentrum Dresden – Rossendorf, Institute of Radiooncology; and f German Cancer Consortium (DKTK) partner sites Dresden and German Cancer Research Center (DKFZ), Heidelberg, Germany
c
Stereotactic ablative body radiotherapy (SABR) has gained considerable momentum, with ever increasing popularity as a potentially curative treatment for localized non-small cell lung cancer (NSCLC) and treatment of oligometastatic disease. The current state of the art in localized NSCLC is described in this issue of Radiotherapy and Oncology by Louie et al. [1] and provides an excellent, comprehensive summary for the radiation oncology community. SABR in the context of modern radiotherapy SABR can be considered in the range of radiotherapy techniques as hypofractionated high precision conformal radiotherapy to small targets. SABR employs all the current high end spectrum of technological options available to achieve precision including motion management, image guidance and various forms of conformal delivery aiming for steep dose gradients between the target and normal tissues [2]. However, it should be recognized that SABR is a misnomer as ‘‘stereotaxy’’ is no longer employed. The term ‘‘ablative’’, representing a biologically effective (BED) threshold dose leading to death of all cancer cells, is radiobiologically not sound, clinically largely not defined and may simply be wishful thinking. While the terminology remains an effective branding, the mystique it generates is not necessarily helpful either for objective assessment of the technique’s comparative value or wider cost effective application outside the current indications; the terminology also potentially leads to restrictive practices. SABR in the context of management of stage I and II NSCLC SABR is one of the available options for treating localized NSCLC. It is currently employed largely in patients with significant comorbidity, considered medically inoperable. Although the apparent efficacy would argue for extending its use to patients with operable disease, SABR is not alone in this aspiration. Newer surgical techniques of thoracoscopy assisted sublobar resections [3,4] ⇑ Corresponding author at: University of Liverpool, Department of Molecular and Clinical Cancer Medicine, and Department of Radiation Oncology, Clatterbridge Cancer Centre NHS Foundation Trust, Bebington, Wirral CH63 4JY, UK. E-mail address: [email protected] (M. Brada).
and image guided radiofrequency/thermal ablation (RFA) [5,6] provide single session minimally invasive alternatives. The latter, although less publicized within the radiotherapy community, may on the currently available evidence provide equivalent tumour control to that achieved with SABR [5,6]. Conventionally fractionated conformal radiotherapy has largely been discounted as a viable alternative. While there is little doubt that short hypofractionated regimens provide from the patients’ perspective a more convenient treatment, in terms of efficacy and cost effectiveness the chapter may not yet be closed [4]. SABR unresolved issues The popular perception of SABR is of a highly effective, potentially curative treatment for localized NSCLC and a possible alternative to surgery. Whilst this may indeed be the case this conviction ignores a number of unresolved issues and some potentially worrying outcome data. Tumour control The perception of outstanding tumour control is largely based on investigator evaluated endpoint, recognized to be difficult to assess in the setting of associated radiation changes [7]. Even as series with longer follow-up of individual lesions become increasingly available, thereby easing doubts about underreported local failures, the preoccupation with local disease control is not necessarily appropriate. While of clear value in terms of assessing the efficacy of a local treatment modality, albeit somewhat subjective and prone to statistical uncertainty in the context of limited survival, local control is of questionable relevance to the patient unless also offering survival or quality of life benefit. Survival In the absence of appropriately powered randomized studies the attempts at comparing surgery with SABR show that when corrected for prognostic factors the efficacy in terms of tumour control and survival is equivalent [3,8,9]. This is supportive evidence as far as it goes but disguises the fact that patients with small localized NSCLC and significant comorbidity treated with SABR have a rela-
http://dx.doi.org/10.1016/j.radonc.2015.01.012 0167-8140/Ó 2015 Elsevier Ireland Ltd. All rights reserved.
Please cite this article in press as: Brada M et al. SABR in NSCLC – The beginning of the end or the end of the beginning?. Radiother Oncol (2015), http:// dx.doi.org/10.1016/j.radonc.2015.01.012
2
SABR in NSCLC – The beginning of the end or the end of the beginning?
tively poor outcome, with a 2 year survival in the region of 60–70% and in some studies considerably less [8–10]. While ascribed to comorbidity, which may well be the principal cause (although a somewhat circular argument), the causes of death are unfortunately poorly documented. Such data are key to address the question whether local tumour control achieved with SABR in patients with small localized NSCLC and significant comorbidity alters life expectancy. With limited life expectancy it is important to assess the competing risks of NSCLC and comorbidity on survival, as well as their potential interactions. While it may sound provocative, it remains unclear whether the use of SABR could alter the natural history of comorbid conditions as patients with high comorbidity scores have the worst outcome [11] and survival in SABR cohorts is related to ‘‘operability’’ [9] which is a likely surrogate for comorbidity. Studies of the causes of death in this group of patients combined with known prognostic factors [12] and detailed comorbidity scores may provide prognostic and ideally predictive factors for survival. This information is essential in identifying patients who may benefit from SABR and avoid treating patients with limited life expectancy from comorbid conditions such as severe chronic obstructive pulmonary disease (COPD) and ischaemic heart disease [11]. Comparing the expected and actual survival for comorbid conditions may also reveal potential interactions of SABR and underlying non-malignant disease. Such research is timely as initial evidence from radiation treatment of lung or oesophageal cancer suggests that for example early cardiovascular side effects may have to date been underestimated [13–17].
SABR dose fractionation The technical ability of high precision irradiation to deliver localized doses has led to ever increasing biologically effective doses using hypofractionated regimens. Yet the data on dose response with primary focus on local disease control are mostly from retrospective studies confounded by patient selection [18– 21] with limited regard given to other parameters affecting local control such as tumour volume, motion and invasiveness [22]. Dose response data with survival as the principal endpoint, also affected by patient selection bias, are limited [19,20], with some studies suggesting that high BED (P100 Gy) may not be necessary [23]. Based on the information available, the possibility that the current trend to deliver very high BED may be detrimental for survival, or quality of life, in the population of patients currently treated has not been excluded. The limitations of SABR and the future Judged by the exponential increase in publications and their positive tone, radiation oncology should be wary of overconfidence and self congratulation around SABR. It is undoubtedly an effective treatment at controlling small lesions. However, despite the suggestion of improved survival of the elderly early stage NSCLC patient population associated with increasing use of SABR [24], the impact of SABR as currently administered on the outcome of the totality of patients with NSCLC is likely to be limited. While the technique as practiced is only safely deliverable to small lesions in restricted locations, it carries a not insignificant morbidity, particularly in larger tumours [25], in central locations [26,27] and lesions close to the chest wall [28,29]. The interaction with respiratory and cardiac co-morbidity is not defined and bears further scrutiny. The development and wide implementation of SABR undoubtedly signifies progress in the delivery of radiotherapy, providing novel solutions to motion management, conformal delivery, image
guidance and hypofractionation. However, despite the apparently successful use in patients with poor lung function [21] and the theoretical benefit suggested in elderly patients [30], it remains to be shown that SABR in elderly patients with early stage NSCLC and multiple comorbidities improves survival. Careful evaluation of causes of death and the development of prognostic and predictive indices should allow for better patient selection reserving SABR for those most likely to benefit from it. There is a need for prospective dose finding studies not only for patients with central tumours (as in RTOG 0813 study [31]) but also for peripheral tumours with survival and QOL as primary endpoints as the current high BED approach may not be optimal. This is likely to need increased focus on morbidity, which should include all causes and not only what is assumed to be radiation related damage. The most testing challenge is how to transfer the current technical expertise in targeting early stage disease to locally advanced disease. The aim should be not only to improve the technological application of radiotherapy, but to translate it into improved survival in what is a far more commonly encountered indication for radical radiotherapy. Conclusion The introduction and wide implementation of SABR is undoubtedly an advance in radiotherapy. However this does not mean we can rest on our laurels. While SABR can be used for localized NSCLC achieving good disease control, it remains wanting in terms of survival, is only suitable for a limited proportion of patients and is not without morbidity. As the challenge of photon technology has been largely solved (image guided hypofractionated high dose particle therapy yet to be investigated), the time has come to ensure we do no harm and make it available to larger proportion of NSCLC patients as a more effective and safe treatment. This means prospective clinical studies with survival and toxicity/QOL endpoints moving away from the restrictive focus on local tumour control. This should be the end of the beginning for high precision hypofractionated conformal radiotherapy in NSCLC. Call it SABR if you will. . .. References [1] Louie AV, Palma DA, Dahele M, Rodrigues GB, Sensn S. Management of earlystage non-small cell lung cancer using stereotactic ablative radiotherapy: controversies, insights, and changing horizons. Radiat Oncol 2015. [2] De Ruysscher D, Faivre-Finn C, Nestle U, et al. European Organisation for Research and Treatment of Cancer recommendations for planning and delivery of high-dose, high-precision radiotherapy for lung cancer. J Clin Oncol 2010;28:5301–10. [3] Matsuo Y, Chen F, Hamaji M, et al. Comparison of long-term survival outcomes between stereotactic body radiotherapy and sublobar resection for stage I nonsmall-cell lung cancer in patients at high risk for lobectomy: a propensity score matching analysis. Eur J Cancer 2014;50:2932–8. [4] Shirvani SM, Jiang J, Chang JY, et al. Comparative effectiveness of 5 treatment strategies for early-stage non-small cell lung cancer in the elderly. Int J Radiat Oncol Biol Phys 2012;84:1060–70. [5] Renaud S, Falcoz PE, Olland A, Massard G. Is radiofrequency ablation or stereotactic ablative radiotherapy the best treatment for radically treatable primary lung cancer unfit for surgery? Interact Cardiovasc Thorac Surg 2013;16:68–73. [6] Simon TG, Beland MD, Machan JT, Dipetrillo T, Dupuy DE. Charlson Comorbidity Index predicts patient outcome, in cases of inoperable nonsmall cell lung cancer treated with radiofrequency ablation. Eur J Radiol 2012;81:4167–72. [7] Huang K, Dahele M, Senan S, et al. Radiographic changes after lung stereotactic ablative radiotherapy (SABR)–can we distinguish recurrence from fibrosis? A systematic review of the literature. Radiother Oncol 2012;102:335–42. [8] Solda F, Lodge M, Ashley S. Stereotactic radiotherapy (SABR) for the treatment of primary non-small cell lung cancer; systematic review and comparison with a surgical cohort. Radiother Oncol 2013;109:1. [9] Zheng X, Schipper M, Kidwell K, et al. Survival outcome after stereotactic body radiation therapy and surgery for stage I non-small cell lung cancer: a metaanalysis. Int J Radiat Oncol Biol Phys 2014;90:603–11.
Please cite this article in press as: Brada M et al. SABR in NSCLC – The beginning of the end or the end of the beginning?. Radiother Oncol (2015), http:// dx.doi.org/10.1016/j.radonc.2015.01.012
M. Brada et al. / Radiotherapy and Oncology xxx (2015) xxx–xxx [10] Timmerman R, Paulus R, Galvin J, et al. Stereotactic body radiation therapy for inoperable early stage lung cancer. JAMA 2010;303:1070–6. [11] Kopek N, Paludan M, Petersen J, et al. Co-morbidity index predicts for mortality after stereotactic body radiotherapy for medically inoperable earlystage non-small cell lung cancer. Radiother Oncol 2009;93:402–7. [12] Matsuo Y, Shibuya K, Nagata Y, et al. Prognostic factors in stereotactic body radiotherapy for non-small-cell lung cancer. Int J Radiat Oncol Biol Phys 2011;79:1104–11. [13] Evans JD, Gomez DR, Chang JY, et al. Cardiac (1)(8)F-fluorodeoxyglucose uptake on positron emission tomography after thoracic stereotactic body radiation therapy. Radiother Oncol 2013;109:82–8. [14] Basu S, Borde C, Kand P. Increasing cardiac (18)F-fluorodeoxyglucose (FDG) uptake on PET-CT as a biomarker for cardiotoxicity of chemo-radiotherapy in cancer: A myth or a reality? Radiother Oncol 2014;112:451–2. [15] Lutkenhaus LJ, Kamphuis M, van Wieringen N, Hulshof MC, Bel A. Reduction in cardiac volume during chemoradiotherapy for patients with esophageal cancer. Radiother Oncol 2013;109:200–3. [16] Nalbantov G, Kietselaer B, Vandecasteele K, et al. Cardiac comorbidity is an independent risk factor for radiation-induced lung toxicity in lung cancer patients. Radiother Oncol 2013;109:100–6. [17] Edmunds K, Brooks C, Hansen VN, Harris V, Tait DM. Cardiac volume effects during chemoradiotherapy for esophageal cancer (Regarding Lutkenhaus et al. reduction in cardiac volume during chemoradiotherapy for patients with esophageal cancer). Radiother Oncol 2014. [18] Kestin L, Grills I, Guckenberger M, et al. Dose-response relationship with clinical outcome for lung stereotactic body radiotherapy (SBRT) delivered via online image guidance. Radiother Oncol 2014;110:499–504. [19] Onishi H, Shirato H, Nagata Y, et al. Hypofractionated stereotactic radiotherapy (HypoFXSRT) for stage I non-small cell lung cancer: updated results of 257 patients in a Japanese multi-institutional study. J Thorac Oncol 2007;2:S94–S100. [20] Olsen JR, Robinson CG, El Naqa I, et al. Dose-response for stereotactic body radiotherapy in early-stage non-small-cell lung cancer. Int J Radiat Oncol Biol Phys 2011;81:e299–303. [21] Guckenberger M, Kestin LL, Hope AJ, et al. Is there a lower limit of pretreatment pulmonary function for safe and effective stereotactic body
[22]
[23]
[24]
[25]
[26]
[27]
[28]
[29]
[30]
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radiotherapy for early-stage non-small cell lung cancer? J Thorac Oncol 2012;7:542–51. Salguero FJ, Belderbos JS, Rossi MM, et al. Microscopic disease extensions as a risk factor for loco-regional recurrence of NSCLC after SBRT. Radiother Oncol 2013;109:26–31. van Baardwijk A, Tome WA, van Elmpt W. Is high-dose stereotactic body radiotherapy (SBRT) for stage I non-small cell lung cancer (NSCLC) overkill? A systematic review. Radiother Oncol 2012. Haasbeek CJ, Palma D, Visser O, et al. Early-stage lung cancer in elderly patients: a population-based study of changes in treatment patterns and survival in The Netherlands. Ann Oncol 2012;23:2743–7. Bongers EM, Botticella A, Palma DA, et al. Predictive parameters of symptomatic radiation pneumonitis following stereotactic or hypofractionated radiotherapy delivered using volumetric modulated arcs. Radiother Oncol 2013;109:95–9. Senthi S, Haasbeek CJ, Slotman BJ, Senan S. Outcomes of stereotactic ablative radiotherapy for central lung tumours: a systematic review. Radiother Oncol 2013;106:276–82. 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;24:4833–9. Andolino DL, Forquer JA, Henderson MA, et al. Chest wall toxicity after stereotactic body radiotherapy for malignant lesions of the lung and liver. Int J Radiat Oncol Biol Phys 2011;80:692–7. Stephans KL, Djemil T, Tendulkar RD, et al. Prediction of chest wall toxicity from lung stereotactic body radiotherapy (SBRT). Int J Radiat Oncol Biol Phys 2012;82:974–80. Louie AV, Rodrigues G, Hannouf M, et al. Withholding stereotactic radiotherapy in elderly patients with stage I non-small cell lung cancer and co-existing COPD is not justified: outcomes of a Markov model analysis. Radiother Oncol 2011;99:161–5. RTOG0813, http://www.rtog.org/ClinicalTrials/ProtocolTable/StudyDetails. aspx?study=0813.
Please cite this article in press as: Brada M et al. SABR in NSCLC – The beginning of the end or the end of the beginning?. Radiother Oncol (2015), http:// dx.doi.org/10.1016/j.radonc.2015.01.012
