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Do protons have a role in the treatment of locally advanced NSCLC with radiotherapy?
Lung Cancer xxx (xxxx) xxx–xxx
Contents lists available at ScienceDirect
Lung Cancer journal homepage: www.elsevier.com/locate/lungcan
Editorial
Do protons have a role in the treatment of locally advanced NSCLC with radiotherapy?
1. Introduction Photon external bean radiotherapy remains the cornerstone of radical treatment for inoperable locally advanced non-small cell lung cancer (LANSCLC) given concomitantly with platinum-based chemotherapy [1]. With a median overall survival of approximately 25–29 months [2,3], research efforts continue to explore how both advanced radiotherapy techniques and novel systemic therapy and radiotherapy combination treatments can improve outcomes for this patient group. The goal of radical treatment is to achieve optimal therapeutic benefit with a high probability of tumour control for minimal toxicity. The Radiation Therapy Oncology Group (RTOG) randomised phase III 0617 study [3] comparing standard dose (60 Gy) to dose escalated radiotherapy (74 Gy) given with concomitant systemic therapy has highlighted in the modern era the importance of the dose received by normal tissues and toxicity in relation to overall survival, with the maximum grade of oesophageal toxicity and the proportion of heart receiving radiation dose both being predictive factors of inferior survival. 2. Advances in photon technology The last two decades have seen many technical advances in photon radiotherapy. For treatment planning, the objective is to attain conformity of the planned dose to the target volume within minimal dose to surrounding normal tissues. There have been incremental advances in planning with improved robustness of photon planning algorithms and the ability to plan intensity modulated radiotherapy (IMRT) and volumetric modulated arc therapy (VMAT). There have also been important advances in assessment and management of target and organ motion within the thorax and use of techniques to individualise treatment based on the motion to improve the treatment accuracy [4,5]. For radiotherapy delivery over the course of treatment, the objective is consistency between the planned and delivered dose distributions. With recent widespread availability of cone-beam computerised tomography (CBCT) it is now possible to use these images to assess of the shape and position of the radiotherapy target in relation to the planned dose delivery prior to treatment, image guided radiotherapy (IGRT), to improve accuracy of treatment delivery and where necessary to use this information to adapt treatment based, image guided adaptive radiotherapy (IGART) [6]. Establishing clinical benefit with these incremental advances is challenging, however improved median survival in the standard arm of recent randomised trials [2,3] compared to historical trials suggests that technical advances may have played a role. Additionally, there are retrospective data from a large series that suggest IMRT in particular may be associated with improved outcome in stage III NSCLC with T3 and T4 tumours [7] and a recent secondary analysis of the RTOG 0617 trial suggests use of IMRT compared to 3D conformal techniques is associated with lower severe lung toxicity and lower cardiac doses [8]. 3. The promise of proton therapy A relevant limitation of photon based radiotherapy is its characteristic dose deposition curve within normal tissue with a long tail of dose fall-off limiting the conformality of target dose distributions. This important physical aspect is potentially improved by use of proton compared to photon therapy due to the characteristic advantage of the Bragg peak deposition of dose within tissue that is associated with lower entrance dose and minimal exit dose. The improved dosimetry of proton radiotherapy plans has been demonstrated in multiple planning studies with target coverage associated with reduction in dose to surrounding normal tissue compared to photon radiotherapy plans [9,10]. Thus, definitive evidence of a clinical benefit from the use of proton compared to photon therapy is eagerly awaited. 4. Retrospective clinical data for proton therapy Over the last few years there has been increasing use of protons for radical NSCLC treatment, albeit without randomised evidence to provide clear evidence of benefit. The recent retrospective analysis of survival outcomes from the U.S. national cancer database comparing proton versus photon therapy is the largest published dataset in treatment of NSCLC [11]. The study in patients with stage I–IV NSCLC includes 348 treated with protons http://dx.doi.org/10.1016/j.lungcan.2017.05.013 Received 10 May 2017 0169-5002/ Crown Copyright © 2017 Published by Elsevier Ireland Ltd. All rights reserved.
Lung Cancer xxx (xxxx) xxx–xxx
Editorial
and over 240,000 patients treated with photons between 2004 and 2012. While demonstrating a significant 5-year survival benefit in the patients treated with protons (23.1%) over all photon therapy (13.5%), no significant difference was observed for proton therapy over the photon therapy group treated with IMRT (HR 1.05; CI 0.91–1.20), including on propensity matched multi-variate analysis to minimise treatment selection bias. For the sub-group of patients with stage II–III NSCLC, no significant survival advantage was demonstrated for proton therapy over photon therapy with either 3D conformal radiotherapy (HR 1.12; CI 0.94–1.34) or IMRT (HR 1.02; CI 0.85–1.22). An important limitation of this study is the lack of dosevolume histogram data and important clinical data within the database, including toxicity and quality of life scores. Large radiotherapy population databases are a valuable resource and provide important insights, particularly in settings where randomised trials would be difficult to conduct [12]. Prospectively data collection is associated with less risk of bias than retrospective, however, the data from observational studies do not replace the need for validation of findings in a randomised setting where possible. 5. Randomised clinical data for proton therapy Despite the challenge, randomised data are on their way. The results of a multi-institution randomised phase II trial comparing photon IMRT to passively scattered proton therapy (PSPT) in LA-NSCLC with concomitant chemotherapy (NCT00915005) were presented in abstract form at the American Society of Clinical Oncology (ASCO) annual meeting in 2016 [13]. Patients in the study had paired radiotherapy plans created using both treatment modalities to either 74 Gy if achievable or to 66 Gy if achievable. Only patients with the same dose achieved within the protocol defined normal tissue constraints were eligible for randomisation. The dual primary endpoint of severe radiation pneumonitis and freedom from local disease failure was not significantly different between those treated with proton therapy and photon IMRT. Notably the proton therapy plans were associated with significantly lower cardiac doses than the photon plans. The full report for the trial is eagerly awaited. Furthermore, the RTOG 1308 trial (NCT 01993810) is a phase III trial of radical concomitant chemo-radiotherapy in LA-NSCLC comparing 70 Gy delivered with protons compared to photons with a primary endpoint of overall survival. This study is actively recruiting and had achieved over 15% accrual by March 2017. 6. Evolving proton technology and clinical experience Proton technology is at a disadvantage to photon therapy due to its relative infancy in technological development. For example, over the course of the phase II randomised trial mentioned above, PSPT using wide proton beams that are conformally shaped to the target volume using customized apertures and compensators, was largely been replaced with intensity-modulated proton therapy (IMPT), which uses magnetic steering of multiple narrow proton beams (pencil beam scanning (PBS)) with modulation of the weight of each narrow beam to deliver high-dose conformity to the target volume. The emergence of a new technology such as proton therapy is also associated with a clinical learning curve, including a need for better understanding of relative biological effectiveness (RBE) of proton prescriptions [14]. In the abstract of the randomised trial, it is interesting to note that the local disease failure rates in the photon therapy arm remained similar whether a patient was enrolled in the first or second half of the study, however in the proton arm, the local failure was significantly lower in the group of patients recruited in the second half of the study compared to the first half, reflecting the evolving nature of proton technology and clinical experience implementing it [13]. In comparison with the recent advances in photon therapy outlined earlier, the rapid evolution of proton therapy over the next few years will see more robust treatment planning with advanced algorithms, introduction of arc proton beam therapy and wide spread use of volumetric image guidance. Proton therapy is additionally more vulnerable than photon therapy to beam path changes, particularly associated with organ motion and heterogeneous tissue interfaces and therefore proton therapy is likely to gain more than photon therapy when technological solutions for increased ability to adapt treatment, including with real-time adaptive solutions, are available. Therefore, the full potential of proton therapy in improving outcomes from NSCLC compared to photon therapy may not yet be realised. 7. Proving the promise of protons Rigorous and comprehensive evaluation of proton therapy remains challenging [15]. The RTOG 1308 trial team should be congratulated on their recruitment so far and on-going work to provide level I evidence to guide clinical practice, particularly in a landscape where the majority of ongoing proton trials are not randomised [16]. There is a limited window of opportunity to conduct these trials before loss of collective clinical equipoise and widespread availability of proton therapy ‘off-trial’ without robust evidence: only multicentre collaboration can accomplish this in a timely manner. Funding of proton treatment for patients treated within trials, who are randomised to receive proton therapy, should be prioritised. Finally, proving the promise of protons remains key to ensuring subsequent widespread access of the potential of protons for patients with NSCLC. References [1] A. Aupérin, C. Le Péchoux, E. Rolland, W.J. Curran, K. Furuse, P. Fournel, et al., Meta-analysis of concomitant versus sequential radiochemotherapy in locally advanced non – smallcell lung cancer, J. Clin. Oncol. 28 (13) (2010) 2181–2190. [2] S. Senan, A. Brade, L.H. Wang, J. Vansteenkiste, S. Dakhil, B. Biesma, et al., PROCLAIM: randomized Phase III trial of pemetrexed-cisplatin or etoposide-cisplatin plus thoracic radiation therapy followed by consolidation chemotherapy in locally advanced nonsquamous non-small-cell lung cancer, J. Clin. Oncol. 34 (9) (2016) 953–962. [3] J.D. Bradley, R. Paulus, R. Komaki, G. Masters, G. Blumenschein, S. Schild, et al., Standard-dose versus high-dose conformal radiotherapy with concurrent and consolidation carboplatin plus paclitaxel with or without cetuximab for patients with stage IIIA or IIIB non-small-cell lung cancer (RTOG 0617): A randomised, two-by-two factorial p, Lancet Oncol. 16 (2) (2015) 187–199. [4] J. Cole, G.G. Hanna, S. Jain, J.M. O’Sullivan, Motion management for radical radiotherapy in non-small cell lung cancer, Clin. Oncol. (R. Coll. Radiol.) 26 (2) (2013) 67–80. Available from: 10.1016/j.clon.2013.11.001%5Cn http://www.ncbi.nlm.nih.gov/pubmed/24290238. [5] J.W.H. Wolthaus, J.-J. Sonke, M. van Herk, J.S. Belderbos, M.M.G. Rossi, J.V. Lebesque, et al., Comparison of different strategies to use four-dimensional computed tomography in treatment planning for lung cancer patients, Int. J. Radiat. Oncol. Biol. Phys. 70 (4) (2008) 1138–1229. [6] M. Kwint, S. Conijn, E. Schaake, J. Knegjens, M. Rossi, P. Remeijer, et al., Intra thoracic anatomical changes in lung cancer patients during the course of radiotherapy, Radiother. Oncol. 113 (3) (2014) 392–397, http://dx.doi.org/10.1016/j.radonc.2014.10.009 Available from. [7] N. Jegadeesh, Y. Liu, T. Gillespie, F. Fernandez, S. Ramalingam, J. Mikell, et al., Evaluating intensity-Modulated radiation therapy in locally advanced non-small-cell lung cancer: results from the national cancer data base, Clin. Lung Cancer (2016) 1–8, http://dx.doi.org/10.1016/j.cllc.2016.01.007 Available from. [8] S.G. Chun, C. Hu, H. Choy, R.U. Komaki, R.D. Timmerman, S.E. Schild, et al., Impact of intensity-modulated radiation therapy technique for locally advanced non-small-cell lung cancer: a secondary analysis of the NRG oncology RTOG 0617 randomized clinical trial, J. Clin. Oncol. (2016), http://dx.doi.org/10.1200/JCO.2016.69.1378 Available from. [9] J.Y. Chang, X. Zhang, X. Wang, Y. Kang, B. Riley, S. Bilton, et al., Significant reduction of normal tissue dose by proton radiotherapy compared with three-dimensional conformal or
2
Lung Cancer xxx (xxxx) xxx–xxx
Editorial
intensity-modulated radiation therapy in Stage I or Stage III non-small-cell lung cancer, Int. J. Radiat. Oncol. Biol. Phys. 65 (4) (2006) 1087–1096. [10] J.Y. Chang, H. Li, X.R. Zhu, Z. Liao, L. Zhao, A. Liu, et al., Clinical implementation of intensity modulated proton therapy for thoracic malignancies, Int. J. Radiat. Oncol. Biol. Phys. 90 (4) (2014) 809–818, http://dx.doi.org/10.1016/j.ijrobp.2014.07.045 Available from. [11] K.A. Higgins, K. O’Connell, Y. Liu, T.W. Gillespie, M.W. McDonald, R.N. Pillai, et al., National cancer database analysis of proton versus photon radiotherapy in non-small cell lung cancer (NSCLC), Int. J. Radiat. Oncol. Biol. Phys. (2017) 128–137, http://dx.doi.org/10.1016/j.ijrobp.2016.10.001 Available from. [12] D. Palma, O. Visser, F.J. Lagerwaard, J. Belderbos, B.J. Slotman, S. Senan, Impact of introducing stereotactic lung radiotherapy for elderly patients with stage I non-small-cell lung cancer: a population-based time-trend analysis, J. Clin. Oncol. 28 (35) (2010) 5153–5159. [13] Z. Liao, J. Lee, R. Komaki, D. Gomez, M. O’Reilly, P. Allen, et al., Bayesian randomised trial comparing intensity modulated radiation therapy versus passively scattered proton therapy for locally advanced non-small cell lung cancer, ASCO Annu. Meet. 65 (suppl) (2016) 65–66. [14] T.I. Marshall, P. Chaudhary, A. Michaelidesov, J. Vachelov, M. Davdkov, V. Vondrek, et al., Investigating the implications of a variable RBE on proton dose fractionation across a clinical pencil beam scanned spread-out bragg peak, Int. J. Radiat. Oncol. Biol. Phys. 95 (1) (2016) 70–77. [15] J. Van Loon, J. Grutters, F. Macbeth, Evaluation of novel radiotherapy technologies: what evidence is needed to assess their clinical and cost effectiveness, and how should we get it? Lancet Oncol. 13 (4) (2012) e169–e177, http://dx.doi.org/10.1016/S1470-2045(11)70379-5 Available from. [16] M.V. Mishra, S. Aggarwal, S.M. Bentzen, N. Knight, M.P. Mehta, W.F. Regine, Establishing evidence-based indications for proton therapy: an overview of current clinical trials, Int. J. Radiat. Oncol. Biol. Phys. (2) (2016) Available from: http://linkinghub.elsevier.com/retrieve/pii/S0360301616334204. ⁎
Fiona McDonald The Royal Marsden NHS Foundation Trust Associate Honorary Faculty, UK E-mail address: fi[email protected]
Gerard G. Hanna Centre for Cancer Research and Cell Biology, Queens University, UK
⁎
Corresponding author at: The Royal Marsden NHS Foundation Trust, UK.
3
Contents lists available at ScienceDirect
Lung Cancer journal homepage: www.elsevier.com/locate/lungcan
Editorial
Do protons have a role in the treatment of locally advanced NSCLC with radiotherapy?
1. Introduction Photon external bean radiotherapy remains the cornerstone of radical treatment for inoperable locally advanced non-small cell lung cancer (LANSCLC) given concomitantly with platinum-based chemotherapy [1]. With a median overall survival of approximately 25–29 months [2,3], research efforts continue to explore how both advanced radiotherapy techniques and novel systemic therapy and radiotherapy combination treatments can improve outcomes for this patient group. The goal of radical treatment is to achieve optimal therapeutic benefit with a high probability of tumour control for minimal toxicity. The Radiation Therapy Oncology Group (RTOG) randomised phase III 0617 study [3] comparing standard dose (60 Gy) to dose escalated radiotherapy (74 Gy) given with concomitant systemic therapy has highlighted in the modern era the importance of the dose received by normal tissues and toxicity in relation to overall survival, with the maximum grade of oesophageal toxicity and the proportion of heart receiving radiation dose both being predictive factors of inferior survival. 2. Advances in photon technology The last two decades have seen many technical advances in photon radiotherapy. For treatment planning, the objective is to attain conformity of the planned dose to the target volume within minimal dose to surrounding normal tissues. There have been incremental advances in planning with improved robustness of photon planning algorithms and the ability to plan intensity modulated radiotherapy (IMRT) and volumetric modulated arc therapy (VMAT). There have also been important advances in assessment and management of target and organ motion within the thorax and use of techniques to individualise treatment based on the motion to improve the treatment accuracy [4,5]. For radiotherapy delivery over the course of treatment, the objective is consistency between the planned and delivered dose distributions. With recent widespread availability of cone-beam computerised tomography (CBCT) it is now possible to use these images to assess of the shape and position of the radiotherapy target in relation to the planned dose delivery prior to treatment, image guided radiotherapy (IGRT), to improve accuracy of treatment delivery and where necessary to use this information to adapt treatment based, image guided adaptive radiotherapy (IGART) [6]. Establishing clinical benefit with these incremental advances is challenging, however improved median survival in the standard arm of recent randomised trials [2,3] compared to historical trials suggests that technical advances may have played a role. Additionally, there are retrospective data from a large series that suggest IMRT in particular may be associated with improved outcome in stage III NSCLC with T3 and T4 tumours [7] and a recent secondary analysis of the RTOG 0617 trial suggests use of IMRT compared to 3D conformal techniques is associated with lower severe lung toxicity and lower cardiac doses [8]. 3. The promise of proton therapy A relevant limitation of photon based radiotherapy is its characteristic dose deposition curve within normal tissue with a long tail of dose fall-off limiting the conformality of target dose distributions. This important physical aspect is potentially improved by use of proton compared to photon therapy due to the characteristic advantage of the Bragg peak deposition of dose within tissue that is associated with lower entrance dose and minimal exit dose. The improved dosimetry of proton radiotherapy plans has been demonstrated in multiple planning studies with target coverage associated with reduction in dose to surrounding normal tissue compared to photon radiotherapy plans [9,10]. Thus, definitive evidence of a clinical benefit from the use of proton compared to photon therapy is eagerly awaited. 4. Retrospective clinical data for proton therapy Over the last few years there has been increasing use of protons for radical NSCLC treatment, albeit without randomised evidence to provide clear evidence of benefit. The recent retrospective analysis of survival outcomes from the U.S. national cancer database comparing proton versus photon therapy is the largest published dataset in treatment of NSCLC [11]. The study in patients with stage I–IV NSCLC includes 348 treated with protons http://dx.doi.org/10.1016/j.lungcan.2017.05.013 Received 10 May 2017 0169-5002/ Crown Copyright © 2017 Published by Elsevier Ireland Ltd. All rights reserved.
Lung Cancer xxx (xxxx) xxx–xxx
Editorial
and over 240,000 patients treated with photons between 2004 and 2012. While demonstrating a significant 5-year survival benefit in the patients treated with protons (23.1%) over all photon therapy (13.5%), no significant difference was observed for proton therapy over the photon therapy group treated with IMRT (HR 1.05; CI 0.91–1.20), including on propensity matched multi-variate analysis to minimise treatment selection bias. For the sub-group of patients with stage II–III NSCLC, no significant survival advantage was demonstrated for proton therapy over photon therapy with either 3D conformal radiotherapy (HR 1.12; CI 0.94–1.34) or IMRT (HR 1.02; CI 0.85–1.22). An important limitation of this study is the lack of dosevolume histogram data and important clinical data within the database, including toxicity and quality of life scores. Large radiotherapy population databases are a valuable resource and provide important insights, particularly in settings where randomised trials would be difficult to conduct [12]. Prospectively data collection is associated with less risk of bias than retrospective, however, the data from observational studies do not replace the need for validation of findings in a randomised setting where possible. 5. Randomised clinical data for proton therapy Despite the challenge, randomised data are on their way. The results of a multi-institution randomised phase II trial comparing photon IMRT to passively scattered proton therapy (PSPT) in LA-NSCLC with concomitant chemotherapy (NCT00915005) were presented in abstract form at the American Society of Clinical Oncology (ASCO) annual meeting in 2016 [13]. Patients in the study had paired radiotherapy plans created using both treatment modalities to either 74 Gy if achievable or to 66 Gy if achievable. Only patients with the same dose achieved within the protocol defined normal tissue constraints were eligible for randomisation. The dual primary endpoint of severe radiation pneumonitis and freedom from local disease failure was not significantly different between those treated with proton therapy and photon IMRT. Notably the proton therapy plans were associated with significantly lower cardiac doses than the photon plans. The full report for the trial is eagerly awaited. Furthermore, the RTOG 1308 trial (NCT 01993810) is a phase III trial of radical concomitant chemo-radiotherapy in LA-NSCLC comparing 70 Gy delivered with protons compared to photons with a primary endpoint of overall survival. This study is actively recruiting and had achieved over 15% accrual by March 2017. 6. Evolving proton technology and clinical experience Proton technology is at a disadvantage to photon therapy due to its relative infancy in technological development. For example, over the course of the phase II randomised trial mentioned above, PSPT using wide proton beams that are conformally shaped to the target volume using customized apertures and compensators, was largely been replaced with intensity-modulated proton therapy (IMPT), which uses magnetic steering of multiple narrow proton beams (pencil beam scanning (PBS)) with modulation of the weight of each narrow beam to deliver high-dose conformity to the target volume. The emergence of a new technology such as proton therapy is also associated with a clinical learning curve, including a need for better understanding of relative biological effectiveness (RBE) of proton prescriptions [14]. In the abstract of the randomised trial, it is interesting to note that the local disease failure rates in the photon therapy arm remained similar whether a patient was enrolled in the first or second half of the study, however in the proton arm, the local failure was significantly lower in the group of patients recruited in the second half of the study compared to the first half, reflecting the evolving nature of proton technology and clinical experience implementing it [13]. In comparison with the recent advances in photon therapy outlined earlier, the rapid evolution of proton therapy over the next few years will see more robust treatment planning with advanced algorithms, introduction of arc proton beam therapy and wide spread use of volumetric image guidance. Proton therapy is additionally more vulnerable than photon therapy to beam path changes, particularly associated with organ motion and heterogeneous tissue interfaces and therefore proton therapy is likely to gain more than photon therapy when technological solutions for increased ability to adapt treatment, including with real-time adaptive solutions, are available. Therefore, the full potential of proton therapy in improving outcomes from NSCLC compared to photon therapy may not yet be realised. 7. Proving the promise of protons Rigorous and comprehensive evaluation of proton therapy remains challenging [15]. The RTOG 1308 trial team should be congratulated on their recruitment so far and on-going work to provide level I evidence to guide clinical practice, particularly in a landscape where the majority of ongoing proton trials are not randomised [16]. There is a limited window of opportunity to conduct these trials before loss of collective clinical equipoise and widespread availability of proton therapy ‘off-trial’ without robust evidence: only multicentre collaboration can accomplish this in a timely manner. Funding of proton treatment for patients treated within trials, who are randomised to receive proton therapy, should be prioritised. Finally, proving the promise of protons remains key to ensuring subsequent widespread access of the potential of protons for patients with NSCLC. References [1] A. Aupérin, C. Le Péchoux, E. Rolland, W.J. Curran, K. Furuse, P. Fournel, et al., Meta-analysis of concomitant versus sequential radiochemotherapy in locally advanced non – smallcell lung cancer, J. Clin. Oncol. 28 (13) (2010) 2181–2190. [2] S. Senan, A. Brade, L.H. Wang, J. Vansteenkiste, S. Dakhil, B. Biesma, et al., PROCLAIM: randomized Phase III trial of pemetrexed-cisplatin or etoposide-cisplatin plus thoracic radiation therapy followed by consolidation chemotherapy in locally advanced nonsquamous non-small-cell lung cancer, J. Clin. Oncol. 34 (9) (2016) 953–962. [3] J.D. Bradley, R. Paulus, R. Komaki, G. Masters, G. Blumenschein, S. Schild, et al., Standard-dose versus high-dose conformal radiotherapy with concurrent and consolidation carboplatin plus paclitaxel with or without cetuximab for patients with stage IIIA or IIIB non-small-cell lung cancer (RTOG 0617): A randomised, two-by-two factorial p, Lancet Oncol. 16 (2) (2015) 187–199. [4] J. Cole, G.G. Hanna, S. Jain, J.M. O’Sullivan, Motion management for radical radiotherapy in non-small cell lung cancer, Clin. Oncol. (R. Coll. Radiol.) 26 (2) (2013) 67–80. Available from: 10.1016/j.clon.2013.11.001%5Cn http://www.ncbi.nlm.nih.gov/pubmed/24290238. [5] J.W.H. Wolthaus, J.-J. Sonke, M. van Herk, J.S. Belderbos, M.M.G. Rossi, J.V. Lebesque, et al., Comparison of different strategies to use four-dimensional computed tomography in treatment planning for lung cancer patients, Int. J. Radiat. Oncol. Biol. Phys. 70 (4) (2008) 1138–1229. [6] M. Kwint, S. Conijn, E. Schaake, J. Knegjens, M. Rossi, P. Remeijer, et al., Intra thoracic anatomical changes in lung cancer patients during the course of radiotherapy, Radiother. Oncol. 113 (3) (2014) 392–397, http://dx.doi.org/10.1016/j.radonc.2014.10.009 Available from. [7] N. Jegadeesh, Y. Liu, T. Gillespie, F. Fernandez, S. Ramalingam, J. Mikell, et al., Evaluating intensity-Modulated radiation therapy in locally advanced non-small-cell lung cancer: results from the national cancer data base, Clin. Lung Cancer (2016) 1–8, http://dx.doi.org/10.1016/j.cllc.2016.01.007 Available from. [8] S.G. Chun, C. Hu, H. Choy, R.U. Komaki, R.D. Timmerman, S.E. Schild, et al., Impact of intensity-modulated radiation therapy technique for locally advanced non-small-cell lung cancer: a secondary analysis of the NRG oncology RTOG 0617 randomized clinical trial, J. Clin. Oncol. (2016), http://dx.doi.org/10.1200/JCO.2016.69.1378 Available from. [9] J.Y. Chang, X. Zhang, X. Wang, Y. Kang, B. Riley, S. Bilton, et al., Significant reduction of normal tissue dose by proton radiotherapy compared with three-dimensional conformal or
2
Lung Cancer xxx (xxxx) xxx–xxx
Editorial
intensity-modulated radiation therapy in Stage I or Stage III non-small-cell lung cancer, Int. J. Radiat. Oncol. Biol. Phys. 65 (4) (2006) 1087–1096. [10] J.Y. Chang, H. Li, X.R. Zhu, Z. Liao, L. Zhao, A. Liu, et al., Clinical implementation of intensity modulated proton therapy for thoracic malignancies, Int. J. Radiat. Oncol. Biol. Phys. 90 (4) (2014) 809–818, http://dx.doi.org/10.1016/j.ijrobp.2014.07.045 Available from. [11] K.A. Higgins, K. O’Connell, Y. Liu, T.W. Gillespie, M.W. McDonald, R.N. Pillai, et al., National cancer database analysis of proton versus photon radiotherapy in non-small cell lung cancer (NSCLC), Int. J. Radiat. Oncol. Biol. Phys. (2017) 128–137, http://dx.doi.org/10.1016/j.ijrobp.2016.10.001 Available from. [12] D. Palma, O. Visser, F.J. Lagerwaard, J. Belderbos, B.J. Slotman, S. Senan, Impact of introducing stereotactic lung radiotherapy for elderly patients with stage I non-small-cell lung cancer: a population-based time-trend analysis, J. Clin. Oncol. 28 (35) (2010) 5153–5159. [13] Z. Liao, J. Lee, R. Komaki, D. Gomez, M. O’Reilly, P. Allen, et al., Bayesian randomised trial comparing intensity modulated radiation therapy versus passively scattered proton therapy for locally advanced non-small cell lung cancer, ASCO Annu. Meet. 65 (suppl) (2016) 65–66. [14] T.I. Marshall, P. Chaudhary, A. Michaelidesov, J. Vachelov, M. Davdkov, V. Vondrek, et al., Investigating the implications of a variable RBE on proton dose fractionation across a clinical pencil beam scanned spread-out bragg peak, Int. J. Radiat. Oncol. Biol. Phys. 95 (1) (2016) 70–77. [15] J. Van Loon, J. Grutters, F. Macbeth, Evaluation of novel radiotherapy technologies: what evidence is needed to assess their clinical and cost effectiveness, and how should we get it? Lancet Oncol. 13 (4) (2012) e169–e177, http://dx.doi.org/10.1016/S1470-2045(11)70379-5 Available from. [16] M.V. Mishra, S. Aggarwal, S.M. Bentzen, N. Knight, M.P. Mehta, W.F. Regine, Establishing evidence-based indications for proton therapy: an overview of current clinical trials, Int. J. Radiat. Oncol. Biol. Phys. (2) (2016) Available from: http://linkinghub.elsevier.com/retrieve/pii/S0360301616334204. ⁎
Fiona McDonald The Royal Marsden NHS Foundation Trust Associate Honorary Faculty, UK E-mail address: fi[email protected]
Gerard G. Hanna Centre for Cancer Research and Cell Biology, Queens University, UK
⁎
Corresponding author at: The Royal Marsden NHS Foundation Trust, UK.
3