Review
High-dose re-irradiation following radical radiotherapy for non-small-cell lung cancer Dirk De Ruysscher, Corinne Faivre-Finn, Cecile Le Pechoux, Stéphanie Peeters, José Belderbos
As the prognosis of lung cancer patients improves, more patients are at risk of developing local recurrence or a new primary tumour in previously irradiated areas. Technological advances in radiotherapy and imaging have made treatment of patients with high-dose re-irradiation possible, with the aim of long-term disease-free survival and even cure. However, high-dose re-irradiation with overlapping volumes of previously irradiated tissues is not without risks. Late, irreversible, and potentially serious normal tissue damage may occur because of injury to surrounding thoracic structures and organs at risk. In this Review, we aimed to report the efficacy and toxic effects of high-dose re-irradiation for locoregional recurrent non-small-cell lung cancer. Our findings indicate that high-dose re-irradiation might be beneficial in selected patients; however, patients and physicians should be aware of the scarcity of high-quality data when considering this treatment.
Introduction Radiotherapy has a major role in the radical treatment of patients with non-small-cell lung cancer (NSCLC),1 and advances in radiotherapy have resulted in improved local tumour control and long-term survival.1–4 These advances include stereotactic body radiotherapy (SBRT), the use of image-guided radiotherapy, and integration of molecular imaging to optimise dose distribution and delivery, four-dimensional CT scans, and high-quality radiotherapy delivery along with the integration of systemic treatments. The risk of patients developing local recurrence or a new primary tumour in previously irradiated areas increases as the prognosis of patients with NSCLC improves.1 However, owing to technological advances in radiotherapy and imaging, high-dose re-irradiation is now available to some of these patients, and could be used to improve long-term disease-free survival. The use of high-dose re-irradiation that overlaps with previously irradiated volumes is not without risks.5 Potentially serious and irreversible normal tissue damage might occur because of injury to blood vessels (large and small), bone, cartilage, and connective tissue. Radiation pneumonitis is a major risk after re-irradiation of lung tumours and severe fibrosis, fistula, and bleeding can also be noted as a result of the very high cumulative doses delivered to critical organs. Our understanding of the relation between the dose, volume, and late effects of irradiation has improved substantially in the past decade;6 however, radiation sensitivity varies greatly between tumours and normal tissues and between individuals, which might partly be explained by genetic differences.7–9 Furthermore, the tolerance of normal tissue in the context of re-irradiation is unknown. Preclinical data suggest some tissue repair takes place after primary irradiation, leading to the possibility of re-delivering high doses of irradiation without undue injury.10,11 Clinical experience suggested that high-dose re-irradiation is possible in selected patients, although this was mostly in head and neck, pelvic, brain, and breast cancers, and lethal bleeding has been reported.12–16 www.thelancet.com/oncology Vol 15 December 2014
Long-term local tumour control has been demonstrated, even in cases for which the tumour recurred in the same volume that was previously exposed to high-dose radiotherapy. There is growing interest in the use of re-irradiation in NSCLC. Despite radical radiotherapy, 20–44% of patients will have loco-regional progression at 2 years, and in cases of locoregional relapse, most tumours are not resectable.1 Systemic treatment is generally given with palliative intent in these cases, with less than 30% of patients achieving an objective response and a median overall survival of 10–12 months, which is similar to de-novo stage IV disease.17 These observations, along with our improved understanding of the importance of local control and its effect on survival in patients with NSCLC, make the concept of re-irradiation very attractive. The use of high-dose radiotherapy for second cancers in previously irradiated areas, a situation that can be seen in diseases such as Hodgkin’s lymphoma, will not be discussed within this Review. We summarised the available literature-based evidence to support the use of high-dose re-irradiation in patients with loco-regional NSCLC after high-dose primary irradiation, with or without systemic therapy. We then investigated the safety and efficacy of high-dose reirradiation, and whether we could identify patients most likely to benefit from this treatment.
Lancet Oncol 2014; 15: e620–24 Radiation Oncology, University Hospitals Leuven/KU Leuven, Leuven, Belgium (Prof D De Ruysscher MD, S Peeters MD); Radiation Related Research, The Christie NHS Foundation Trust and University of Manchester, Manchester, UK (C Faivre-Finn MD); Department of Radiation Oncology, Institut Gustave Roussy, Villejuif, France (C Le Pechoux MD); and Department of Radiation Oncology, Netherlands Cancer Institute, Amsterdam, Netherlands (J Belderbos MD) Correspondence to: Prof Dirk De Ruysscher, University Hospitals Leuven/KU Leuven, Radiation Oncology, Herestraat 49, 3000 Leuven, Belgium [email protected]
Identified studies We did a literature search to compile evidence from studies reporting on the efficacy and toxicity of high-dose re-irradiation. The search identified 24 studies, and ten were discarded as the radiation doses delivered were not curative. Of the 14 studies that fulfilled the criteria of this Review, 13 were retrospective studies and one was a small prospective study. We did not identify any randomised studies (table 1, table 2). 408 patients were reported on, and the number of patients included in the studies ranged from 12 to 72 patients. The median follow-up time was 16·5 months e620
Review
Mean reirradiation dose (Gy)
Toxic effects
Reason for exclusion
Green et al18
35
Palliative radiotherapy dose
Jackson et al19
30
Palliative radiotherapy dose
Montebello et al20
30
Palliative radiotherapy dose
Gressen et al21
30
Palliative radiotherapy dose
Kramer et al22
16
Palliative radiotherapy dose
Poltinnikov et al23
32
Palliative radiotherapy dose
Ebara et al24
40
Palliative radiotherapy dose
Cetingoz et al25
25
Palliative radiotherapy dose
Tada et al26
50
Only one patient treated with radical intent
Kruser et al27
30
Palliative radiotherapy dose
Table 1: Excluded studies
Number of patients
Median follow-up (months)
Initial dose*
Re-RT dose†
Type
Re-RT technique
Wu et al28
Prospective
3DCRT
13 (radical)
Okamoto et al29
Retrospective
3DCRT
18 (radical)
Peulen et al30‡
Retrospective
SABR
29
12
104 Gy§
104 Gy§
Coon et al31
Retrospective
SABR
12
12
Not stated
60 Gy in 3 fractions
Kelly et al32
Retrospective
SABR
36
15
15 Not stated
66 Gy conv
51 Gy conv
60 Gy conv
50 Gy conv
61·5 Gy conv
Evans et al33
Retrospective
SABR
35
42
54 Gy conv
Liu et al34
Retrospective
SABR
72
16
63 Gy conv
50 Gy in 4 fractions 60 Gy conv 50 Gy in 4 fractions
Meijneke et al35
Retrospective
SABR
20
12
McAvoy et al36
Retrospective
Protons
33
11
Reyngold et al37
Retrospective
SABR
39
12·6
61 Gy conv
70·4 Gy
Kilburn et al38
Retrospective
SABR/conv
34/3
17
60 Gy
50 Gy in 10 fractions
Yoshitake et al39
Retrospective
3DCRT
17
12·6
Trovo et al40
Retrospective
SABR
17
18
50–60 Gy conv
30 Gy in 5–6 fractions
Retrospective
3DCRT
24
19·3
59·8 Gy conv
60 Gy in 30 fractions
Griffioen et al
41
110 Gy§ 63 Gy conv
Not stated
87 Gy§ 66 Gy conv
60 Gy in 30 fractions
Re-RT=re-irradiation. 3DCRT=three-dimensionalradiotherapy. SABR=stereotactic ablative radiotherapy. Conv=conventional fractionation (ie, 1·8–2·0 Gy per fraction, 4–5 times per week; in ref. 24: 1·5–2·0 Gy). *Median radiotherapy dose for the initial primary treatment. †Median radiotherapy dose for the high-dose re-irradiation. ‡SABR for primary treatment and for recurrence. §Biological equivalent dose of 2 Gy per fraction for the tumour.
Table 2: Characteristics of included studies of high-dose re-irradiation
(2–37). The techniques of re-irradiation were 3D conformal radiotherapy, stereotactic ablative radiotherapy (SABR), combined 3D-conformal radiotherapy and SABR, and proton therapy (table 2). The mean initial radiation dose was approximately 70 Gy, although a wide range was reported. In most series, SABR was used for re-irradiation. We did not estimate biological doses in the individual studies because the reported technical details were not always sufficient to do this adequately. e621
Information on toxic effects is summarised in table 3. Owing to the retrospective nature of the studies, we expected under-reporting of less severe toxic effects (ie, grades 1–3), since there evidence that toxic effects of grade 3 and below are under-reported in retrospective studies. Therefore, only toxic effects of grade 3 or more will be discussed, although we compiled grade 1 and 2 toxicities when they were reported. Grade 3–4 lung toxic effects, mostly defined as radiation pneumonitis requiring oxygen (grade 3) or ventilator support (grade 4), was noted in 0–21% of patients (average of 7%). The incidence of severe lung toxic effects did not differ greatly in patients treated with conventional 3D conformal radiotherapy compared with patients treated with SABR. Grade 3 oesophagitis, which was defined as requiring tube or intravenous feeding, was noted in 0–9% of the patients, with a mean incidence of 2%. Grade 5 (ie, lethal) bleeding was reported in 12 of 408 patients (3%; range 0–12). Peulen and colleagues30 assessed the toxic effects of re-irradiation of 32 lung lesions (11 central lesions and 21 peripheral lesions) in 29 patients who were initially treated with SABR and re-irradiated with SABR. Toxic effects of grade 2 or higher was reported according to the location of the tumour, dose delivered, and volume of irradiation.30 Larger clinical target volumes and central tumour localisation were associated with more severe toxic effects. All toxic effects of grade 4 or higher were seen in patients with central tumours. Of the 11 patients with central tumours and treated with SABR after primary treatment with SABR, one patient had grade 4 superior vena cava stenosis and a grade 4 fistula, and three died because of massive bleeding. Grade 5 (ie, lethal) lung toxic effects was reported in two (0·5%) of 408 patients.
Prognostic factors of toxic effects Data for dose-volume histogram variables related to toxic effects of re-irradiation are scarce. Notably, most series did not use elastic deformation and therefore an accurate assessment of the cumulative radiation doses to the organs at risk is not possible. The incidence of lethal aortic bleeding was as high as 25% in some series. In one series,33 it was only noted in patients who received composite doses of 120 Gy or more to 1 cm³ of the aorta. In a series of 20 patients, it was reported that no severe toxic effects occurred when the cumulative V20 (the percentage of the lungs receiving ≥20 Gy) and maximum dose to the heart (115 Gy), trachea (89 Gy), and oesophagus (85 Gy, biologically corrected for an α/β value of 3 Gy) were less than 16%.35
Efficacy Data for median overall survival and time to disease progression are presented in table 4. The median time between radiotherapy for the primary NSCLC and www.thelancet.com/oncology Vol 15 December 2014
Review
re-irradiation was 23 months, and the median time to disease progression was 10 months. The mean overall survival was 17·7 months. Unfortunately, no data are available on symptom control with high-dose re-irradiation versus lower dose re-irradiation and palliative doses of radiotherapy. We found no data for quality of life. Second-line therapy, which could have affected overall survival, was not well documented in the published series.
Re-RT Grade 1–2 toxicity technique Wu et al28
3DCRT
Okamoto et al29 3DCRT
≥Grade 3 toxicity
G1+G2 lung (22%); None G1+G2 oesophagus (9%) G2 oesophagus (24%)
G3 lung (21%); G3 oesophagus (6%)
Peulen et al30
SABR
Coon et al31
SABR
Kelly et al32
SABR
Effects and safety of high-dose re-irradiation
Evans et al33
SABR
··
G5 bleeding (6%)
The prognosis of patients with NSCLC has improved substantially.1,17 As a result, more individuals present with local recurrences in areas that have been irradiated to high doses. Current radiotherapy techniques, including SABR, allow re-irradiation of these patients to high doses. However, the question remains: is high-dose re-irradiation beneficial for patients and does it improve survival without undue toxic effects? Unfortunately, high-quality data in this field are scarce, as shown by our systematic review of the medical literature that identified no randomised studies, one small prospective study,28 and 13 retrospective studies.29–41 High-dose re-irradiation results in median overall survival of about 17 months in selected patients, with median time to progression of about 10 months. A small proportion of patients could possibly even be cured with this approach, since there are a few patients without recurrence at follow-up.36 These results compare favourably to systemic treatment in stage IV NSCLC.17 However, in all published series, the time interval between the first radiotherapy course and high-dose re-irradiation was more than 12 months, with a mean of about 23 months. Allowing a treatment gap of more than a year before re-irradiation seems sensible since it will exclude patients with aggressive tumours who are likely to develop early distant metastases and will also allow for normal tissue repair. However, robust quantitative models for tissue repair are missing. Obviously, tissue repair is a major selection criterion that makes a fair comparison with systemic treatments difficult. Moreover, most series included patients treated with SABR, therefore selecting patients with tumours without detectable nodal or metastatic disease who are amenable to this treatment. Furthermore, time to progression was measured differently across the series, and recurrences were not always documented with pathology. Post-radiation fibrosis might mimic tumour recurrence and FDG avidity might be due to non-malignant inflammatory processes.2,3 Severe (grade 3–4) toxic effects were noted in a low proportion (6%) of patients. Grade 3–4 lung toxic effects occurred in 10% of patients. This percentage is lower than the incidence of severe lung toxic effects reported in patients with stage III NSCLC treated with chemoradiotherapy (15–20%), but higher than the incidence (20 years). Although no data are available about the use of ¹⁸F-FDG PET/CT scans to define target volumes, it seems logical to re-irradiate with a high level of geometrical accuracy to reduce the margins around the recurrent tumour volume and to keep the volume of the surrounding normal tissues as low as possible. Special care must be given to organ motion, and variations in delineation and patient set-up. Image-guided radiotherapy would be useful in this context. When assessing the toxic effects of high-dose re-irradiation, issues regarding its reporting must be considered. First, the retrospective nature of 13 out of 14 studies could have resulted in the underreporting of toxic effects (especially for grade 1 and 2 toxic effects that did not result in hospital admission). Furthermore, the grading of toxic effects was not standardised, with different scoring systems used. Second, with a median follow-up of about 16 months, some late toxic effects could have not yet been identified. Third, treatment-related deaths might have been underestimated in the studies since patients generally die at home or at their local hospital with death often being classified as lung cancer death. Finally, it should be noted that only crude toxicity rates are available from these studies rather than actuarial toxicity rates. The correlation between dose-volume and toxic effects after high-dose re-irradiation is not well defined by contrast with the primary treatment setting. Several factors contribute to these uncertainties, including a scarcity of prospective data and standardised toxicity scoring, a short follow-up, the effect of second-line systemic treatment, and the absence of cumulative dose–volume histograms. In the future, genetic e623
information and detailed data for tissue characteristics such as perfusion and hypoxia could identify individuals that can safely be re-treated.7–9 The results of high-dose re-irradiation should be placed in the context of palliative re-irradiation after previous radical intent radiotherapy. Following palliative re-irradiation, median survival is only about 5 months.18–24 Overall, symptom control (eg, haemoptysis, cough, chest pain, and dyspnoea) is achieved in more than 60% of patients after palliative re-irradiation. In the absence of randomised studies, firm conclusions cannot be drawn, but high-dose re-irradiation may have at least similar symptom control and higher survival than palliative re-irradiation.18–26 Prospective high-quality trials are needed for the field of high-dose re-irradiation to progress. In the meantime, carefully selected patients could be offered high-dose re-irradiation as long as they are informed of the little data available and the potential risk of toxic effects. Contributors DR had the idea for the paper and conducted the data analysis. DR, CF-F, CLP, and SP conducted the literature search and drafted the manuscript. DR and JB interpreted the data. Declaration of interests We declare that we have no competing interests. References 1 Vansteenkiste J, De Ruysscher D, Eberhardt WE, et al, and the ESMO Guidelines Working Group. Early and locally advanced non-small-cell lung cancer (NSCLC): ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol 2013; 24: vi89–98. 2 De Ruysscher D, Belderbos J, Reymen B, et al. State of the art radiation therapy for lung cancer 2012: a glimpse of the future. Clin Lung Cancer 2013; 14: 89–95. 3 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. 4 van Meerbeeck JP, Fennell DA, De Ruysscher DK. Small-cell lung cancer. Lancet 2011; 378: 1741–55. 5 Moding EJ, Kastan MB, Kirsch DG. Strategies for optimizing the response of cancer and normal tissues to radiation. Nat Rev Drug Discov 2013; 12: 526–42. 6 Marks LB, Bentzen SM, Deasy JO, et al. Radiation dose–volume effects in the lung. Int J Radiat Oncol Biol Phys 2010; 76: S70–76. 7 Kerns SL, De Ruysscher D, Andreassen CN, et al. STROGAR – STrengthening the Reporting Of Genetic Association studies in Radiogenomics. Radiother Oncol 2014; 110: 182–88. 8 Andreassen CN, Barnett GC, Langendijk JA, et al. Conducting radiogenomic research – do not forget careful consideration of the clinical data. Radiother Oncol 2012; 105: 337–40. 9 Barnett GC, Coles CE, Elliott RM, et al. Independent validation of genes and polymorphisms reported to be associated with radiation toxicity: a prospective analysis study. Lancet Oncol 2012; 13: 65–77. 10 Ang KK, Jiang GL, Feng Y, Stephens LC, Tucker SL, Price RE. Extent and kinetics of recovery of occult spinal cord injury. Int J Radiat Oncol Biol Phys 2001; 50: 1013–20. 11 Nieder C, Milas L, Ang KK. Tissue tolerance to reirradiation. Semin Radiat Oncol 2000; 10: 200–09. 12 Tortochaux J, Tao Y, Tournay E, et al. Randomized phase III trial (GORTEC 9803) comparing re-irradiation plus chemotherapy versus methotrexate in patients with recurrent or a second primary head and neck squamous cell carcinoma, treated with a palliative intent. Radiother Oncol 2011; 100: 70–75. 13 Abusaris H, Hoogeman M, Nuyttens JJ. Re-irradiation: outcome, cumulative dose and toxicity in patients retreated with stereotactic radiotherapy in the abdominal or pelvic region. Technol Cancer Res Treat 2012; 11: 591–97.
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Review
14
15
16
17
18 19 20
21
22
23
24
25
26
27
28
Linthorst M, van Geel AN, Baaijens M, et al. Re-irradiation and hyperthermia after surgery for recurrent breast cancer. Radiother Oncol 2013; 109: 188–93. Scharp M, Hauswald H, Bischof M, Debus J, Combs SE. Reirradiation in the treatment of patients with cerebral metastases of solid tumors: retrospective analysis. Radiat Oncol 2014; 9: 4. Combs SE, Edler L, Rausch R, Welzel T, Wick W, Debus J. Generation and validation of a prognostic score to predict outcome after re-irradiation of recurrent glioma. Acta Oncol 2013; 52: 147–52. Peters S, Adjei AA, Gridelli C, Reck M, Kerr K, Felip E, and the ESMO Guidelines Working Group. Metastatic non-small-cell lung cancer (NSCLC): ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol 2012; 23: vii56–64. Green N, Melbye RW. Lung cancer: retreatment of local recurrence after definitive irradiation. Cancer 1982; 49: 865–68. Jackson MA, Ball DL. Palliative retreatment of locally-recurrent lung cancer after radical radiotherapy. Med J Aust 1987; 147: 391–94. Montebello JF, Aron BS, Manatunga AK, Horvath JL, Peyton FW. The reirradiation of recurrent bronchogenic carcinoma with external beam irradiation. Am J Clin Oncol 1993; 16: 482–88. Gressen EL, Werner-Wasik M, Cohn J, Topham A, Curran WJ Jr. Thoracic reirradiation for symptomatic relief after prior radiotherapeutic management for lung cancer. Am J Clin Oncol 2000; 23: 160–63. Kramer GWPM, Gans S, Ullmann E, van Meerbeeck JP, Legrand CC, Leer JW. Hypofractionated external beam radiotherapy as retreatment for symptomatic non-small-cell lung carcinoma: an effective treatment? Int J Radiat Oncol Biol Phys 2004; 58: 1388–93. Poltinnikov IM, Fallon K, Xiao Y, Reiff JE, Curran WJ Jr, Werner-Wasik M. Combination of longitudinal and circumferential three-dimensional esophageal dose distribution predicts acute esophagitis in hypofractionated reirradiation of patients with nonsmall-cell lung cancer treated in stereotactic body frame. Int J Radiat Oncol Biol Phys 2005; 62: 652–58. Ebara T, Tanio N, Etoh T, Shichi I, Honda A, Nakajima N. Palliative re-irradiation for in-field recurrence after definitive radiotherapy in patients with primary lung cancer. Anticancer Res 2007; 27: 531–34. Cetingoz R, Arican-Alicikus Z, Nur-Demiral A, Durmak-Isman B, Bakis-Altas B, Kinay M. Is re-irradiation effective in symptomatic local recurrence of non small cell lung cancer patients? A single institution experience and review of the literature. J BUON 2009; 14: 33–40. Tada T, Fukuda H, Matsui K, et al. Non-small-cell lung cancer: reirradiation for loco-regional relapse previously treated with radiation therapy. Int J Clin Oncol 2005; 10: 247–50. Kruser TJ, McCabe BP, Mehta MP, et al. Reirradiation for locoregionally recurrent lung cancer: outcomes in small cell and non-small cell lung carcinoma. Am J Clin Oncol 2014; 37: 70–76. Wu K-L, Jiang G-L, Qian H, et al. Three-dimensional conformal radiotherapy for locoregionally recurrent lung carcinoma after external beam irradiation: a prospective phase I–II clinical trial. Int J Radiat Oncol Biol Phys 2003; 57: 1345–50.
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30
31
32
33 34
35
36
37
38
39
40
41
42
Okamoto Y, Murakami M, Yoden E, et al. Reirradiation for locally recurrent lung cancer previously treated with radiation therapy. Int J Radiat Oncol Biol Phys 2002; 52: 390–96. Peulen H, Karlsson K, Lindberg K, et al. Toxicity after reirradiation of pulmonary tumours with stereotactic body radiotherapy. Radiother Oncol 2011; 101: 260–66. Coon D, Gokhale AS, Burton SA, Heron DE, Ozhasoglu C, Christie N. Fractionated stereotactic body radiation therapy in the treatment of primary, recurrent, and metastatic lung tumors: the role of positron emission tomography/computed tomography-based treatment planning. Clin Lung Cancer 2008; 9: 217–21. Kelly P, Balter PA, Rebueno N, et al. Stereotactic body radiation therapy for patients with lung cancer previously treated with thoracic radiation. Int J Radiat Oncol Biol Phys 2010; 78: 1387–93. Evans JD, Gomez DR, Amini A, et al. Aortic dose constraints when reirradiating thoracic tumors. Radiother Oncol 2013; 106: 327–32. Liu H, Zhang X, Vinogradskiy YY, Swisher SG, Komaki R, Chang JY. Predicting radiation pneumonitis after stereotactic ablative radiation therapy in patients previously treated with conventional thoracic radiation therapy. Int J Radiat Oncol Biol Phys 2012; 84: 1017–23. Meijneke TR, Petit SF, Wentzler D, Hoogeman M, Nuyttens JJ. Reirradiation and stereotactic radiotherapy for tumors in the lung: dose summation and toxicity. Radiother Oncol 2013; 107: 423–27. McAvoy SA, Ciura KT, Rineer JM, et al. Feasibility of proton beam therapy for reirradiation of locoregionally recurrent non-small cell lung cancer. Radiother Oncol 2013; 109: 38–44. Reyngold M, Wu AJ, McLane A, et al. Toxicity and outcomes of thoracic re-irradiation using stereotactic body radiation therapy (SBRT). Radiat Oncol 2013; 8: 99. Kilburn JM, Kuremsky JG, Blackstock AW, et al. Thoracic reirradiation using stereotactic body radiotherapy (SBRT) techniques as first or second course of treatment. Radiother Oncol 2014; 110: 505–10. Yoshitake T, Shioyama Y, Nakamura K, et al. Definitive fractionated re-irradiation for local recurrence following stereotactic body radiotherapy for primary lung cancer. Anticancer Res 2013; 33: 5649–53. Trovo M, Minatel E, Durofil E, et al. Stereotactic body radiation therapy for re-irradiation of persistent or recurrent non-small cell lung cancer. Int J Radiat Oncol Biol Phys 2014; 88: 1114–19. Griffioen GH, Dahele M, de Haan PF, van de Ven PM, Slotman BJ, Senan S. High-dose, conventionally fractionated thoracic reirradiation for lung tumors. Lung Cancer 2014; 83: 356–62. Senthi S, Lagerwaard FJ, Haasbeek CJ, Slotman BJ, Senan S. Patterns of disease recurrence after stereotactic ablative radiotherapy for early stage non-small-cell lung cancer: a retrospective analysis. Lancet Oncol 2012; 13: 802–09.
e624
High-dose re-irradiation following radical radiotherapy for non-small-cell lung cancer Dirk De Ruysscher, Corinne Faivre-Finn, Cecile Le Pechoux, Stéphanie Peeters, José Belderbos
As the prognosis of lung cancer patients improves, more patients are at risk of developing local recurrence or a new primary tumour in previously irradiated areas. Technological advances in radiotherapy and imaging have made treatment of patients with high-dose re-irradiation possible, with the aim of long-term disease-free survival and even cure. However, high-dose re-irradiation with overlapping volumes of previously irradiated tissues is not without risks. Late, irreversible, and potentially serious normal tissue damage may occur because of injury to surrounding thoracic structures and organs at risk. In this Review, we aimed to report the efficacy and toxic effects of high-dose re-irradiation for locoregional recurrent non-small-cell lung cancer. Our findings indicate that high-dose re-irradiation might be beneficial in selected patients; however, patients and physicians should be aware of the scarcity of high-quality data when considering this treatment.
Introduction Radiotherapy has a major role in the radical treatment of patients with non-small-cell lung cancer (NSCLC),1 and advances in radiotherapy have resulted in improved local tumour control and long-term survival.1–4 These advances include stereotactic body radiotherapy (SBRT), the use of image-guided radiotherapy, and integration of molecular imaging to optimise dose distribution and delivery, four-dimensional CT scans, and high-quality radiotherapy delivery along with the integration of systemic treatments. The risk of patients developing local recurrence or a new primary tumour in previously irradiated areas increases as the prognosis of patients with NSCLC improves.1 However, owing to technological advances in radiotherapy and imaging, high-dose re-irradiation is now available to some of these patients, and could be used to improve long-term disease-free survival. The use of high-dose re-irradiation that overlaps with previously irradiated volumes is not without risks.5 Potentially serious and irreversible normal tissue damage might occur because of injury to blood vessels (large and small), bone, cartilage, and connective tissue. Radiation pneumonitis is a major risk after re-irradiation of lung tumours and severe fibrosis, fistula, and bleeding can also be noted as a result of the very high cumulative doses delivered to critical organs. Our understanding of the relation between the dose, volume, and late effects of irradiation has improved substantially in the past decade;6 however, radiation sensitivity varies greatly between tumours and normal tissues and between individuals, which might partly be explained by genetic differences.7–9 Furthermore, the tolerance of normal tissue in the context of re-irradiation is unknown. Preclinical data suggest some tissue repair takes place after primary irradiation, leading to the possibility of re-delivering high doses of irradiation without undue injury.10,11 Clinical experience suggested that high-dose re-irradiation is possible in selected patients, although this was mostly in head and neck, pelvic, brain, and breast cancers, and lethal bleeding has been reported.12–16 www.thelancet.com/oncology Vol 15 December 2014
Long-term local tumour control has been demonstrated, even in cases for which the tumour recurred in the same volume that was previously exposed to high-dose radiotherapy. There is growing interest in the use of re-irradiation in NSCLC. Despite radical radiotherapy, 20–44% of patients will have loco-regional progression at 2 years, and in cases of locoregional relapse, most tumours are not resectable.1 Systemic treatment is generally given with palliative intent in these cases, with less than 30% of patients achieving an objective response and a median overall survival of 10–12 months, which is similar to de-novo stage IV disease.17 These observations, along with our improved understanding of the importance of local control and its effect on survival in patients with NSCLC, make the concept of re-irradiation very attractive. The use of high-dose radiotherapy for second cancers in previously irradiated areas, a situation that can be seen in diseases such as Hodgkin’s lymphoma, will not be discussed within this Review. We summarised the available literature-based evidence to support the use of high-dose re-irradiation in patients with loco-regional NSCLC after high-dose primary irradiation, with or without systemic therapy. We then investigated the safety and efficacy of high-dose reirradiation, and whether we could identify patients most likely to benefit from this treatment.
Lancet Oncol 2014; 15: e620–24 Radiation Oncology, University Hospitals Leuven/KU Leuven, Leuven, Belgium (Prof D De Ruysscher MD, S Peeters MD); Radiation Related Research, The Christie NHS Foundation Trust and University of Manchester, Manchester, UK (C Faivre-Finn MD); Department of Radiation Oncology, Institut Gustave Roussy, Villejuif, France (C Le Pechoux MD); and Department of Radiation Oncology, Netherlands Cancer Institute, Amsterdam, Netherlands (J Belderbos MD) Correspondence to: Prof Dirk De Ruysscher, University Hospitals Leuven/KU Leuven, Radiation Oncology, Herestraat 49, 3000 Leuven, Belgium [email protected]
Identified studies We did a literature search to compile evidence from studies reporting on the efficacy and toxicity of high-dose re-irradiation. The search identified 24 studies, and ten were discarded as the radiation doses delivered were not curative. Of the 14 studies that fulfilled the criteria of this Review, 13 were retrospective studies and one was a small prospective study. We did not identify any randomised studies (table 1, table 2). 408 patients were reported on, and the number of patients included in the studies ranged from 12 to 72 patients. The median follow-up time was 16·5 months e620
Review
Mean reirradiation dose (Gy)
Toxic effects
Reason for exclusion
Green et al18
35
Palliative radiotherapy dose
Jackson et al19
30
Palliative radiotherapy dose
Montebello et al20
30
Palliative radiotherapy dose
Gressen et al21
30
Palliative radiotherapy dose
Kramer et al22
16
Palliative radiotherapy dose
Poltinnikov et al23
32
Palliative radiotherapy dose
Ebara et al24
40
Palliative radiotherapy dose
Cetingoz et al25
25
Palliative radiotherapy dose
Tada et al26
50
Only one patient treated with radical intent
Kruser et al27
30
Palliative radiotherapy dose
Table 1: Excluded studies
Number of patients
Median follow-up (months)
Initial dose*
Re-RT dose†
Type
Re-RT technique
Wu et al28
Prospective
3DCRT
13 (radical)
Okamoto et al29
Retrospective
3DCRT
18 (radical)
Peulen et al30‡
Retrospective
SABR
29
12
104 Gy§
104 Gy§
Coon et al31
Retrospective
SABR
12
12
Not stated
60 Gy in 3 fractions
Kelly et al32
Retrospective
SABR
36
15
15 Not stated
66 Gy conv
51 Gy conv
60 Gy conv
50 Gy conv
61·5 Gy conv
Evans et al33
Retrospective
SABR
35
42
54 Gy conv
Liu et al34
Retrospective
SABR
72
16
63 Gy conv
50 Gy in 4 fractions 60 Gy conv 50 Gy in 4 fractions
Meijneke et al35
Retrospective
SABR
20
12
McAvoy et al36
Retrospective
Protons
33
11
Reyngold et al37
Retrospective
SABR
39
12·6
61 Gy conv
70·4 Gy
Kilburn et al38
Retrospective
SABR/conv
34/3
17
60 Gy
50 Gy in 10 fractions
Yoshitake et al39
Retrospective
3DCRT
17
12·6
Trovo et al40
Retrospective
SABR
17
18
50–60 Gy conv
30 Gy in 5–6 fractions
Retrospective
3DCRT
24
19·3
59·8 Gy conv
60 Gy in 30 fractions
Griffioen et al
41
110 Gy§ 63 Gy conv
Not stated
87 Gy§ 66 Gy conv
60 Gy in 30 fractions
Re-RT=re-irradiation. 3DCRT=three-dimensionalradiotherapy. SABR=stereotactic ablative radiotherapy. Conv=conventional fractionation (ie, 1·8–2·0 Gy per fraction, 4–5 times per week; in ref. 24: 1·5–2·0 Gy). *Median radiotherapy dose for the initial primary treatment. †Median radiotherapy dose for the high-dose re-irradiation. ‡SABR for primary treatment and for recurrence. §Biological equivalent dose of 2 Gy per fraction for the tumour.
Table 2: Characteristics of included studies of high-dose re-irradiation
(2–37). The techniques of re-irradiation were 3D conformal radiotherapy, stereotactic ablative radiotherapy (SABR), combined 3D-conformal radiotherapy and SABR, and proton therapy (table 2). The mean initial radiation dose was approximately 70 Gy, although a wide range was reported. In most series, SABR was used for re-irradiation. We did not estimate biological doses in the individual studies because the reported technical details were not always sufficient to do this adequately. e621
Information on toxic effects is summarised in table 3. Owing to the retrospective nature of the studies, we expected under-reporting of less severe toxic effects (ie, grades 1–3), since there evidence that toxic effects of grade 3 and below are under-reported in retrospective studies. Therefore, only toxic effects of grade 3 or more will be discussed, although we compiled grade 1 and 2 toxicities when they were reported. Grade 3–4 lung toxic effects, mostly defined as radiation pneumonitis requiring oxygen (grade 3) or ventilator support (grade 4), was noted in 0–21% of patients (average of 7%). The incidence of severe lung toxic effects did not differ greatly in patients treated with conventional 3D conformal radiotherapy compared with patients treated with SABR. Grade 3 oesophagitis, which was defined as requiring tube or intravenous feeding, was noted in 0–9% of the patients, with a mean incidence of 2%. Grade 5 (ie, lethal) bleeding was reported in 12 of 408 patients (3%; range 0–12). Peulen and colleagues30 assessed the toxic effects of re-irradiation of 32 lung lesions (11 central lesions and 21 peripheral lesions) in 29 patients who were initially treated with SABR and re-irradiated with SABR. Toxic effects of grade 2 or higher was reported according to the location of the tumour, dose delivered, and volume of irradiation.30 Larger clinical target volumes and central tumour localisation were associated with more severe toxic effects. All toxic effects of grade 4 or higher were seen in patients with central tumours. Of the 11 patients with central tumours and treated with SABR after primary treatment with SABR, one patient had grade 4 superior vena cava stenosis and a grade 4 fistula, and three died because of massive bleeding. Grade 5 (ie, lethal) lung toxic effects was reported in two (0·5%) of 408 patients.
Prognostic factors of toxic effects Data for dose-volume histogram variables related to toxic effects of re-irradiation are scarce. Notably, most series did not use elastic deformation and therefore an accurate assessment of the cumulative radiation doses to the organs at risk is not possible. The incidence of lethal aortic bleeding was as high as 25% in some series. In one series,33 it was only noted in patients who received composite doses of 120 Gy or more to 1 cm³ of the aorta. In a series of 20 patients, it was reported that no severe toxic effects occurred when the cumulative V20 (the percentage of the lungs receiving ≥20 Gy) and maximum dose to the heart (115 Gy), trachea (89 Gy), and oesophagus (85 Gy, biologically corrected for an α/β value of 3 Gy) were less than 16%.35
Efficacy Data for median overall survival and time to disease progression are presented in table 4. The median time between radiotherapy for the primary NSCLC and www.thelancet.com/oncology Vol 15 December 2014
Review
re-irradiation was 23 months, and the median time to disease progression was 10 months. The mean overall survival was 17·7 months. Unfortunately, no data are available on symptom control with high-dose re-irradiation versus lower dose re-irradiation and palliative doses of radiotherapy. We found no data for quality of life. Second-line therapy, which could have affected overall survival, was not well documented in the published series.
Re-RT Grade 1–2 toxicity technique Wu et al28
3DCRT
Okamoto et al29 3DCRT
≥Grade 3 toxicity
G1+G2 lung (22%); None G1+G2 oesophagus (9%) G2 oesophagus (24%)
G3 lung (21%); G3 oesophagus (6%)
Peulen et al30
SABR
Coon et al31
SABR
Kelly et al32
SABR
Effects and safety of high-dose re-irradiation
Evans et al33
SABR
··
G5 bleeding (6%)
The prognosis of patients with NSCLC has improved substantially.1,17 As a result, more individuals present with local recurrences in areas that have been irradiated to high doses. Current radiotherapy techniques, including SABR, allow re-irradiation of these patients to high doses. However, the question remains: is high-dose re-irradiation beneficial for patients and does it improve survival without undue toxic effects? Unfortunately, high-quality data in this field are scarce, as shown by our systematic review of the medical literature that identified no randomised studies, one small prospective study,28 and 13 retrospective studies.29–41 High-dose re-irradiation results in median overall survival of about 17 months in selected patients, with median time to progression of about 10 months. A small proportion of patients could possibly even be cured with this approach, since there are a few patients without recurrence at follow-up.36 These results compare favourably to systemic treatment in stage IV NSCLC.17 However, in all published series, the time interval between the first radiotherapy course and high-dose re-irradiation was more than 12 months, with a mean of about 23 months. Allowing a treatment gap of more than a year before re-irradiation seems sensible since it will exclude patients with aggressive tumours who are likely to develop early distant metastases and will also allow for normal tissue repair. However, robust quantitative models for tissue repair are missing. Obviously, tissue repair is a major selection criterion that makes a fair comparison with systemic treatments difficult. Moreover, most series included patients treated with SABR, therefore selecting patients with tumours without detectable nodal or metastatic disease who are amenable to this treatment. Furthermore, time to progression was measured differently across the series, and recurrences were not always documented with pathology. Post-radiation fibrosis might mimic tumour recurrence and FDG avidity might be due to non-malignant inflammatory processes.2,3 Severe (grade 3–4) toxic effects were noted in a low proportion (6%) of patients. Grade 3–4 lung toxic effects occurred in 10% of patients. This percentage is lower than the incidence of severe lung toxic effects reported in patients with stage III NSCLC treated with chemoradiotherapy (15–20%), but higher than the incidence (20 years). Although no data are available about the use of ¹⁸F-FDG PET/CT scans to define target volumes, it seems logical to re-irradiate with a high level of geometrical accuracy to reduce the margins around the recurrent tumour volume and to keep the volume of the surrounding normal tissues as low as possible. Special care must be given to organ motion, and variations in delineation and patient set-up. Image-guided radiotherapy would be useful in this context. When assessing the toxic effects of high-dose re-irradiation, issues regarding its reporting must be considered. First, the retrospective nature of 13 out of 14 studies could have resulted in the underreporting of toxic effects (especially for grade 1 and 2 toxic effects that did not result in hospital admission). Furthermore, the grading of toxic effects was not standardised, with different scoring systems used. Second, with a median follow-up of about 16 months, some late toxic effects could have not yet been identified. Third, treatment-related deaths might have been underestimated in the studies since patients generally die at home or at their local hospital with death often being classified as lung cancer death. Finally, it should be noted that only crude toxicity rates are available from these studies rather than actuarial toxicity rates. The correlation between dose-volume and toxic effects after high-dose re-irradiation is not well defined by contrast with the primary treatment setting. Several factors contribute to these uncertainties, including a scarcity of prospective data and standardised toxicity scoring, a short follow-up, the effect of second-line systemic treatment, and the absence of cumulative dose–volume histograms. In the future, genetic e623
information and detailed data for tissue characteristics such as perfusion and hypoxia could identify individuals that can safely be re-treated.7–9 The results of high-dose re-irradiation should be placed in the context of palliative re-irradiation after previous radical intent radiotherapy. Following palliative re-irradiation, median survival is only about 5 months.18–24 Overall, symptom control (eg, haemoptysis, cough, chest pain, and dyspnoea) is achieved in more than 60% of patients after palliative re-irradiation. In the absence of randomised studies, firm conclusions cannot be drawn, but high-dose re-irradiation may have at least similar symptom control and higher survival than palliative re-irradiation.18–26 Prospective high-quality trials are needed for the field of high-dose re-irradiation to progress. In the meantime, carefully selected patients could be offered high-dose re-irradiation as long as they are informed of the little data available and the potential risk of toxic effects. Contributors DR had the idea for the paper and conducted the data analysis. DR, CF-F, CLP, and SP conducted the literature search and drafted the manuscript. DR and JB interpreted the data. Declaration of interests We declare that we have no competing interests. References 1 Vansteenkiste J, De Ruysscher D, Eberhardt WE, et al, and the ESMO Guidelines Working Group. Early and locally advanced non-small-cell lung cancer (NSCLC): ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol 2013; 24: vi89–98. 2 De Ruysscher D, Belderbos J, Reymen B, et al. State of the art radiation therapy for lung cancer 2012: a glimpse of the future. Clin Lung Cancer 2013; 14: 89–95. 3 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. 4 van Meerbeeck JP, Fennell DA, De Ruysscher DK. Small-cell lung cancer. Lancet 2011; 378: 1741–55. 5 Moding EJ, Kastan MB, Kirsch DG. Strategies for optimizing the response of cancer and normal tissues to radiation. Nat Rev Drug Discov 2013; 12: 526–42. 6 Marks LB, Bentzen SM, Deasy JO, et al. Radiation dose–volume effects in the lung. Int J Radiat Oncol Biol Phys 2010; 76: S70–76. 7 Kerns SL, De Ruysscher D, Andreassen CN, et al. STROGAR – STrengthening the Reporting Of Genetic Association studies in Radiogenomics. Radiother Oncol 2014; 110: 182–88. 8 Andreassen CN, Barnett GC, Langendijk JA, et al. Conducting radiogenomic research – do not forget careful consideration of the clinical data. Radiother Oncol 2012; 105: 337–40. 9 Barnett GC, Coles CE, Elliott RM, et al. Independent validation of genes and polymorphisms reported to be associated with radiation toxicity: a prospective analysis study. Lancet Oncol 2012; 13: 65–77. 10 Ang KK, Jiang GL, Feng Y, Stephens LC, Tucker SL, Price RE. Extent and kinetics of recovery of occult spinal cord injury. Int J Radiat Oncol Biol Phys 2001; 50: 1013–20. 11 Nieder C, Milas L, Ang KK. Tissue tolerance to reirradiation. Semin Radiat Oncol 2000; 10: 200–09. 12 Tortochaux J, Tao Y, Tournay E, et al. Randomized phase III trial (GORTEC 9803) comparing re-irradiation plus chemotherapy versus methotrexate in patients with recurrent or a second primary head and neck squamous cell carcinoma, treated with a palliative intent. Radiother Oncol 2011; 100: 70–75. 13 Abusaris H, Hoogeman M, Nuyttens JJ. Re-irradiation: outcome, cumulative dose and toxicity in patients retreated with stereotactic radiotherapy in the abdominal or pelvic region. Technol Cancer Res Treat 2012; 11: 591–97.
www.thelancet.com/oncology Vol 15 December 2014
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14
15
16
17
18 19 20
21
22
23
24
25
26
27
28
Linthorst M, van Geel AN, Baaijens M, et al. Re-irradiation and hyperthermia after surgery for recurrent breast cancer. Radiother Oncol 2013; 109: 188–93. Scharp M, Hauswald H, Bischof M, Debus J, Combs SE. Reirradiation in the treatment of patients with cerebral metastases of solid tumors: retrospective analysis. Radiat Oncol 2014; 9: 4. Combs SE, Edler L, Rausch R, Welzel T, Wick W, Debus J. Generation and validation of a prognostic score to predict outcome after re-irradiation of recurrent glioma. Acta Oncol 2013; 52: 147–52. Peters S, Adjei AA, Gridelli C, Reck M, Kerr K, Felip E, and the ESMO Guidelines Working Group. Metastatic non-small-cell lung cancer (NSCLC): ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol 2012; 23: vii56–64. Green N, Melbye RW. Lung cancer: retreatment of local recurrence after definitive irradiation. Cancer 1982; 49: 865–68. Jackson MA, Ball DL. Palliative retreatment of locally-recurrent lung cancer after radical radiotherapy. Med J Aust 1987; 147: 391–94. Montebello JF, Aron BS, Manatunga AK, Horvath JL, Peyton FW. The reirradiation of recurrent bronchogenic carcinoma with external beam irradiation. Am J Clin Oncol 1993; 16: 482–88. Gressen EL, Werner-Wasik M, Cohn J, Topham A, Curran WJ Jr. Thoracic reirradiation for symptomatic relief after prior radiotherapeutic management for lung cancer. Am J Clin Oncol 2000; 23: 160–63. Kramer GWPM, Gans S, Ullmann E, van Meerbeeck JP, Legrand CC, Leer JW. Hypofractionated external beam radiotherapy as retreatment for symptomatic non-small-cell lung carcinoma: an effective treatment? Int J Radiat Oncol Biol Phys 2004; 58: 1388–93. Poltinnikov IM, Fallon K, Xiao Y, Reiff JE, Curran WJ Jr, Werner-Wasik M. Combination of longitudinal and circumferential three-dimensional esophageal dose distribution predicts acute esophagitis in hypofractionated reirradiation of patients with nonsmall-cell lung cancer treated in stereotactic body frame. Int J Radiat Oncol Biol Phys 2005; 62: 652–58. Ebara T, Tanio N, Etoh T, Shichi I, Honda A, Nakajima N. Palliative re-irradiation for in-field recurrence after definitive radiotherapy in patients with primary lung cancer. Anticancer Res 2007; 27: 531–34. Cetingoz R, Arican-Alicikus Z, Nur-Demiral A, Durmak-Isman B, Bakis-Altas B, Kinay M. Is re-irradiation effective in symptomatic local recurrence of non small cell lung cancer patients? A single institution experience and review of the literature. J BUON 2009; 14: 33–40. Tada T, Fukuda H, Matsui K, et al. Non-small-cell lung cancer: reirradiation for loco-regional relapse previously treated with radiation therapy. Int J Clin Oncol 2005; 10: 247–50. Kruser TJ, McCabe BP, Mehta MP, et al. Reirradiation for locoregionally recurrent lung cancer: outcomes in small cell and non-small cell lung carcinoma. Am J Clin Oncol 2014; 37: 70–76. Wu K-L, Jiang G-L, Qian H, et al. Three-dimensional conformal radiotherapy for locoregionally recurrent lung carcinoma after external beam irradiation: a prospective phase I–II clinical trial. Int J Radiat Oncol Biol Phys 2003; 57: 1345–50.
www.thelancet.com/oncology Vol 15 December 2014
29
30
31
32
33 34
35
36
37
38
39
40
41
42
Okamoto Y, Murakami M, Yoden E, et al. Reirradiation for locally recurrent lung cancer previously treated with radiation therapy. Int J Radiat Oncol Biol Phys 2002; 52: 390–96. Peulen H, Karlsson K, Lindberg K, et al. Toxicity after reirradiation of pulmonary tumours with stereotactic body radiotherapy. Radiother Oncol 2011; 101: 260–66. Coon D, Gokhale AS, Burton SA, Heron DE, Ozhasoglu C, Christie N. Fractionated stereotactic body radiation therapy in the treatment of primary, recurrent, and metastatic lung tumors: the role of positron emission tomography/computed tomography-based treatment planning. Clin Lung Cancer 2008; 9: 217–21. Kelly P, Balter PA, Rebueno N, et al. Stereotactic body radiation therapy for patients with lung cancer previously treated with thoracic radiation. Int J Radiat Oncol Biol Phys 2010; 78: 1387–93. Evans JD, Gomez DR, Amini A, et al. Aortic dose constraints when reirradiating thoracic tumors. Radiother Oncol 2013; 106: 327–32. Liu H, Zhang X, Vinogradskiy YY, Swisher SG, Komaki R, Chang JY. Predicting radiation pneumonitis after stereotactic ablative radiation therapy in patients previously treated with conventional thoracic radiation therapy. Int J Radiat Oncol Biol Phys 2012; 84: 1017–23. Meijneke TR, Petit SF, Wentzler D, Hoogeman M, Nuyttens JJ. Reirradiation and stereotactic radiotherapy for tumors in the lung: dose summation and toxicity. Radiother Oncol 2013; 107: 423–27. McAvoy SA, Ciura KT, Rineer JM, et al. Feasibility of proton beam therapy for reirradiation of locoregionally recurrent non-small cell lung cancer. Radiother Oncol 2013; 109: 38–44. Reyngold M, Wu AJ, McLane A, et al. Toxicity and outcomes of thoracic re-irradiation using stereotactic body radiation therapy (SBRT). Radiat Oncol 2013; 8: 99. Kilburn JM, Kuremsky JG, Blackstock AW, et al. Thoracic reirradiation using stereotactic body radiotherapy (SBRT) techniques as first or second course of treatment. Radiother Oncol 2014; 110: 505–10. Yoshitake T, Shioyama Y, Nakamura K, et al. Definitive fractionated re-irradiation for local recurrence following stereotactic body radiotherapy for primary lung cancer. Anticancer Res 2013; 33: 5649–53. Trovo M, Minatel E, Durofil E, et al. Stereotactic body radiation therapy for re-irradiation of persistent or recurrent non-small cell lung cancer. Int J Radiat Oncol Biol Phys 2014; 88: 1114–19. Griffioen GH, Dahele M, de Haan PF, van de Ven PM, Slotman BJ, Senan S. High-dose, conventionally fractionated thoracic reirradiation for lung tumors. Lung Cancer 2014; 83: 356–62. Senthi S, Lagerwaard FJ, Haasbeek CJ, Slotman BJ, Senan S. Patterns of disease recurrence after stereotactic ablative radiotherapy for early stage non-small-cell lung cancer: a retrospective analysis. Lancet Oncol 2012; 13: 802–09.
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