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Salvage surgery for locoregional recurrence or persistent tumor after high dose chemoradiotherapy for locally advanced non-small cell lung cancer
Lung Cancer 94 (2016) 108–113
Contents lists available at ScienceDirect
Lung Cancer journal homepage: www.elsevier.com/locate/lungcan
Salvage surgery for locoregional recurrence or persistent tumor after high dose chemoradiotherapy for locally advanced non-small cell lung cancer C. Dickhoff a,b,∗ , M. Dahele c , M.A. Paul b , P.M. van de Ven d , A.J. de Langen e , S. Senan c , E.F. Smit f , K.J. Hartemink g a
Department of Surgery, VU University Medical Center, P.O. Box 7057, 1007 MB Amsterdam, The Netherlands Department of Cardiothoracic Surgery, VU University Medical Center, P.O. Box 7057, 1007 MB Amsterdam, The Netherlands c Department of Radiation Oncology VU University Medical Center, P.O. Box 7057, 1007 MB Amsterdam, The Netherlands d Department of Epidemiology and Biostatistics, VU University Medical Center, P.O. Box 7057, 1007 MB Amsterdam, The Netherlands e Department of Pulmonary Diseases, VU University Medical Center, P.O. Box 7057, 1007 MB Amsterdam, The Netherlands f Department of Pulmonary Diseases, Netherlands Cancer Institute—Antoni van Leeuwenhoek Hospital, P.O. Box 90203, 1006 BE Amsterdam, The Netherlands g Department of Surgery, Netherlands Cancer Institute—Antoni van Leeuwenhoek Hospital, P.O. Box 90203, 1006 BE Amsterdam, The Netherlands b
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Article history: Received 28 December 2015 Received in revised form 31 January 2016 Accepted 6 February 2016 Keywords: Salvage surgery Non-small cell lung cancer Chemoradiotherapy Locoregional recurrence Survival
a b s t r a c t Objectives: Curative intent treatment options for locoregional recurrence or persistent tumor after radical chemoradiotherapy for locally-advanced non-small cell lung cancer (NSCLC) are limited. In selected patients, surgery can be technically feasible, although it is widely believed to be hazardous. As data regarding the outcome of this approach is sparse, we evaluated our institutional experience with salvage surgery. Materials and methods: Patients with a pulmonary resection for in-field locoregional recurrence or persistent tumor after high dose chemoradiotherapy (≥60 Gy) for the treatment of non-small cell lung cancer, were identified and retrospectively analyzed. Results: A total of 15 patients treated between January 2007 and August 2015 were eligible for evaluation. In 13 patients (87%), the indication for surgery was a locoregional recurrence, while 2 patients had persistent tumor. The prior median radiotherapy dose was 66 Gy (range 60–70). All patients underwent an anatomical resection, with 8 patients having a pneumonectomy, and all pathological specimens revealed the presence of viable tumor. The in-hospital morbidity rate was 40% (6 patients), and the 90-day mortality rate was 6.7% (1 patient). Median follow-up was 12.1 months. The estimated median overall and event-free survivals were 46 months and 43.6 months, respectively. Conclusion: Salvage surgery for locoregional recurrence or persistent tumor after high dose chemoradiotherapy, resulted in acceptable morbidity, mortality and promising outcome. It should be considered as a treatment option for selected patients. © 2016 Elsevier Ireland Ltd. All rights reserved.
1. Introduction The recommended treatment for fit patients with locally advanced non-small cell lung cancer (NSCLC) is a combination of chemotherapy and radiotherapy [1–3]. A median survival of 28.7 months has recently been reported for selected patients treated with concurrent chemoradiotherapy [4]. However, there was a local
∗ Corresponding author at: VU University Medical Center, Department of Surgery and Cardiothoracic Surgery, De Boelelaan 1117, 1081 HV Amsterdam, The Netherlands. E-mail address: [email protected] (C. Dickhoff). http://dx.doi.org/10.1016/j.lungcan.2016.02.005 0169-5002/© 2016 Elsevier Ireland Ltd. All rights reserved.
failure rate of 39% at 2 years in a sub-group of protocol compliant patients [4]. Once locoregional recurrence or persistent tumor is diagnosed after chemoradiotherapy, curative intent treatment options are limited and therapy is often palliative. However, selected patients might be candidates for radical re-irradiation or resection. Due to fibrosis as a result of the interval between chemoradiotherapy and surgery, so-called salvage resections are technically demanding, and associated with higher risks. There are relatively few reports presenting outcome data after salvage surgery following chemoradiotherapy [5–8], and a lack of a uniform definition has hampered proper comparison of outcome
C. Dickhoff et al. / Lung Cancer 94 (2016) 108–113
data. We audited our institutional experience with salvage surgery, defined as a pulmonary resection for locoregional recurrence or persistent tumor in the previously irradiated area, ≥12 weeks after the last day of curative intent high dose (>60 Gy) chemoradiotherapy. 2. Material and methods This retrospective cohort analysis was conducted with Institutional Review Board approval. Patients who underwent salvage pulmonary resection at the VU University medical center between January 2007 and August 2015, after prior curative intent chemoradiotherapy for primary NSCLC, were identified. Before planning surgery, patients had been discussed in our weekly institutional multidisciplinary tumor board (MTB) consisting of surgeons, pulmonary oncologists, radiation oncologists, radiologists, nuclear medicine specialists and pathologists. MTB decisions are based on the patient’s physical and medical status, as well as radiological and pathological findings. Patients were considered candidates for salvage surgery when physical status and objective cardiopulmonary function (e.g. lung function tests, exercise testing, cardiac evaluation) were sufficient to undergo surgical resection and, radiological and endobronchial findings showed that complete resection of all suspicious/proven disease was technically feasible. The absence of pathological confirmation of viable tumor was not a strict exclusion criteria, since percutaneous post-chemoradiotherapy pathology may be unreliable with lower sensitivity and negative predictive value [5]. Patients were excluded from the present analysis if they had 1) surgery as part of a planned trimodality protocol, 2) surgery for complications of definitive chemoradiotherapy, 3) prior single modality treatment, 4) histology other than NSCLC, and 5) stage IV disease prior to chemoradiotherapy. Salvage surgery was defined as a pulmonary resection for locoregional recurrence or persistent tumor in the previously irradiated area, ≥12 weeks after the last day of curative intent high dose (>60 Gy) chemoradiotherapy for the treatment of NSCLC. Data was retrieved from our institutional database and individual patient records, including age, sex, comorbidity, physical status, stage of the index tumor, prior treatment and staging modalities. If data were missing, the patient’s general practitioner or referring hospital were contacted. As the 7th edition of the TNM classification for lung cancer replaced the 6th edition during the study period, both the index tumor and the locoregional recurrence or persistent tumor of all patients was re-staged using the 7th edition. Surgical factors that were evaluated included the type of resection, lymph node dissection, complications, length of intensive care unit (ICU) and in-hospital stay and pathology. The date of surgery was used for survival measures. During follow-up, a CT-scan was routinely performed every 3 months in the first year, every 6 months in the 2nd and 3rd year and thereafter every year, or more frequent when there was clinical suspicion of disease progression. Statistical analyses were performed using the SPSS software package (SPSS, version 20, SPSS Inc, Chicago, IL, USA). Median follow-up times were estimated using the inverse Kaplan-Meier method. Overall survival (OS) and event free survival (EFS) distributions were analyzed using Kaplan-Meier analyses. For event free survival we considered the following events: death from any cause, locoregional recurrence or progression of disease. 3. Results Between January 2007 and August 2015, a total of 183 patients underwent pulmonary resection at our institution after chemoradiotherapy. In total, 21/183 patients were not included in a trimodality protocol, and were operated on more than 12 weeks
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after the last day of high dose chemoradiotherapy, for either locoregional recurrence or persistent tumor within the irradiated area. Four patients had a pathological diagnosis of small cell lung cancer, 1 patient had previous resection and a recurrence treated with chemotherapy with low-dose radiotherapy (30 Gy) and 1 patient had stage IV disease based on a solitary brain metastasis developed during initial treatment, leaving 15 patients eligible for analysis. Between 2007 and 2012, 1 or 2 operations were performed per year for this indication, increasing to 3 in 2014, and 5 in the first 8 months of 2015. The majority of patients (12/15) had their primary treatment with chemoradiotherapy in other hospitals and were referred to our center after being diagnosed with locoregional recurrence or persistent tumor. Detailed patient characteristics are presented in Table 1. The median age at the time of chemoradiotherapy was 59 years (range 41–70) and 73% of patients were male. Median bodymass-index (BMI) was 25.7 (range 20.6–32.8), and median FEV1 was 78% of predicted (range 59–138%). Median Charlson comorbidity score was 4 (range 2–6). Before starting their initial treatment with chemoradiotherapy, 10 patients were staged as IIIA, and 5 patients as IIIB (according to the 7th edition of the TNM), and 10/12 patients with clinical suspicion of mediastinal/supraclavicular nodal involvement had pathologically proven N2 or N3 disease. The median radiotherapy dose was 66 Gy (range 60–70); 80% of patients had concurrent chemotherapy, and 20% sequential. In the majority of patients (n = 13; 87%), the reason for salvage surgery was locoregional recurrence and the remaining 2 patients had persistent tumor. One of the latter had persistent disease after definitive chemoradiotherapy, and was subsequently treated with erlotinib resulting in stable disease, before a decision was made to perform salvage surgery. The other patient had a high suspicion of persistent tumor on follow-up CT and subsequent metabolic imaging soon after finishing curative intent chemoradiotherapy. Before surgery, all patients were staged with a fluorodeoxyglucose (FDG) PET-CT scan to confirm the absence of distant metastases, and 13 patients had a preoperative MRI or CT-scan of the brain, which was negative in all cases. Preoperative confirmation of disease was attempted in 11 of the 15 patients and confirmed in 9 patients. PET-CT identified possible involvement of N2 nodes in 2 patients. Three patients had invasive mediastinal staging with mediastinoscopy (n = 1), esophageal ultrasound (n = 1) or endobronchial ultrasound (n = 1) because of clinical suspicion of N2 involvement (n = 2) or central localization of the recurrent tumor (n = 1). One patient had unforeseen N2-disease on postoperative pathological examination and in one patient an invasive diagnostic mediastinal intervention was omitted because of high suspicion of persistent N2 nodal involvement on PET-CT. The clinical stage of the locoregional recurrence or persistent tumor was IA in 1, IB in 9, IIB in 3 and IIIA in 2 patients. Of the patients with IIIA The median time between the last day of radiotherapy and surgery was 21 months (range 3–95). Surgical data are summarized in Table 2. All patients underwent an anatomical surgical resection consisting of a segmentectomy in 1, lobectomy in 4, bilobectomy in 2 and pneumonectomy in 8 patients (right sided 3/8). The resection was extended with an additional parenchymal resection (e.g. en-bloc wedge resection) in 4 patients. One patient had a superior sulcus tumor and underwent a chest wall resection. Six patients had an intrapericardial dissection of the central structures due to extensive fibrosis of the hilum or because of centrally located tumor. The median number of lymph node stations that were dissected and submitted for pathological examination was 4 (range 1–8). Median duration of surgery was 225 min (range 124–387). In all patients, pathological examination of the resected specimen revealed the presence of tumor. This was invading the resection margin (R1 resection) in 2 patients. Median
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C. Dickhoff et al. / Lung Cancer 94 (2016) 108–113
Fig. 1. Kaplan-Meier estimates for overall survival (OS) of patients treated with salvage surgery.
Table 1 Patient, tumor and treatment characteristics of patients treated with salvage surgery between 2007 and 2015. Patient
Year of resection
Sex
Age at treatment of index tumor
CCI
cTNM
Histology
Radiation dose (Gy)
Reason for salvage surgery
Time last RT to surgery (months)
Attempted PA/PAproven
Pre-salvage mediastinal evaluation (Naruke station)
r-cTNM
r-pTNM
1 2 3
2007 2007 2008
m m f
49 51 56
2 3 3
T4N0sst T4N2 T1N3
scc scc adeno
60* 60 60
PD R R
29 48 13
−/− +/+ +/+
T3N0 T2bN0 T2aN0
T2bN0 T3N1 T1bN0
4 5 6 7 8 9 10 11 12 13 14 15
2009 2010 2012 2012 2014 2014 2014 2015 2015 2015 2015 2015
f m m f f m m m m m m m
41 64 53 43 70 60 56 60 64 60 59 69
2 5 6 3 6 6 3 5 4 4 3 5
T2aN2 T2N3 T2aN2 T2N2 T3N2 T2N2 T2bN2 T4N0 T4N2 T4N0 T2bN3 T3N2
adeno NSCLC adeno NSCLC adeno scc adeno scc scc adeno scc adeno
66 60 66 66* 70* 66 66 66 66 66 66 66
R R R R R R PD R R R R R
22 95 15 75 22 20 3 21 11 38 11 7
−/− +/− +/− +/+ −/− +/+ −/− +/+ +/+ +/+ +/+ +/+
no no Mediastinoscopy (4R, 4L, 7, 2R) no no no no no EUS (7) no EBUS (4R) no no no no
T2aN0 T2aN0 T2aN0 T4N0 T1bN0 T2aN0 T2aN2 T2aN0 T3N0 T3N0 T2aN0 T2aN0
T2aN0 T4N2 T1bN0 T3N0 T2aN0 T2bN0 T2aN2 T2aN0 T3N0 T3N0 T2aN0 T2aN0
m = male, f = female, CCI = Charlson comorbidity Index, c-TNM = clinical TNM stage of index tumor, sst = superior sulcus tumor, EBUS = endobronchial ultrasound, EUS = esophageal ultrasound, RT = radiotherapy, * = sequential, PD = persistent disease, R = recurrence, PA = pathology, r-cTNM = recurrence-clinical TNM, r-pTNM = recurrencepathological TNM.
length of stay on the ICU was 1 day (range 0–4) and median total in-hospital stay was 7 days (range 5–12). Complications were encountered in 6 patients (in hospital morbidity rate: 40%), with 2 events requiring re-thoracotomy, both
after a left-sided pneumonectomy. One patient had an empyema and was re-operated on 4 weeks after resection. The second patient, who underwent an intrapericardial resection of the left lung, developed severe arrhythmias with acute hypotension immediately after
Table 2 Surgical details, morbidity and survival of patients treated with salvage pulmonary resection. Bronchial stump Separate dissected In-hospital cover LN-stations (+ complication indicates positive)
Reintervention ICU/MCU stay (days) <30 days
Hospital stay (days)
Resection margin
Survival Local (LF) or (months) distant progression (DP) after surgery
1
L+W+T
245
+
pericard
5,7,8,10,11
–
–
1
5
R0
–
≥96
2 3 4 5 6 7 8 9 10 11 12 13 14 15
RP BL RP LP L LP S+W LP L+S RP BL LP L+W LP
387 200 174 164 124 142 226 298 219 355 338 225 272 214
+ − − + − − − + − + − + − −
omentum IMF diaphragm IMF IMF pericard pericard ASM IMF ASM IMF IMF IMF IMF
7, 10(+) 4,7,8,10,11,12 4,7,8,9,10 4,5(+), 6,7,9 4,7,8,11 4,5,7,9,10,11 5 4,7 4(+),5,6,7,8,9,10,11 4,7 4,7,11 9,10 2,4,10 5,6,7,10,11
– – – luxation heart pneumonia – – – – FUO FUO atrial flutter – empyema
– – – thoracotomy antibiotics – – – – antibiotics – – – thoracotomy
2 0 1 4 1 1 2 0 0 4 0 1 0 0
7 7 10 5 7 7 6 8 8 12 9 7 6 6
R1 R0 R0 R1 R0 R0 R0 R0 R0 R0 R0 R0 R0 R0
LF, DP – DP – – DP – – – – – – – –
22a ≥90 46a 0b ≥37 5a ≥19 ≥12 ≥11 ≥8 ≥6 ≥4 ≥3 ≥2
ribs 1–4, phrenic nerve, pulmonary artery – – – – – – – – recurrent nerve – – – – –
C. Dickhoff et al. / Lung Cancer 94 (2016) 108–113
Operating time Intrapericardial Additional Patient Type of resection (mins) dissection resection
RP = right pneumonectomy, LP = left pneumonectomy, BL = bilobectomy, L = lobectomy, S = segmentectomy, W = wedge resection, T = thoracic wall resection, IMF = pedicled intercostal muscleflap, ASM = anterior serratus muscle, FUO = fever of unknown origin, ICU = intensive care unit, MCU = medium care unit. a Died of disease progression. b Died of ARDS 6 days after surgery.
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C. Dickhoff et al. / Lung Cancer 94 (2016) 108–113
Fig. 2. Kaplan-Meier estimates for event-free survival (EFS) of patients treated with salvage surgery.
closure of the thorax. After prompt re-thoracotomy, the heart was found to be herniated through the pericardium. The heart was replaced in its anatomical position, the pericardial defect was closed, and after cardioversion, there was normal sinus rhythm and blood pressure recovered. Unfortunately, this patient died 4 days after surgery because of acute respiratory distress syndrome (ARDS). This case represents the only patient who died within 90 days of surgery (90-day mortality rate: 6.7%). No patient received adjuvant therapy. One patient with N2 disease died in the perioperative period (Patient 5, Tables 1 and 2). One patient with N1 disease (patient 2) and one patient with N2 disease (patient 10) underwent close follow-up. Median follow-up was 12.1 months (95% CI: 0–27.1) and estimated median overall and event-free survival was 46 months and 43.6 months respectively (Figs. 1 and 2).
4. Discussion In this highly selected group of patients undergoing salvage surgery for recurrent or persistent tumor after high dose chemoradiotherapy for NSCLC, we have shown that surgery can be performed with acceptable risks and encouraging survival can be achieved. Although the study is retrospective, the cohort is homogeneous in terms of prior treatment, pathology, and indication for surgery. All patients received prior high-dose chemoradiotherapy (minimum dose 60 Gy), were staged with PET-CT+/− invasive medi-
astinal intervention and an MRI of the brain, and had viable tumor in the resected specimen. Furthermore, when compared to other reports [5,6], the median interval between chemoradiotherapy and salvage surgery was considerable, indicating that resections were truly salvage and not part of a (delayed) trimodality approach. This is also a contemporary series, with all surgery carried out in one large tertiary referral thoracic oncology center over the last decade. Based on our limited data, it appears that patients whose disease can be removed with a lobectomy have a good prognosis. Despite the fact that all patients who were deceased at the time of the current analysis had undergone a pneumonectomy, appreciable survival can be still be achieved in this group. This is illustrated by two patients who lived for 22 and 46 months, even after an incomplete (R1) resection. We acknowledge that our overall follow-up is relatively short, and longer follow-up could identify additional data to help guide patient selection, including the optimal selection of patients for pneumonectomy. Despite the large number of pneumonectomies in a group treated with prior high dose chemoradiotherapy, no patients developed a postoperative bronchopleural fistula. This might be attributable to the strict application of vascularized flaps for bronchial stump coverage. In addition, the incidence of postoperative empyema was low, which might be at least partly explained by our routine application of intravenous antibiotics during the first 5 days after surgery. The evidence regarding salvage surgery remains limited: a recent review identified 4 studies, with a total of only 47 patients, and of these 2 studies (9 patients) were related to salvage surgery
C. Dickhoff et al. / Lung Cancer 94 (2016) 108–113
after prior stereotactic body radiotherapy (SBRT), which is a different clinical scenario (for example, the mediastinum is typically not irradiated to a significant dose with lung SBRT) [9]. Furthermore, there is currently no uniform definition of salvage surgery. In our study we used a definition pulmonary resection of locoregional recurrence or persistent tumor in the irradiated area, ≥12 weeks after radical chemoradiotherapy (≥60 Gy) for NSCLC. Bauman et al. reported on 24 patients who underwent resection for evidence of treatment failure after high dose of radiotherapy (>59 Gy), with or without chemotherapy [5]. However, the interval between the end of radiotherapy and surgery was variable, with the shortest being 5.4 weeks and their median time from radiotherapy to surgery was 21 weeks (compared with 21 months in our cohort). Furthermore, Bauman et al. reported on a more heterogeneous patient group which included 1 patient with bronchopleural fistula, and 4 were treated in a trimodality protocol. In addition, only 79% of their operated patients had malignancy confirmed in the resection specimen. Uramoto and Tanaka reported on salvage thoracic operations for 8 patients, but their cohort is heterogeneous and included patients with stage IV disease [7]. Kuzmik et al. analyzed outcomes for 14 patients undergoing resection for recurrence after definitive chemoradiotherapy. However, they included patients treated with radiotherapy doses as low as 30 Gy (median 57 Gy), patients with SCLC as the index tumor, and nearly 50% of patients received a resection for a non-local recurrence (including in a contralateral lobe) [8]. The report on salvage surgery for NSCLC by Yang et al. described 31 patients who were operated at a median of 17.7 weeks after chemoradiotherapy to a median dose of 60 Gy [6]. However, all decisions to proceed to surgery were based solely on imaging with the final pathological examination of the resected specimen revealing no vital tumor in nearly 40% (12/31) of patients. Their patients with a pathological complete response had a significantly better survival than those without, and no patients underwent pneumonectomy, in comparison with 8/15 in our study. The features of the abovementioned studies must be taken into account when studies are compared. A number of potential alternative interventions and specific considerations are relevant to MTB discussions for patients with recurrent or persistent loco-regional disease. High-dose thoracic re-irradiation has been used in selected patients. We have previously reported our institutional results with re-irradiation in this setting [10] and found it to be technically feasible with a median overall survival of 13.5 months. However, we have observed a considerable rate of fatal bleeding (to which tumor and treatment related factors may be contributing) in patients who have high dose overlap of the first and second radiation courses in the hilar/central regions. In a study by McAvoy et al. [11], median survival after re-irradiation was 14.7 months (range 10.3–20.6) with grade ≥3 esophageal toxicity of 7% and grade ≥3 pulmonary toxicity of 10%. Both groups found smaller tumors to be associated with better survival. Another treatment approach is palliative chemotherapy, although it has been observed that response rates to carboplatingemcitabine chemotherapy in patients with recurrent NSCLC who had been formerly treated with platinum-based chemoradiotherapy were low (10%) [12], and this cannot be considered a curative intent treatment option. 5. Conclusion We report that selected patients with locoregional recurrence or persistent tumor after high dose chemoradiotherapy, can undergo
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salvage surgery with acceptable morbidity and mortality, even when a pneumonectomy is required. Factors that might have contributed to these favorable results include adequate pre-operative staging, ability to obtain an R0 resection and a good performance status. Medically operable patients presenting with (high suspicion of) locoregional recurrence or persistent tumor after definitive chemoradiotherapy for NSCLC, should have all treatment options reviewed in an experienced MTB. Conflicts of interest For this research, there were no study sponsors in the study design, in the collection, analysis and interpretation of data, in the writing of the manuscript, and in the decision to submit the manuscript for publication. Dr. Dahele reports grants from Varian Medical Systems, personal fees from Varian Medical Systems, personal fees from Lilly, outside the submitted work. Dr. Senan reports grants and non-financial support from Varian Medical Systems, outside the submitted work. References [1] W.E. Eberhardt, D. De Ruysscher, W. Weder, C. Le Péchoux, P. De Leyn, H. Hoffmann, et al., Panel members. 2nd ESMO consensus conference in lung cancer: locally-advanced stage III non-small-cell lung cancer, Ann. Oncol. 26 (2015) 1573–1588. [2] B.D. Kozower, J.M. Larner, F.C. Detterbeck, D.R. Jones, Special treatment issues in non-small cell lung cancer: diagnosis and management of lung cancer, 3rd ed: American College of Chest Physicians evidence-based clinical practice guidelines, Chest 143 (2013) e369S–e399S. [3] N. O’Rourke, I. Roqué, M. Figuls, N. Farré Bernadó, F. Macbeth, Concurrent chemoradiotherapy in non-small cell lung cancer, Cochrane Database Syst. Rev. 16 (2010) CD002140. [4] 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 phase 3 study, Lancet Oncol. 16 (2015) 187–199. [5] J.E. Bauman, M.S. Mulligan, R.G. Martins, B.F. Kurland, K.D. Eaton, D.E. Wood, Salvage lung resection after definitive radiation (>59 Gy) for non-small cell lung cancer: surgical and oncologic outcomes, Ann. Thorac. Surg. 86 (2008) 1632–1638. [6] C.F. Yang, R.R. Meyerhoff, S.J. Stephens, T. Singhapricha, C.B. Toomey, K.L. Anderson, et al., Long-Term outcomes of lobectomy for non-Small cell lung cancer after definitive radiation treatment, Ann. Thorac. Surg. 99 (2015) 1914–1920. [7] H. Uramoto, F. Tanaka, Salvage thoracic surgery in patients with primary lung cancer, Lung Cancer 84 (2014) 151–155. [8] G.A. Kuzmik, F.C. Detterbeck, R.H. Decker, D.J. Boffa, Z. Wang, I.B. Oliva, et al., Pulmonary resections following prior definitive chemoradiation therapy are associated with acceptable survival, Eur. J. Cardiothorac. Surg. 44 (2013) e66–70. [9] W. Schreiner, W. Dudek, H. Sirbu, Is salvage surgery for recurrent non-small-cell lung cancer after definitive non-operative therapy associated with reasonable survival, Interact. Cardiovasc. Thorac. Surg. 21 (2015) 682–684. [10] S. Tetar, M. Dahele, G. Griffioen, B. Slotman, S. Senan, High-dose conventional thoracic re-irradiation for lung cancer: updated results, Lung Cancer 88 (2015) 235–236. [11] S. McAvoy, K. Ciura, C. Wei, J. Rineer, Z. Liao, J.Y. Chang, et al., Definitive reirradiation for locoregionally recurrent non-small cell lung cancer with proton beam therapy or intensity modulated radiation therapy: predictors of high-grade toxicity and survival outcomes, Int. J. Radiat. Oncol. Biol. Phys. 90 (2014) 819–827. [12] A. Paramanathan, B. Solomon, M. Collins, M. Franco, S. Kofoed, H. Francis, et al., Patients treated with platinum-doublet chemotherapy for advanced non-small-cell lung cancer have inferior outcomes if previously treated with platinum-based chemoradiation, Clin. Lung Cancer 14 (2013) 508–512.
Contents lists available at ScienceDirect
Lung Cancer journal homepage: www.elsevier.com/locate/lungcan
Salvage surgery for locoregional recurrence or persistent tumor after high dose chemoradiotherapy for locally advanced non-small cell lung cancer C. Dickhoff a,b,∗ , M. Dahele c , M.A. Paul b , P.M. van de Ven d , A.J. de Langen e , S. Senan c , E.F. Smit f , K.J. Hartemink g a
Department of Surgery, VU University Medical Center, P.O. Box 7057, 1007 MB Amsterdam, The Netherlands Department of Cardiothoracic Surgery, VU University Medical Center, P.O. Box 7057, 1007 MB Amsterdam, The Netherlands c Department of Radiation Oncology VU University Medical Center, P.O. Box 7057, 1007 MB Amsterdam, The Netherlands d Department of Epidemiology and Biostatistics, VU University Medical Center, P.O. Box 7057, 1007 MB Amsterdam, The Netherlands e Department of Pulmonary Diseases, VU University Medical Center, P.O. Box 7057, 1007 MB Amsterdam, The Netherlands f Department of Pulmonary Diseases, Netherlands Cancer Institute—Antoni van Leeuwenhoek Hospital, P.O. Box 90203, 1006 BE Amsterdam, The Netherlands g Department of Surgery, Netherlands Cancer Institute—Antoni van Leeuwenhoek Hospital, P.O. Box 90203, 1006 BE Amsterdam, The Netherlands b
a r t i c l e
i n f o
Article history: Received 28 December 2015 Received in revised form 31 January 2016 Accepted 6 February 2016 Keywords: Salvage surgery Non-small cell lung cancer Chemoradiotherapy Locoregional recurrence Survival
a b s t r a c t Objectives: Curative intent treatment options for locoregional recurrence or persistent tumor after radical chemoradiotherapy for locally-advanced non-small cell lung cancer (NSCLC) are limited. In selected patients, surgery can be technically feasible, although it is widely believed to be hazardous. As data regarding the outcome of this approach is sparse, we evaluated our institutional experience with salvage surgery. Materials and methods: Patients with a pulmonary resection for in-field locoregional recurrence or persistent tumor after high dose chemoradiotherapy (≥60 Gy) for the treatment of non-small cell lung cancer, were identified and retrospectively analyzed. Results: A total of 15 patients treated between January 2007 and August 2015 were eligible for evaluation. In 13 patients (87%), the indication for surgery was a locoregional recurrence, while 2 patients had persistent tumor. The prior median radiotherapy dose was 66 Gy (range 60–70). All patients underwent an anatomical resection, with 8 patients having a pneumonectomy, and all pathological specimens revealed the presence of viable tumor. The in-hospital morbidity rate was 40% (6 patients), and the 90-day mortality rate was 6.7% (1 patient). Median follow-up was 12.1 months. The estimated median overall and event-free survivals were 46 months and 43.6 months, respectively. Conclusion: Salvage surgery for locoregional recurrence or persistent tumor after high dose chemoradiotherapy, resulted in acceptable morbidity, mortality and promising outcome. It should be considered as a treatment option for selected patients. © 2016 Elsevier Ireland Ltd. All rights reserved.
1. Introduction The recommended treatment for fit patients with locally advanced non-small cell lung cancer (NSCLC) is a combination of chemotherapy and radiotherapy [1–3]. A median survival of 28.7 months has recently been reported for selected patients treated with concurrent chemoradiotherapy [4]. However, there was a local
∗ Corresponding author at: VU University Medical Center, Department of Surgery and Cardiothoracic Surgery, De Boelelaan 1117, 1081 HV Amsterdam, The Netherlands. E-mail address: [email protected] (C. Dickhoff). http://dx.doi.org/10.1016/j.lungcan.2016.02.005 0169-5002/© 2016 Elsevier Ireland Ltd. All rights reserved.
failure rate of 39% at 2 years in a sub-group of protocol compliant patients [4]. Once locoregional recurrence or persistent tumor is diagnosed after chemoradiotherapy, curative intent treatment options are limited and therapy is often palliative. However, selected patients might be candidates for radical re-irradiation or resection. Due to fibrosis as a result of the interval between chemoradiotherapy and surgery, so-called salvage resections are technically demanding, and associated with higher risks. There are relatively few reports presenting outcome data after salvage surgery following chemoradiotherapy [5–8], and a lack of a uniform definition has hampered proper comparison of outcome
C. Dickhoff et al. / Lung Cancer 94 (2016) 108–113
data. We audited our institutional experience with salvage surgery, defined as a pulmonary resection for locoregional recurrence or persistent tumor in the previously irradiated area, ≥12 weeks after the last day of curative intent high dose (>60 Gy) chemoradiotherapy. 2. Material and methods This retrospective cohort analysis was conducted with Institutional Review Board approval. Patients who underwent salvage pulmonary resection at the VU University medical center between January 2007 and August 2015, after prior curative intent chemoradiotherapy for primary NSCLC, were identified. Before planning surgery, patients had been discussed in our weekly institutional multidisciplinary tumor board (MTB) consisting of surgeons, pulmonary oncologists, radiation oncologists, radiologists, nuclear medicine specialists and pathologists. MTB decisions are based on the patient’s physical and medical status, as well as radiological and pathological findings. Patients were considered candidates for salvage surgery when physical status and objective cardiopulmonary function (e.g. lung function tests, exercise testing, cardiac evaluation) were sufficient to undergo surgical resection and, radiological and endobronchial findings showed that complete resection of all suspicious/proven disease was technically feasible. The absence of pathological confirmation of viable tumor was not a strict exclusion criteria, since percutaneous post-chemoradiotherapy pathology may be unreliable with lower sensitivity and negative predictive value [5]. Patients were excluded from the present analysis if they had 1) surgery as part of a planned trimodality protocol, 2) surgery for complications of definitive chemoradiotherapy, 3) prior single modality treatment, 4) histology other than NSCLC, and 5) stage IV disease prior to chemoradiotherapy. Salvage surgery was defined as a pulmonary resection for locoregional recurrence or persistent tumor in the previously irradiated area, ≥12 weeks after the last day of curative intent high dose (>60 Gy) chemoradiotherapy for the treatment of NSCLC. Data was retrieved from our institutional database and individual patient records, including age, sex, comorbidity, physical status, stage of the index tumor, prior treatment and staging modalities. If data were missing, the patient’s general practitioner or referring hospital were contacted. As the 7th edition of the TNM classification for lung cancer replaced the 6th edition during the study period, both the index tumor and the locoregional recurrence or persistent tumor of all patients was re-staged using the 7th edition. Surgical factors that were evaluated included the type of resection, lymph node dissection, complications, length of intensive care unit (ICU) and in-hospital stay and pathology. The date of surgery was used for survival measures. During follow-up, a CT-scan was routinely performed every 3 months in the first year, every 6 months in the 2nd and 3rd year and thereafter every year, or more frequent when there was clinical suspicion of disease progression. Statistical analyses were performed using the SPSS software package (SPSS, version 20, SPSS Inc, Chicago, IL, USA). Median follow-up times were estimated using the inverse Kaplan-Meier method. Overall survival (OS) and event free survival (EFS) distributions were analyzed using Kaplan-Meier analyses. For event free survival we considered the following events: death from any cause, locoregional recurrence or progression of disease. 3. Results Between January 2007 and August 2015, a total of 183 patients underwent pulmonary resection at our institution after chemoradiotherapy. In total, 21/183 patients were not included in a trimodality protocol, and were operated on more than 12 weeks
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after the last day of high dose chemoradiotherapy, for either locoregional recurrence or persistent tumor within the irradiated area. Four patients had a pathological diagnosis of small cell lung cancer, 1 patient had previous resection and a recurrence treated with chemotherapy with low-dose radiotherapy (30 Gy) and 1 patient had stage IV disease based on a solitary brain metastasis developed during initial treatment, leaving 15 patients eligible for analysis. Between 2007 and 2012, 1 or 2 operations were performed per year for this indication, increasing to 3 in 2014, and 5 in the first 8 months of 2015. The majority of patients (12/15) had their primary treatment with chemoradiotherapy in other hospitals and were referred to our center after being diagnosed with locoregional recurrence or persistent tumor. Detailed patient characteristics are presented in Table 1. The median age at the time of chemoradiotherapy was 59 years (range 41–70) and 73% of patients were male. Median bodymass-index (BMI) was 25.7 (range 20.6–32.8), and median FEV1 was 78% of predicted (range 59–138%). Median Charlson comorbidity score was 4 (range 2–6). Before starting their initial treatment with chemoradiotherapy, 10 patients were staged as IIIA, and 5 patients as IIIB (according to the 7th edition of the TNM), and 10/12 patients with clinical suspicion of mediastinal/supraclavicular nodal involvement had pathologically proven N2 or N3 disease. The median radiotherapy dose was 66 Gy (range 60–70); 80% of patients had concurrent chemotherapy, and 20% sequential. In the majority of patients (n = 13; 87%), the reason for salvage surgery was locoregional recurrence and the remaining 2 patients had persistent tumor. One of the latter had persistent disease after definitive chemoradiotherapy, and was subsequently treated with erlotinib resulting in stable disease, before a decision was made to perform salvage surgery. The other patient had a high suspicion of persistent tumor on follow-up CT and subsequent metabolic imaging soon after finishing curative intent chemoradiotherapy. Before surgery, all patients were staged with a fluorodeoxyglucose (FDG) PET-CT scan to confirm the absence of distant metastases, and 13 patients had a preoperative MRI or CT-scan of the brain, which was negative in all cases. Preoperative confirmation of disease was attempted in 11 of the 15 patients and confirmed in 9 patients. PET-CT identified possible involvement of N2 nodes in 2 patients. Three patients had invasive mediastinal staging with mediastinoscopy (n = 1), esophageal ultrasound (n = 1) or endobronchial ultrasound (n = 1) because of clinical suspicion of N2 involvement (n = 2) or central localization of the recurrent tumor (n = 1). One patient had unforeseen N2-disease on postoperative pathological examination and in one patient an invasive diagnostic mediastinal intervention was omitted because of high suspicion of persistent N2 nodal involvement on PET-CT. The clinical stage of the locoregional recurrence or persistent tumor was IA in 1, IB in 9, IIB in 3 and IIIA in 2 patients. Of the patients with IIIA The median time between the last day of radiotherapy and surgery was 21 months (range 3–95). Surgical data are summarized in Table 2. All patients underwent an anatomical surgical resection consisting of a segmentectomy in 1, lobectomy in 4, bilobectomy in 2 and pneumonectomy in 8 patients (right sided 3/8). The resection was extended with an additional parenchymal resection (e.g. en-bloc wedge resection) in 4 patients. One patient had a superior sulcus tumor and underwent a chest wall resection. Six patients had an intrapericardial dissection of the central structures due to extensive fibrosis of the hilum or because of centrally located tumor. The median number of lymph node stations that were dissected and submitted for pathological examination was 4 (range 1–8). Median duration of surgery was 225 min (range 124–387). In all patients, pathological examination of the resected specimen revealed the presence of tumor. This was invading the resection margin (R1 resection) in 2 patients. Median
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Fig. 1. Kaplan-Meier estimates for overall survival (OS) of patients treated with salvage surgery.
Table 1 Patient, tumor and treatment characteristics of patients treated with salvage surgery between 2007 and 2015. Patient
Year of resection
Sex
Age at treatment of index tumor
CCI
cTNM
Histology
Radiation dose (Gy)
Reason for salvage surgery
Time last RT to surgery (months)
Attempted PA/PAproven
Pre-salvage mediastinal evaluation (Naruke station)
r-cTNM
r-pTNM
1 2 3
2007 2007 2008
m m f
49 51 56
2 3 3
T4N0sst T4N2 T1N3
scc scc adeno
60* 60 60
PD R R
29 48 13
−/− +/+ +/+
T3N0 T2bN0 T2aN0
T2bN0 T3N1 T1bN0
4 5 6 7 8 9 10 11 12 13 14 15
2009 2010 2012 2012 2014 2014 2014 2015 2015 2015 2015 2015
f m m f f m m m m m m m
41 64 53 43 70 60 56 60 64 60 59 69
2 5 6 3 6 6 3 5 4 4 3 5
T2aN2 T2N3 T2aN2 T2N2 T3N2 T2N2 T2bN2 T4N0 T4N2 T4N0 T2bN3 T3N2
adeno NSCLC adeno NSCLC adeno scc adeno scc scc adeno scc adeno
66 60 66 66* 70* 66 66 66 66 66 66 66
R R R R R R PD R R R R R
22 95 15 75 22 20 3 21 11 38 11 7
−/− +/− +/− +/+ −/− +/+ −/− +/+ +/+ +/+ +/+ +/+
no no Mediastinoscopy (4R, 4L, 7, 2R) no no no no no EUS (7) no EBUS (4R) no no no no
T2aN0 T2aN0 T2aN0 T4N0 T1bN0 T2aN0 T2aN2 T2aN0 T3N0 T3N0 T2aN0 T2aN0
T2aN0 T4N2 T1bN0 T3N0 T2aN0 T2bN0 T2aN2 T2aN0 T3N0 T3N0 T2aN0 T2aN0
m = male, f = female, CCI = Charlson comorbidity Index, c-TNM = clinical TNM stage of index tumor, sst = superior sulcus tumor, EBUS = endobronchial ultrasound, EUS = esophageal ultrasound, RT = radiotherapy, * = sequential, PD = persistent disease, R = recurrence, PA = pathology, r-cTNM = recurrence-clinical TNM, r-pTNM = recurrencepathological TNM.
length of stay on the ICU was 1 day (range 0–4) and median total in-hospital stay was 7 days (range 5–12). Complications were encountered in 6 patients (in hospital morbidity rate: 40%), with 2 events requiring re-thoracotomy, both
after a left-sided pneumonectomy. One patient had an empyema and was re-operated on 4 weeks after resection. The second patient, who underwent an intrapericardial resection of the left lung, developed severe arrhythmias with acute hypotension immediately after
Table 2 Surgical details, morbidity and survival of patients treated with salvage pulmonary resection. Bronchial stump Separate dissected In-hospital cover LN-stations (+ complication indicates positive)
Reintervention ICU/MCU stay (days) <30 days
Hospital stay (days)
Resection margin
Survival Local (LF) or (months) distant progression (DP) after surgery
1
L+W+T
245
+
pericard
5,7,8,10,11
–
–
1
5
R0
–
≥96
2 3 4 5 6 7 8 9 10 11 12 13 14 15
RP BL RP LP L LP S+W LP L+S RP BL LP L+W LP
387 200 174 164 124 142 226 298 219 355 338 225 272 214
+ − − + − − − + − + − + − −
omentum IMF diaphragm IMF IMF pericard pericard ASM IMF ASM IMF IMF IMF IMF
7, 10(+) 4,7,8,10,11,12 4,7,8,9,10 4,5(+), 6,7,9 4,7,8,11 4,5,7,9,10,11 5 4,7 4(+),5,6,7,8,9,10,11 4,7 4,7,11 9,10 2,4,10 5,6,7,10,11
– – – luxation heart pneumonia – – – – FUO FUO atrial flutter – empyema
– – – thoracotomy antibiotics – – – – antibiotics – – – thoracotomy
2 0 1 4 1 1 2 0 0 4 0 1 0 0
7 7 10 5 7 7 6 8 8 12 9 7 6 6
R1 R0 R0 R1 R0 R0 R0 R0 R0 R0 R0 R0 R0 R0
LF, DP – DP – – DP – – – – – – – –
22a ≥90 46a 0b ≥37 5a ≥19 ≥12 ≥11 ≥8 ≥6 ≥4 ≥3 ≥2
ribs 1–4, phrenic nerve, pulmonary artery – – – – – – – – recurrent nerve – – – – –
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Operating time Intrapericardial Additional Patient Type of resection (mins) dissection resection
RP = right pneumonectomy, LP = left pneumonectomy, BL = bilobectomy, L = lobectomy, S = segmentectomy, W = wedge resection, T = thoracic wall resection, IMF = pedicled intercostal muscleflap, ASM = anterior serratus muscle, FUO = fever of unknown origin, ICU = intensive care unit, MCU = medium care unit. a Died of disease progression. b Died of ARDS 6 days after surgery.
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Fig. 2. Kaplan-Meier estimates for event-free survival (EFS) of patients treated with salvage surgery.
closure of the thorax. After prompt re-thoracotomy, the heart was found to be herniated through the pericardium. The heart was replaced in its anatomical position, the pericardial defect was closed, and after cardioversion, there was normal sinus rhythm and blood pressure recovered. Unfortunately, this patient died 4 days after surgery because of acute respiratory distress syndrome (ARDS). This case represents the only patient who died within 90 days of surgery (90-day mortality rate: 6.7%). No patient received adjuvant therapy. One patient with N2 disease died in the perioperative period (Patient 5, Tables 1 and 2). One patient with N1 disease (patient 2) and one patient with N2 disease (patient 10) underwent close follow-up. Median follow-up was 12.1 months (95% CI: 0–27.1) and estimated median overall and event-free survival was 46 months and 43.6 months respectively (Figs. 1 and 2).
4. Discussion In this highly selected group of patients undergoing salvage surgery for recurrent or persistent tumor after high dose chemoradiotherapy for NSCLC, we have shown that surgery can be performed with acceptable risks and encouraging survival can be achieved. Although the study is retrospective, the cohort is homogeneous in terms of prior treatment, pathology, and indication for surgery. All patients received prior high-dose chemoradiotherapy (minimum dose 60 Gy), were staged with PET-CT+/− invasive medi-
astinal intervention and an MRI of the brain, and had viable tumor in the resected specimen. Furthermore, when compared to other reports [5,6], the median interval between chemoradiotherapy and salvage surgery was considerable, indicating that resections were truly salvage and not part of a (delayed) trimodality approach. This is also a contemporary series, with all surgery carried out in one large tertiary referral thoracic oncology center over the last decade. Based on our limited data, it appears that patients whose disease can be removed with a lobectomy have a good prognosis. Despite the fact that all patients who were deceased at the time of the current analysis had undergone a pneumonectomy, appreciable survival can be still be achieved in this group. This is illustrated by two patients who lived for 22 and 46 months, even after an incomplete (R1) resection. We acknowledge that our overall follow-up is relatively short, and longer follow-up could identify additional data to help guide patient selection, including the optimal selection of patients for pneumonectomy. Despite the large number of pneumonectomies in a group treated with prior high dose chemoradiotherapy, no patients developed a postoperative bronchopleural fistula. This might be attributable to the strict application of vascularized flaps for bronchial stump coverage. In addition, the incidence of postoperative empyema was low, which might be at least partly explained by our routine application of intravenous antibiotics during the first 5 days after surgery. The evidence regarding salvage surgery remains limited: a recent review identified 4 studies, with a total of only 47 patients, and of these 2 studies (9 patients) were related to salvage surgery
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after prior stereotactic body radiotherapy (SBRT), which is a different clinical scenario (for example, the mediastinum is typically not irradiated to a significant dose with lung SBRT) [9]. Furthermore, there is currently no uniform definition of salvage surgery. In our study we used a definition pulmonary resection of locoregional recurrence or persistent tumor in the irradiated area, ≥12 weeks after radical chemoradiotherapy (≥60 Gy) for NSCLC. Bauman et al. reported on 24 patients who underwent resection for evidence of treatment failure after high dose of radiotherapy (>59 Gy), with or without chemotherapy [5]. However, the interval between the end of radiotherapy and surgery was variable, with the shortest being 5.4 weeks and their median time from radiotherapy to surgery was 21 weeks (compared with 21 months in our cohort). Furthermore, Bauman et al. reported on a more heterogeneous patient group which included 1 patient with bronchopleural fistula, and 4 were treated in a trimodality protocol. In addition, only 79% of their operated patients had malignancy confirmed in the resection specimen. Uramoto and Tanaka reported on salvage thoracic operations for 8 patients, but their cohort is heterogeneous and included patients with stage IV disease [7]. Kuzmik et al. analyzed outcomes for 14 patients undergoing resection for recurrence after definitive chemoradiotherapy. However, they included patients treated with radiotherapy doses as low as 30 Gy (median 57 Gy), patients with SCLC as the index tumor, and nearly 50% of patients received a resection for a non-local recurrence (including in a contralateral lobe) [8]. The report on salvage surgery for NSCLC by Yang et al. described 31 patients who were operated at a median of 17.7 weeks after chemoradiotherapy to a median dose of 60 Gy [6]. However, all decisions to proceed to surgery were based solely on imaging with the final pathological examination of the resected specimen revealing no vital tumor in nearly 40% (12/31) of patients. Their patients with a pathological complete response had a significantly better survival than those without, and no patients underwent pneumonectomy, in comparison with 8/15 in our study. The features of the abovementioned studies must be taken into account when studies are compared. A number of potential alternative interventions and specific considerations are relevant to MTB discussions for patients with recurrent or persistent loco-regional disease. High-dose thoracic re-irradiation has been used in selected patients. We have previously reported our institutional results with re-irradiation in this setting [10] and found it to be technically feasible with a median overall survival of 13.5 months. However, we have observed a considerable rate of fatal bleeding (to which tumor and treatment related factors may be contributing) in patients who have high dose overlap of the first and second radiation courses in the hilar/central regions. In a study by McAvoy et al. [11], median survival after re-irradiation was 14.7 months (range 10.3–20.6) with grade ≥3 esophageal toxicity of 7% and grade ≥3 pulmonary toxicity of 10%. Both groups found smaller tumors to be associated with better survival. Another treatment approach is palliative chemotherapy, although it has been observed that response rates to carboplatingemcitabine chemotherapy in patients with recurrent NSCLC who had been formerly treated with platinum-based chemoradiotherapy were low (10%) [12], and this cannot be considered a curative intent treatment option. 5. Conclusion We report that selected patients with locoregional recurrence or persistent tumor after high dose chemoradiotherapy, can undergo
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salvage surgery with acceptable morbidity and mortality, even when a pneumonectomy is required. Factors that might have contributed to these favorable results include adequate pre-operative staging, ability to obtain an R0 resection and a good performance status. Medically operable patients presenting with (high suspicion of) locoregional recurrence or persistent tumor after definitive chemoradiotherapy for NSCLC, should have all treatment options reviewed in an experienced MTB. Conflicts of interest For this research, there were no study sponsors in the study design, in the collection, analysis and interpretation of data, in the writing of the manuscript, and in the decision to submit the manuscript for publication. Dr. Dahele reports grants from Varian Medical Systems, personal fees from Varian Medical Systems, personal fees from Lilly, outside the submitted work. Dr. Senan reports grants and non-financial support from Varian Medical Systems, outside the submitted work. References [1] W.E. Eberhardt, D. De Ruysscher, W. Weder, C. Le Péchoux, P. De Leyn, H. Hoffmann, et al., Panel members. 2nd ESMO consensus conference in lung cancer: locally-advanced stage III non-small-cell lung cancer, Ann. Oncol. 26 (2015) 1573–1588. [2] B.D. Kozower, J.M. Larner, F.C. Detterbeck, D.R. Jones, Special treatment issues in non-small cell lung cancer: diagnosis and management of lung cancer, 3rd ed: American College of Chest Physicians evidence-based clinical practice guidelines, Chest 143 (2013) e369S–e399S. [3] N. O’Rourke, I. Roqué, M. Figuls, N. Farré Bernadó, F. Macbeth, Concurrent chemoradiotherapy in non-small cell lung cancer, Cochrane Database Syst. Rev. 16 (2010) CD002140. [4] 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 phase 3 study, Lancet Oncol. 16 (2015) 187–199. [5] J.E. Bauman, M.S. Mulligan, R.G. Martins, B.F. Kurland, K.D. Eaton, D.E. Wood, Salvage lung resection after definitive radiation (>59 Gy) for non-small cell lung cancer: surgical and oncologic outcomes, Ann. Thorac. Surg. 86 (2008) 1632–1638. [6] C.F. Yang, R.R. Meyerhoff, S.J. Stephens, T. Singhapricha, C.B. Toomey, K.L. Anderson, et al., Long-Term outcomes of lobectomy for non-Small cell lung cancer after definitive radiation treatment, Ann. Thorac. Surg. 99 (2015) 1914–1920. [7] H. Uramoto, F. Tanaka, Salvage thoracic surgery in patients with primary lung cancer, Lung Cancer 84 (2014) 151–155. [8] G.A. Kuzmik, F.C. Detterbeck, R.H. Decker, D.J. Boffa, Z. Wang, I.B. Oliva, et al., Pulmonary resections following prior definitive chemoradiation therapy are associated with acceptable survival, Eur. J. Cardiothorac. Surg. 44 (2013) e66–70. [9] W. Schreiner, W. Dudek, H. Sirbu, Is salvage surgery for recurrent non-small-cell lung cancer after definitive non-operative therapy associated with reasonable survival, Interact. Cardiovasc. Thorac. Surg. 21 (2015) 682–684. [10] S. Tetar, M. Dahele, G. Griffioen, B. Slotman, S. Senan, High-dose conventional thoracic re-irradiation for lung cancer: updated results, Lung Cancer 88 (2015) 235–236. [11] S. McAvoy, K. Ciura, C. Wei, J. Rineer, Z. Liao, J.Y. Chang, et al., Definitive reirradiation for locoregionally recurrent non-small cell lung cancer with proton beam therapy or intensity modulated radiation therapy: predictors of high-grade toxicity and survival outcomes, Int. J. Radiat. Oncol. Biol. Phys. 90 (2014) 819–827. [12] A. Paramanathan, B. Solomon, M. Collins, M. Franco, S. Kofoed, H. Francis, et al., Patients treated with platinum-doublet chemotherapy for advanced non-small-cell lung cancer have inferior outcomes if previously treated with platinum-based chemoradiation, Clin. Lung Cancer 14 (2013) 508–512.