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Differential analysis of local and regional failure in locally advanced non-small cell lung cancer patients treated with concurrent chemoradiotherapy
Radiotherapy and Oncology xxx (2016) xxx–xxx
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Original article
Differential analysis of local and regional failure in locally advanced non-small cell lung cancer patients treated with concurrent chemoradiotherapy Judi N.A. van Diessen a, Chun Chen a, Michel M. van den Heuvel b, José S.A. Belderbos a, Jan-Jakob Sonke a,⇑ a
Department of Radiation Oncology; and b Department of Thoracic Oncology, The Netherlands Cancer Institute, Amsterdam, The Netherlands
a r t i c l e
i n f o
Article history: Received 7 September 2015 Received in revised form 2 February 2016 Accepted 4 February 2016 Available online xxxx Keywords: Chemoradiotherapy NSCLC Differentiated dose prescription
a b s t r a c t Background and purpose: Concurrent chemoradiotherapy (CCRT) is the standard treatment in locally advanced non-small cell lung cancer (NSCLC) patients. In clinical practice, the primary tumor (PT) and involved lymph nodes (LNs) receive the same radiotherapy dose. This study investigates differences between local failure (LF) and regional failure (RF). Material and methods: Patients were irradiated with 66 Gy in 24 fractions (using IMRT) combined with daily low dose cisplatin. The PT and LNs were contoured on the planning CT-scan registered with a 18 FDG-PET-scan. Log10(Volume) and SUVmax of PT and LNs, location (LNs versus PT), performance status, age and gender were tested as prognostic factors for lesion failure using cox regression analysis. Results: In total, 226 patients were analyzed. LF or RF as first event was seen in 37 PT (16%) and 14 LNs (6%). Log10(Volume), location and SUVmax were significantly associated with failure in univariate analysis. In multivariate analysis, only log10(Volume) remained as a significant factor. Conclusions: A LF and RF as first event of respectively 16% and 6% were observed in locally advanced NSCLC patients treated with CCRT. This difference was primarily associated with the difference in log10(Volume) of the primary tumor and lymph nodes. Ó 2016 Elsevier Ireland Ltd. All rights reserved. Radiotherapy and Oncology xxx (2016) xxx–xxx
A large proportion of non-small cell lung cancer (NSCLC) patients are diagnosed with locally advanced disease. The treatment of choice for this patient group is definitive concurrent chemoradiotherapy (CCRT). This results in an improved overall survival (OS) compared to sequential chemoradiotherapy or radiotherapy (RT) alone, which is mainly attributed to a better local tumor control. The outcomes, however, are poor with 2-year OS rates of 30–35% and 2-year progression-free survival rates of 24% [1,2]. Although an intensified treatment as CCRT improves locoregional control, still about 30% develops locoregional failures (LRF) and about 40% distant metastases (DM) [1]. In literature, LRF after CCRT are seldom analyzed in detail; therefore differences in incidence between local failures (LF) and regional failures (RF) are unknown [1,2]. If there are differences, it would be of interest to identify possible reasons, that might influence the radiation treatment strategy such as differentiating the total radiation dose to the primary tumor (PT) and involved lymph nodes (LNs). In clinical practice, both PT and LNs typically receive the same prescribed radiation dose during CCRT. One of the dose-limiting ⇑ Corresponding author at: Department of Radiation Oncology, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX Amsterdam, The Netherlands. E-mail address: [email protected] (J.-J. Sonke).
toxicities of CCRT is radiation-esophagitis. Between 15 and 35% of the patients develops acute grade 3 esophagitis mainly caused by irradiation of involved mediastinal LNs [3,4]. Grade 3 esophagitis as well as the volume of the esophagus treated with a radiation dose >76 Gy (EQD2) are predictors for developing severe late esophageal toxicity, such as esophageal stenosis, perforation or trachea-esophageal fistulas [5]. Thus, if a significant difference exists between RF and LF rates, this could be a strong argument to explore new RT treatment strategies with differentiated prescription doses to the PT and the LNs. The aim of this study was to investigate the pattern of LF and RF and possibly related parameters in an unselected patient group with locally advanced NSCLC treated with CCRT. Methods and materials Patient selection A total of 356 patients with cytologically or histologically proven locally advanced NSCLC were treated with CCRT between 2007 and 2011 at The Netherlands Cancer Institute, Amsterdam, The Netherlands. Medical records and treatment characteristics of these patients were retrospectively reviewed. Patients were
http://dx.doi.org/10.1016/j.radonc.2016.02.008 0167-8140/Ó 2016 Elsevier Ireland Ltd. All rights reserved.
Please cite this article in press as: van Diessen JNA et al. Differential analysis of local and regional failure in locally advanced non-small cell lung cancer patients treated with concurrent chemoradiotherapy. Radiother Oncol (2016), http://dx.doi.org/10.1016/j.radonc.2016.02.008
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Local and regional failure in advanced NSCLC
excluded if a resection of the PT before (N = 7) or after (N = 42) CCRT was performed. Other reasons for exclusion were: radiotherapy schedules other than 66 Gy in 24 fractions (N = 32), chemotherapy schedules other than daily cisplatin (N = 10), missing follow-up (FU) (N = 12), a missing baseline 18FDG-PET-scan (N = 15) or inability to calculate the maximal standardized uptake value (SUVmax) (N = 12). Work-up and chemoradiotherapy treatment Routine work-up consisted of a computed tomography (CT)-thorax, a whole body 18Fluorodeoxyglucose Positron Emission Tomography (18FDG-PET)-scan <6 weeks before start RT, according to the NEDPass protocol [6], CT- or Magnetic Resonance Imaging (MRI)-scan of the brain and a pulmonary function test. Cytology or histology of the PT and/or involved LNs was obtained by bronchoscopy, transthoracic biopsy or endoscopic ultrasound of the bronchus (EBUS) or esophagus (EUS). The aim was to prove the highest N-level and one positive mediastinal lymph node was usually sufficient. Patients were treated with hypofractionated intensity modulated radiotherapy (IMRT) and concurrent chemotherapy. The prescribed dose given was 66 Gy in 24 fractions of 2.75 Gy, 5 fractions per week. This was combined with daily low dose Cisplatin (6 mg/m2, maximum 12 mg), intravenously administered as a bolus 1–2 h before RT. Thirty-three patients were included in a randomized trial with or without the addition of a monoclonal antibody targeting the epidermal growth factor receptor (Cetuximab) [7]. A four-dimensional planning CT-scan (4DCT) with intravenous contrast was acquired for RT-planning in order to minimize the respiratory-induced systematic errors and to access the breathing amplitude of the PT. A mid-ventilation scan (MidV) in which the tumor is closest to its time-averaged mean position was reconstructed from the 4DCT. Subsequently, the 18FDG-PET-scan was matched with the MidV-scan. This MidV-scan was used to delineate the gross tumor volume (GTV) of the primary tumor (GTV-PT), the involved LNs and organs at risk (OARs). As not all involved LNs were pathologically proven, the following LNs were also considered malignant in the absence of pathological evidence: high FDG-uptake on the 18FDG-PET-scan, consisting of clusters of small LNs or growth of LNs on CT combined with weak activity on the 18FDG-PET-scan. A total nodal volume was calculated (GTV-LNs) since in clinical practice separate nodal stations were often contoured as one volume, especially when in continuation with each other. The delineation of each patient was evaluated thoroughly with two dedicated radiation-oncologists and checked during a multidisciplinary meeting. If necessary, a nuclear physician was consulted. The GTV-PT was expanded to a planning target volume (PTV) using margins of 12 mm plus 1/4 of the GTV-PT peak-to-peak amplitude in orthogonal directions as observed in the 4DCT [8]. An isotropic PTV margin of 12 mm was used for the LNs in all patients. The following OARs were contoured according to departmental protocol: heart, spinal cord, lungs and esophagus. Dose constraints and objectives were defined in biologically equivalent dose in 2 Gy per fraction (EQD2). Dose objectives for the OARs were: mean lung dose 620 Gy (a/b = 3 Gy), spinal cord 652 Gy (a/b = 2 Gy), total mean heart dose 640 Gy, 2/3 heart 650 Gy, and 1/3 heart 666 Gy (a/b = 4 Gy). For the esophagus, a V35 <65% (a/b = 10 Gy) was encouraged when optimizing the IMRT-plan. An IMRT treatment-plan was designed with 10-MV photons. Dose distributions were calculated using inhomogeneity correction (Pinnacle version 9.2, Philips, Best, The Netherlands). The dose inhomogeneity of the PTV was within 90-115%. Treatment verification was done by Electronic Portal Imaging Device (EPID)
dosimetry and cone-beam CT-scans according to an offline setup correction protocol. In case of significant anatomical changes, such as atelectasis or tumor baseline shifts, re-planning was pursued [9]. Follow-up and endpoint definition FU consisted of a CT-thorax 6–8 weeks after completing treatment, followed by a 3-monthly chest X-ray or CT-scan up to 2 years after CCRT. LF was defined as a recurrence or progression of GTV-PT and RF as a recurrence or progression of GTV-LNs. In both cases, an increase in tumor diameter of at least 20% compared with the pre-treatment CT-scan, was scored as a failure (according to RECIST). If the post-radiotherapy 18FDG-PET-scan showed no decrease in SUVmax compared to the pre-treatment 18FDG-PETscan, this was also scored as a failure. Patients developing DM were not censored. Primary outcome is a LF or RF as first event. Consequently, once a LF or RF was observed in a patient, subsequent LF or RF was not scored. Similarly, in case a patient developed a second primary tumor and/or out-of-field LN failure (LNF), they were scored as out-of-field failures and subsequent LRF was not scored. These clinical endpoints were classified based on FU-records and repeat CT-scans by two physicians: a radiation-oncologist and thoraciconcologist. Statistical analysis Time to LF, RF and death was calculated from the first day of RT. Patient-specific variables (age, gender, performance status) together with tumor-specific variables (histology, log10(Volume) and SUVmax of both GTV-PT and GTV-LNs) were tested as prognostic factors for LF and RF. GTV-PT and GTV-LNs were calculated according to the delineated target on the planning CT. Lesion volume was adopted as terminology to refer to either GTV-PT or GTV-LNs. SUVmax was calculated on the pre-treatment 18 FDG-PET-scan for both lesions separately. First, the actuarial incidence of LF, RF and OS were calculated according to the Kaplan–Meier method. Log10(Volume) and SUVmax of the GTV-PT and GTV-LNs were compared using the Wilcoxon-rank-sum test. Second, a univariate analysis was conducted on all variables to test them as prognostic factors for lesion failure, using mixed effect Cox proportional hazard model with patient as random effect. This model was employed as both GTVPT and GTV-LNs were entered as separate lesions in the analysis. Finally, a multivariate analysis (MVA) was done by including all variables in the model. The best model was selected based on stepwise backward selection using the likelihood ratio test. P-values less than 0.05 were considered statistically significant. The data were analyzed using the software package R 2.14.1 (R Development Core Team, Vienna, Austria). Results Two hundred and twenty-six patients were eligible for this retrospective study. The median age was 64 years and 40% of the patients were female. The majority (61%) of the patients had TNM stage IIIA, 31% had stage IIIB and 8% had stage IA to IIB. Other patient characteristics are shown in Table 1. The median volume of the GTV-PT (N = 219) and GTV-LNs (N = 180) was 77.9 cc (range, 0.8–1820) and 27.1 cc (range 0.4–206.3), respectively (p < 0.01). The median SUVmax of the GTV-PT and the GTV-LNs was 12.4 (range, 2.5–38.3) and 5.4 (range 0.9–28.3), respectively (p < 0.01). With a median FU of 29 months (95% CI, 24–34 months), 112 (50%) patients showed no LF, RF and/or DM. The median OS was 28 months (95% CI, 22–31 months). The 1- and 2-year OS rates were 72% and 52%, respectively (Fig. 2a).
Please cite this article in press as: van Diessen JNA et al. Differential analysis of local and regional failure in locally advanced non-small cell lung cancer patients treated with concurrent chemoradiotherapy. Radiother Oncol (2016), http://dx.doi.org/10.1016/j.radonc.2016.02.008
J.N.A. van Diessen et al. / Radiotherapy and Oncology xxx (2016) xxx–xxx Table 1 Patient characteristics of the patient group (N = 226). Characteristic Median age (range)
64 (37-87)
Gender (%) Male Female
136 (60%) 90 (40%)
Performance status (%) WHO 0 WHO 1 WHO 2
75 (33%) 146 (65%) 5 (2%)
TNM stage (%) IA–IB IIA–IIB IIIA IIIB
5 (2%) 13 (6%) 137 (61%) 71 (31%)
Tumor stage (%) T0–T1 T2 T3 T4 Missing
46 (20%) 70 (31%) 46 (20%) 63 (28%) 1 (<1%)
Nodal stage (%) N0 N1 N2 N3 Missing
30 (13%) 18 (8%) 133 (59%) 44 (19%) 1 (<1%)
Histology (%) SCC NSCLC NOS AC Other Missing
76 (34%) 71 (31%) 65 (29%) 11 (5%) 3 (1%)
Additional weekly Cetuximab (%) Yes No
33 (15%) 193 (85%)
SCC = squamous cell AC = adenocarcinoma
carcinoma;
NOS = not
otherwise
specified;
226 paents
9 paents excluded: second primary or out-of-field LNF
Tumor control 112 (50%)
LF and/or RF 44 (19%)
DM only 61 (27%)
With DM: 25 (57%) Without DM: 19 (43%)
LF only 24 (55%)
LF and RF 7 (16%)
LF and out-offield LNF 6 (14%)*
RF only 7 (16%)
Fig. 1. Patterns of failure in the 226 patients treated with concurrent chemoradiotherapy. Final LF and RF rates calculated as part of the 44 patients with a LF and/or RF. (⁄) Including 1 patient with a second primary tumor as well. DM = distant metastases; LF = local failure; RF = regional failure; LNF = lymph node failure.
Median time to progression was 15 months (95% CI, 12– 19 months). Patterns of failure of the 226 patients are shown in Fig. 1. Thirty-seven of the 226 patients (16%) had a LF, of which the majority (N = 24) had a LF only. RF was observed in 14 patients
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(6%) of the 226 patients. Seven patients had a LF with a RF and 5 developed a LF with an out-of-field lymph node failure (LNF). Seven other patients had an isolated RF. Ultimately, forty-four patients (19%) developed a LF and/or RF (Fig. 1). The 1- and 2-year LF rates were 16% and 26%, whereas the 1- and 2-year RF rates were 8% and 14% for LNs (Fig. 2c). Eighty-seven patients (38%) developed DM. Although excluded from the analysis, it is important to note that 4 patients (2%) developed a second primary tumor and in six patients (3%) an out-of-field LNF was observed. Univariate analysis revealed a significant association of the log10(Volume) of PT and LNs (p < 0.01) and SUVmax (p = 0.02) with lesion failure (Table 2). Furthermore, LNs have a significantly lower risk of tumor failure as compared to the PT (p = 0.02). There were no significant patient-related factors for LF and RF, although performance status had a trend toward significance (p = 0.08). Histology also was not significantly associated with lesion failure. Similarly, testing the association of GTV-PT and GTV-LNs with LF and RF respectively, did not reach statistical significance (not shown). In the MVA, the log10(Volume) remained the only significant prognostic factor for locoregional failure (p < 0.01) (Table 2). Similar results were obtained with lesion volume (Table S1). Fig. 3a and b show the 1- and 2-year failure rates related to log10(Volume), divided in subgroups. These figures illustrate that there is no clear difference of log10(Volume) on the failure probability. The nonsignificant association of SUVmax in the MVA might indicate a correlation between volume and SUVmax. This was confirmed by the Pearson’s correlation coefficient of 0.60 (0.54–0.66), implying a considerable linear correlation (Figure in Supplemental material).
Discussion In this study, we scored LF and RF as first event in patients with locally advanced NSCLC treated with concurrent chemoradiotherapy and observed about a 2.5-fold higher absolute risk to develop a LF (16%) than a RF (6%). This is the first study that analyzed factors that influenced lesion control probability and demonstrated that in MVA, log10(Volume) of the lesion was the only significant prognostic factor for failure after CCRT. The location of the lesion (LNs versus PT) was not significantly correlated with failure in the MVA, suggesting that the difference in LF and RF incidence is primarily caused by the average volume differences. Earlier reports were published concerning volume in relation to survival and LRF. Ball et al. investigated PT volume related to OS in 509 patients [10]. Their results showed that volume adversely affected OS, mainly in the first 18 months after treatment, probably due to a combination of factors, such as radiosensitivity and metastatic potential. Schytte et al. reported their results on the pattern of LRF after definitive RT in mainly stage III patients [11]. Ninetythree (28%) of 331 patients developed a LF (20.5%), a RF (0.3%) or both (7.3%). The treatment consisted of a large variety of RTschedules (minimum 60 Gy) and only 36% received CCRT. Patients who developed LF in the presence of DM were excluded, as well as patients with overall tumor control. Combined PT and LNs volume was the only significant risk factor for recurrence. Their results seem comparable to ours, but 51 patients with synchronously developed LF and DM were not included. If included, the actual LF rate would be 43%, which is higher than our results. In both analyses of Schytte and Ball, the use of FDG-PET-scans was optional and performed in a subgroup of the patients, which might have caused an underestimation in volume of both PT and involved LNs, as well as an increase in the risk of inadequate staging [12]. It is not unlikely that this has influenced the observed failure and OS rates. In addition, assessing the metabolic tumor volume of the PT
Please cite this article in press as: van Diessen JNA et al. Differential analysis of local and regional failure in locally advanced non-small cell lung cancer patients treated with concurrent chemoradiotherapy. Radiother Oncol (2016), http://dx.doi.org/10.1016/j.radonc.2016.02.008
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Local and regional failure in advanced NSCLC
Fig. 2. Kaplan–Meier estimates of OS (a), locoregional control (b) of the 226 patients treated with CCRT. Fig. 2c depicts the Kaplan–Meier estimates of local failure (GTV-PT, N = 219) and regional failure (GTV-LN, N = 180).
and LNs on FDG-PET-scans was recently observed as an independent prognostic factor for disease-free survival and OS above the yp-stage in patients treated with CCRT and additional surgery [13]. Furthermore, not all patients with locally advanced NSCLC received CCRT, which is the standard of care in this patient group. The results of the current analysis are based on a homogeneous patient group, diagnosed with NSCLC according to the same work-up and treated with the same CCRT-schedule. Therefore, uncertainty due to heterogeneity in differences in work-up or treatment is unlikely. Despite the homogeneous patient group, work-up and treatment, the failure rates in our analysis may be underestimated. Firstly, this analysis is retrospective. In metastasized patients the FU-schedule is guided toward palliation and locoregional control
is assessed less frequently. However, we found that in most of the metastasized patients a chest X-ray or CT-thorax was performed less than 4 months before death. Similarly, we did not score subsequent LF/RF in a patient once a LF or RF was observed, due to the start of e.g. systemic treatment that affects the results. Another argument related to bias applies to the number of RF. In this analysis, a RF rate of 6% was observed. A total nodal volume was calculated, because in clinical practice separate nodal stations are often contoured as one volume. Hilar nodes may often have been included in the GTV of the PT when in close relation to the hilum, which limits the strength of this analysis. We analyzed lesion volume as a continuous variable and did not find obvious cut-off points for either PT or LNs. Ball et al. did report a cut-off point of 3 cm of the PT diameter for OS after CCRT but did not
Please cite this article in press as: van Diessen JNA et al. Differential analysis of local and regional failure in locally advanced non-small cell lung cancer patients treated with concurrent chemoradiotherapy. Radiother Oncol (2016), http://dx.doi.org/10.1016/j.radonc.2016.02.008
J.N.A. van Diessen et al. / Radiotherapy and Oncology xxx (2016) xxx–xxx Table 2 Univariate and multivariate analyses of patient and tumor characteristics related to the risk of a LF or RF. The multivariate analysis is performed using stepwise backward selection. The variables are presented in the order of deleted variables. Variable Univariate analysis Log10(Volume) SUVmax LNs vs PT PS P 1 vs 0 Age per 10 years Gender (female vs male) Histology SCC vs AC Other vs AC Multivariate analysis SUVmax LNs vs PT Log10(Volume)
Hazard ratio (95% CI)
P-Value
3.47 1.07 0.45 2.87 1.44 0.54
(1.59–7.59) (1.01–1.13) (0.24–0.85) (0.87–9.41) (0.84–2.49) (0.18–1.56)
<0.01 0.02 0.02 0.08 0.18 0.25
1.28 (0.27–6.20) 0.50 (0.10–2.57)
0.21
0.98 (0.90–1.07) 0.63 (0.31–1.28) 3.47 (1.59–7.59)
0.66 0.20 <0.01
LF = local failure; RF = regional failure; LN vs PT = involved lymph nodes versus primary tumor; PS = performance status; SCC = squamous cell carcinoma; AC = adenocarcinoma.
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report on locoregional control [14]. In MVA, LNs had a reduced hazard ratio of 0.63 although not significant. This could suggest that LNs have a higher radiosensitivity or that their volume on PET-CT is overestimated. Additionally, not all LNs were pathologically proven and, as described in the methods section, also unproven nodes that were considered malignant, were irradiated. This could also explain the lower regional failure rate, since the percentage of uninvolved LNs in this analysis is unknown. It might be helpful to classify LNs based on clinicopathological features, such as discrete enlargement on CT and the close vicinity of involved LNs to the PT [15]. Although both features were associated with a more favorable PFS and OS, local relapses were frequently observed, as was the case in the subgroup of pathological proven LNs. Another solution might be to calculate the ratio of LNs SUV to PT SUV instead of the SUVmax, which was reported to be more reliable when assessing nodes of low to intermediate SUV [16]. A future analysis to assess the regional failure rate in pathologically proven versus unproven LNs could guide clinicians in selecting suspect lymph nodes. The SUVmax of a pre-RT 18FDG-PET-scan correlates with OS in locally advanced NSCLC patients, treated with definitive RT or CCRT [17]. Recently, the results of a secondary analysis of the ACRIN-study were published, showing that high residual FDGactivity in LNs on PET-scans is correlated with worse locoregional control [18]. Our results revealed a correlation between SUVmax and LRF in the univariate analysis, but no longer in the MVA when volume was accounted for (Table 2). This is explained by the correlation between log10(Volume) and log10(SUVmax), suggesting that SUVmax is not a strong prognostic factor in itself to predict LF or RF. Therefore, differentiating LNs metastases on PET might be complicated due to their smaller volume. In our analysis, the local and regional failure rate is primarily explained by the log10(Volume). This could be clarified by the proportionally higher number of clonogenic tumor cells in the PT than in LNs that need to be eradicated by chemoradiation. In the era of personalized treatment, the dose prescription could therefore be directed toward individual volumes of the PT and/or LNs. This is technically feasible using an integrated boost technique. Changing the dose to the PT and/or LNs might be a strategy to improve local control as well as a lower toxicity rate, e.g. acute esophagitis. An increase in grade 3 radiation-esophagitis is caused by a minimal radiotherapy dose of 50 Gy to an increasing volume of the esophagus (V50) [19,20]. Dose de-escalation to the mediastinum might therefore be considered. However, a concern is that higher RF rates may be encountered with this strategy and potentially translate in a reduced PFS and OS [21]. Therefore, dose-escalation to the PT only is an alternative based on the same rationale, as is currently being investigated in the international randomized phase II PETboost trial [22]. In conclusion, our regimen of hypofractionated radiotherapy combined with daily low-dose cisplatin results in relatively low LF and RF rates as first event in LA-NSCLC patients. With a median FU of 29 months, the recurrence rate in irradiated LNs was only 6%, whereas the recurrence rate of the PT was 16%. This is primarily explained by the difference in log10(Volume). Conflict of interest None.
Fig. 3. Proportion of failure at 1-year (a) and 2-year (b) for PT and LNs at different volume classes. The 4 volume subgroups for PT and LNs were defined by the 25%, 50%, 75% percentiles of the log10 transformed volume, and the points were plotted at the x-axis at the median volume of each subgroup. The y-axis gives the Kaplan– Meier estimates of the 1- and 2-year proportion of failure (with 95% confidence interval). Note that the 4th subgroup of the LNs is not plotted at 2-year since no events were observed after 15 months (either lost to FU or died within 2 year) (3b).
Appendix A. Supplementary data Supplementary data associated with this article can be found, in the online version, at http://dx.doi.org/10.1016/j.radonc.2016.02. 008.
Please cite this article in press as: van Diessen JNA et al. Differential analysis of local and regional failure in locally advanced non-small cell lung cancer patients treated with concurrent chemoradiotherapy. Radiother Oncol (2016), http://dx.doi.org/10.1016/j.radonc.2016.02.008
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Local and regional failure in advanced NSCLC
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Please cite this article in press as: van Diessen JNA et al. Differential analysis of local and regional failure in locally advanced non-small cell lung cancer patients treated with concurrent chemoradiotherapy. Radiother Oncol (2016), http://dx.doi.org/10.1016/j.radonc.2016.02.008
Contents lists available at ScienceDirect
Radiotherapy and Oncology journal homepage: www.thegreenjournal.com
Original article
Differential analysis of local and regional failure in locally advanced non-small cell lung cancer patients treated with concurrent chemoradiotherapy Judi N.A. van Diessen a, Chun Chen a, Michel M. van den Heuvel b, José S.A. Belderbos a, Jan-Jakob Sonke a,⇑ a
Department of Radiation Oncology; and b Department of Thoracic Oncology, The Netherlands Cancer Institute, Amsterdam, The Netherlands
a r t i c l e
i n f o
Article history: Received 7 September 2015 Received in revised form 2 February 2016 Accepted 4 February 2016 Available online xxxx Keywords: Chemoradiotherapy NSCLC Differentiated dose prescription
a b s t r a c t Background and purpose: Concurrent chemoradiotherapy (CCRT) is the standard treatment in locally advanced non-small cell lung cancer (NSCLC) patients. In clinical practice, the primary tumor (PT) and involved lymph nodes (LNs) receive the same radiotherapy dose. This study investigates differences between local failure (LF) and regional failure (RF). Material and methods: Patients were irradiated with 66 Gy in 24 fractions (using IMRT) combined with daily low dose cisplatin. The PT and LNs were contoured on the planning CT-scan registered with a 18 FDG-PET-scan. Log10(Volume) and SUVmax of PT and LNs, location (LNs versus PT), performance status, age and gender were tested as prognostic factors for lesion failure using cox regression analysis. Results: In total, 226 patients were analyzed. LF or RF as first event was seen in 37 PT (16%) and 14 LNs (6%). Log10(Volume), location and SUVmax were significantly associated with failure in univariate analysis. In multivariate analysis, only log10(Volume) remained as a significant factor. Conclusions: A LF and RF as first event of respectively 16% and 6% were observed in locally advanced NSCLC patients treated with CCRT. This difference was primarily associated with the difference in log10(Volume) of the primary tumor and lymph nodes. Ó 2016 Elsevier Ireland Ltd. All rights reserved. Radiotherapy and Oncology xxx (2016) xxx–xxx
A large proportion of non-small cell lung cancer (NSCLC) patients are diagnosed with locally advanced disease. The treatment of choice for this patient group is definitive concurrent chemoradiotherapy (CCRT). This results in an improved overall survival (OS) compared to sequential chemoradiotherapy or radiotherapy (RT) alone, which is mainly attributed to a better local tumor control. The outcomes, however, are poor with 2-year OS rates of 30–35% and 2-year progression-free survival rates of 24% [1,2]. Although an intensified treatment as CCRT improves locoregional control, still about 30% develops locoregional failures (LRF) and about 40% distant metastases (DM) [1]. In literature, LRF after CCRT are seldom analyzed in detail; therefore differences in incidence between local failures (LF) and regional failures (RF) are unknown [1,2]. If there are differences, it would be of interest to identify possible reasons, that might influence the radiation treatment strategy such as differentiating the total radiation dose to the primary tumor (PT) and involved lymph nodes (LNs). In clinical practice, both PT and LNs typically receive the same prescribed radiation dose during CCRT. One of the dose-limiting ⇑ Corresponding author at: Department of Radiation Oncology, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX Amsterdam, The Netherlands. E-mail address: [email protected] (J.-J. Sonke).
toxicities of CCRT is radiation-esophagitis. Between 15 and 35% of the patients develops acute grade 3 esophagitis mainly caused by irradiation of involved mediastinal LNs [3,4]. Grade 3 esophagitis as well as the volume of the esophagus treated with a radiation dose >76 Gy (EQD2) are predictors for developing severe late esophageal toxicity, such as esophageal stenosis, perforation or trachea-esophageal fistulas [5]. Thus, if a significant difference exists between RF and LF rates, this could be a strong argument to explore new RT treatment strategies with differentiated prescription doses to the PT and the LNs. The aim of this study was to investigate the pattern of LF and RF and possibly related parameters in an unselected patient group with locally advanced NSCLC treated with CCRT. Methods and materials Patient selection A total of 356 patients with cytologically or histologically proven locally advanced NSCLC were treated with CCRT between 2007 and 2011 at The Netherlands Cancer Institute, Amsterdam, The Netherlands. Medical records and treatment characteristics of these patients were retrospectively reviewed. Patients were
http://dx.doi.org/10.1016/j.radonc.2016.02.008 0167-8140/Ó 2016 Elsevier Ireland Ltd. All rights reserved.
Please cite this article in press as: van Diessen JNA et al. Differential analysis of local and regional failure in locally advanced non-small cell lung cancer patients treated with concurrent chemoradiotherapy. Radiother Oncol (2016), http://dx.doi.org/10.1016/j.radonc.2016.02.008
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Local and regional failure in advanced NSCLC
excluded if a resection of the PT before (N = 7) or after (N = 42) CCRT was performed. Other reasons for exclusion were: radiotherapy schedules other than 66 Gy in 24 fractions (N = 32), chemotherapy schedules other than daily cisplatin (N = 10), missing follow-up (FU) (N = 12), a missing baseline 18FDG-PET-scan (N = 15) or inability to calculate the maximal standardized uptake value (SUVmax) (N = 12). Work-up and chemoradiotherapy treatment Routine work-up consisted of a computed tomography (CT)-thorax, a whole body 18Fluorodeoxyglucose Positron Emission Tomography (18FDG-PET)-scan <6 weeks before start RT, according to the NEDPass protocol [6], CT- or Magnetic Resonance Imaging (MRI)-scan of the brain and a pulmonary function test. Cytology or histology of the PT and/or involved LNs was obtained by bronchoscopy, transthoracic biopsy or endoscopic ultrasound of the bronchus (EBUS) or esophagus (EUS). The aim was to prove the highest N-level and one positive mediastinal lymph node was usually sufficient. Patients were treated with hypofractionated intensity modulated radiotherapy (IMRT) and concurrent chemotherapy. The prescribed dose given was 66 Gy in 24 fractions of 2.75 Gy, 5 fractions per week. This was combined with daily low dose Cisplatin (6 mg/m2, maximum 12 mg), intravenously administered as a bolus 1–2 h before RT. Thirty-three patients were included in a randomized trial with or without the addition of a monoclonal antibody targeting the epidermal growth factor receptor (Cetuximab) [7]. A four-dimensional planning CT-scan (4DCT) with intravenous contrast was acquired for RT-planning in order to minimize the respiratory-induced systematic errors and to access the breathing amplitude of the PT. A mid-ventilation scan (MidV) in which the tumor is closest to its time-averaged mean position was reconstructed from the 4DCT. Subsequently, the 18FDG-PET-scan was matched with the MidV-scan. This MidV-scan was used to delineate the gross tumor volume (GTV) of the primary tumor (GTV-PT), the involved LNs and organs at risk (OARs). As not all involved LNs were pathologically proven, the following LNs were also considered malignant in the absence of pathological evidence: high FDG-uptake on the 18FDG-PET-scan, consisting of clusters of small LNs or growth of LNs on CT combined with weak activity on the 18FDG-PET-scan. A total nodal volume was calculated (GTV-LNs) since in clinical practice separate nodal stations were often contoured as one volume, especially when in continuation with each other. The delineation of each patient was evaluated thoroughly with two dedicated radiation-oncologists and checked during a multidisciplinary meeting. If necessary, a nuclear physician was consulted. The GTV-PT was expanded to a planning target volume (PTV) using margins of 12 mm plus 1/4 of the GTV-PT peak-to-peak amplitude in orthogonal directions as observed in the 4DCT [8]. An isotropic PTV margin of 12 mm was used for the LNs in all patients. The following OARs were contoured according to departmental protocol: heart, spinal cord, lungs and esophagus. Dose constraints and objectives were defined in biologically equivalent dose in 2 Gy per fraction (EQD2). Dose objectives for the OARs were: mean lung dose 620 Gy (a/b = 3 Gy), spinal cord 652 Gy (a/b = 2 Gy), total mean heart dose 640 Gy, 2/3 heart 650 Gy, and 1/3 heart 666 Gy (a/b = 4 Gy). For the esophagus, a V35 <65% (a/b = 10 Gy) was encouraged when optimizing the IMRT-plan. An IMRT treatment-plan was designed with 10-MV photons. Dose distributions were calculated using inhomogeneity correction (Pinnacle version 9.2, Philips, Best, The Netherlands). The dose inhomogeneity of the PTV was within 90-115%. Treatment verification was done by Electronic Portal Imaging Device (EPID)
dosimetry and cone-beam CT-scans according to an offline setup correction protocol. In case of significant anatomical changes, such as atelectasis or tumor baseline shifts, re-planning was pursued [9]. Follow-up and endpoint definition FU consisted of a CT-thorax 6–8 weeks after completing treatment, followed by a 3-monthly chest X-ray or CT-scan up to 2 years after CCRT. LF was defined as a recurrence or progression of GTV-PT and RF as a recurrence or progression of GTV-LNs. In both cases, an increase in tumor diameter of at least 20% compared with the pre-treatment CT-scan, was scored as a failure (according to RECIST). If the post-radiotherapy 18FDG-PET-scan showed no decrease in SUVmax compared to the pre-treatment 18FDG-PETscan, this was also scored as a failure. Patients developing DM were not censored. Primary outcome is a LF or RF as first event. Consequently, once a LF or RF was observed in a patient, subsequent LF or RF was not scored. Similarly, in case a patient developed a second primary tumor and/or out-of-field LN failure (LNF), they were scored as out-of-field failures and subsequent LRF was not scored. These clinical endpoints were classified based on FU-records and repeat CT-scans by two physicians: a radiation-oncologist and thoraciconcologist. Statistical analysis Time to LF, RF and death was calculated from the first day of RT. Patient-specific variables (age, gender, performance status) together with tumor-specific variables (histology, log10(Volume) and SUVmax of both GTV-PT and GTV-LNs) were tested as prognostic factors for LF and RF. GTV-PT and GTV-LNs were calculated according to the delineated target on the planning CT. Lesion volume was adopted as terminology to refer to either GTV-PT or GTV-LNs. SUVmax was calculated on the pre-treatment 18 FDG-PET-scan for both lesions separately. First, the actuarial incidence of LF, RF and OS were calculated according to the Kaplan–Meier method. Log10(Volume) and SUVmax of the GTV-PT and GTV-LNs were compared using the Wilcoxon-rank-sum test. Second, a univariate analysis was conducted on all variables to test them as prognostic factors for lesion failure, using mixed effect Cox proportional hazard model with patient as random effect. This model was employed as both GTVPT and GTV-LNs were entered as separate lesions in the analysis. Finally, a multivariate analysis (MVA) was done by including all variables in the model. The best model was selected based on stepwise backward selection using the likelihood ratio test. P-values less than 0.05 were considered statistically significant. The data were analyzed using the software package R 2.14.1 (R Development Core Team, Vienna, Austria). Results Two hundred and twenty-six patients were eligible for this retrospective study. The median age was 64 years and 40% of the patients were female. The majority (61%) of the patients had TNM stage IIIA, 31% had stage IIIB and 8% had stage IA to IIB. Other patient characteristics are shown in Table 1. The median volume of the GTV-PT (N = 219) and GTV-LNs (N = 180) was 77.9 cc (range, 0.8–1820) and 27.1 cc (range 0.4–206.3), respectively (p < 0.01). The median SUVmax of the GTV-PT and the GTV-LNs was 12.4 (range, 2.5–38.3) and 5.4 (range 0.9–28.3), respectively (p < 0.01). With a median FU of 29 months (95% CI, 24–34 months), 112 (50%) patients showed no LF, RF and/or DM. The median OS was 28 months (95% CI, 22–31 months). The 1- and 2-year OS rates were 72% and 52%, respectively (Fig. 2a).
Please cite this article in press as: van Diessen JNA et al. Differential analysis of local and regional failure in locally advanced non-small cell lung cancer patients treated with concurrent chemoradiotherapy. Radiother Oncol (2016), http://dx.doi.org/10.1016/j.radonc.2016.02.008
J.N.A. van Diessen et al. / Radiotherapy and Oncology xxx (2016) xxx–xxx Table 1 Patient characteristics of the patient group (N = 226). Characteristic Median age (range)
64 (37-87)
Gender (%) Male Female
136 (60%) 90 (40%)
Performance status (%) WHO 0 WHO 1 WHO 2
75 (33%) 146 (65%) 5 (2%)
TNM stage (%) IA–IB IIA–IIB IIIA IIIB
5 (2%) 13 (6%) 137 (61%) 71 (31%)
Tumor stage (%) T0–T1 T2 T3 T4 Missing
46 (20%) 70 (31%) 46 (20%) 63 (28%) 1 (<1%)
Nodal stage (%) N0 N1 N2 N3 Missing
30 (13%) 18 (8%) 133 (59%) 44 (19%) 1 (<1%)
Histology (%) SCC NSCLC NOS AC Other Missing
76 (34%) 71 (31%) 65 (29%) 11 (5%) 3 (1%)
Additional weekly Cetuximab (%) Yes No
33 (15%) 193 (85%)
SCC = squamous cell AC = adenocarcinoma
carcinoma;
NOS = not
otherwise
specified;
226 paents
9 paents excluded: second primary or out-of-field LNF
Tumor control 112 (50%)
LF and/or RF 44 (19%)
DM only 61 (27%)
With DM: 25 (57%) Without DM: 19 (43%)
LF only 24 (55%)
LF and RF 7 (16%)
LF and out-offield LNF 6 (14%)*
RF only 7 (16%)
Fig. 1. Patterns of failure in the 226 patients treated with concurrent chemoradiotherapy. Final LF and RF rates calculated as part of the 44 patients with a LF and/or RF. (⁄) Including 1 patient with a second primary tumor as well. DM = distant metastases; LF = local failure; RF = regional failure; LNF = lymph node failure.
Median time to progression was 15 months (95% CI, 12– 19 months). Patterns of failure of the 226 patients are shown in Fig. 1. Thirty-seven of the 226 patients (16%) had a LF, of which the majority (N = 24) had a LF only. RF was observed in 14 patients
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(6%) of the 226 patients. Seven patients had a LF with a RF and 5 developed a LF with an out-of-field lymph node failure (LNF). Seven other patients had an isolated RF. Ultimately, forty-four patients (19%) developed a LF and/or RF (Fig. 1). The 1- and 2-year LF rates were 16% and 26%, whereas the 1- and 2-year RF rates were 8% and 14% for LNs (Fig. 2c). Eighty-seven patients (38%) developed DM. Although excluded from the analysis, it is important to note that 4 patients (2%) developed a second primary tumor and in six patients (3%) an out-of-field LNF was observed. Univariate analysis revealed a significant association of the log10(Volume) of PT and LNs (p < 0.01) and SUVmax (p = 0.02) with lesion failure (Table 2). Furthermore, LNs have a significantly lower risk of tumor failure as compared to the PT (p = 0.02). There were no significant patient-related factors for LF and RF, although performance status had a trend toward significance (p = 0.08). Histology also was not significantly associated with lesion failure. Similarly, testing the association of GTV-PT and GTV-LNs with LF and RF respectively, did not reach statistical significance (not shown). In the MVA, the log10(Volume) remained the only significant prognostic factor for locoregional failure (p < 0.01) (Table 2). Similar results were obtained with lesion volume (Table S1). Fig. 3a and b show the 1- and 2-year failure rates related to log10(Volume), divided in subgroups. These figures illustrate that there is no clear difference of log10(Volume) on the failure probability. The nonsignificant association of SUVmax in the MVA might indicate a correlation between volume and SUVmax. This was confirmed by the Pearson’s correlation coefficient of 0.60 (0.54–0.66), implying a considerable linear correlation (Figure in Supplemental material).
Discussion In this study, we scored LF and RF as first event in patients with locally advanced NSCLC treated with concurrent chemoradiotherapy and observed about a 2.5-fold higher absolute risk to develop a LF (16%) than a RF (6%). This is the first study that analyzed factors that influenced lesion control probability and demonstrated that in MVA, log10(Volume) of the lesion was the only significant prognostic factor for failure after CCRT. The location of the lesion (LNs versus PT) was not significantly correlated with failure in the MVA, suggesting that the difference in LF and RF incidence is primarily caused by the average volume differences. Earlier reports were published concerning volume in relation to survival and LRF. Ball et al. investigated PT volume related to OS in 509 patients [10]. Their results showed that volume adversely affected OS, mainly in the first 18 months after treatment, probably due to a combination of factors, such as radiosensitivity and metastatic potential. Schytte et al. reported their results on the pattern of LRF after definitive RT in mainly stage III patients [11]. Ninetythree (28%) of 331 patients developed a LF (20.5%), a RF (0.3%) or both (7.3%). The treatment consisted of a large variety of RTschedules (minimum 60 Gy) and only 36% received CCRT. Patients who developed LF in the presence of DM were excluded, as well as patients with overall tumor control. Combined PT and LNs volume was the only significant risk factor for recurrence. Their results seem comparable to ours, but 51 patients with synchronously developed LF and DM were not included. If included, the actual LF rate would be 43%, which is higher than our results. In both analyses of Schytte and Ball, the use of FDG-PET-scans was optional and performed in a subgroup of the patients, which might have caused an underestimation in volume of both PT and involved LNs, as well as an increase in the risk of inadequate staging [12]. It is not unlikely that this has influenced the observed failure and OS rates. In addition, assessing the metabolic tumor volume of the PT
Please cite this article in press as: van Diessen JNA et al. Differential analysis of local and regional failure in locally advanced non-small cell lung cancer patients treated with concurrent chemoradiotherapy. Radiother Oncol (2016), http://dx.doi.org/10.1016/j.radonc.2016.02.008
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Local and regional failure in advanced NSCLC
Fig. 2. Kaplan–Meier estimates of OS (a), locoregional control (b) of the 226 patients treated with CCRT. Fig. 2c depicts the Kaplan–Meier estimates of local failure (GTV-PT, N = 219) and regional failure (GTV-LN, N = 180).
and LNs on FDG-PET-scans was recently observed as an independent prognostic factor for disease-free survival and OS above the yp-stage in patients treated with CCRT and additional surgery [13]. Furthermore, not all patients with locally advanced NSCLC received CCRT, which is the standard of care in this patient group. The results of the current analysis are based on a homogeneous patient group, diagnosed with NSCLC according to the same work-up and treated with the same CCRT-schedule. Therefore, uncertainty due to heterogeneity in differences in work-up or treatment is unlikely. Despite the homogeneous patient group, work-up and treatment, the failure rates in our analysis may be underestimated. Firstly, this analysis is retrospective. In metastasized patients the FU-schedule is guided toward palliation and locoregional control
is assessed less frequently. However, we found that in most of the metastasized patients a chest X-ray or CT-thorax was performed less than 4 months before death. Similarly, we did not score subsequent LF/RF in a patient once a LF or RF was observed, due to the start of e.g. systemic treatment that affects the results. Another argument related to bias applies to the number of RF. In this analysis, a RF rate of 6% was observed. A total nodal volume was calculated, because in clinical practice separate nodal stations are often contoured as one volume. Hilar nodes may often have been included in the GTV of the PT when in close relation to the hilum, which limits the strength of this analysis. We analyzed lesion volume as a continuous variable and did not find obvious cut-off points for either PT or LNs. Ball et al. did report a cut-off point of 3 cm of the PT diameter for OS after CCRT but did not
Please cite this article in press as: van Diessen JNA et al. Differential analysis of local and regional failure in locally advanced non-small cell lung cancer patients treated with concurrent chemoradiotherapy. Radiother Oncol (2016), http://dx.doi.org/10.1016/j.radonc.2016.02.008
J.N.A. van Diessen et al. / Radiotherapy and Oncology xxx (2016) xxx–xxx Table 2 Univariate and multivariate analyses of patient and tumor characteristics related to the risk of a LF or RF. The multivariate analysis is performed using stepwise backward selection. The variables are presented in the order of deleted variables. Variable Univariate analysis Log10(Volume) SUVmax LNs vs PT PS P 1 vs 0 Age per 10 years Gender (female vs male) Histology SCC vs AC Other vs AC Multivariate analysis SUVmax LNs vs PT Log10(Volume)
Hazard ratio (95% CI)
P-Value
3.47 1.07 0.45 2.87 1.44 0.54
(1.59–7.59) (1.01–1.13) (0.24–0.85) (0.87–9.41) (0.84–2.49) (0.18–1.56)
<0.01 0.02 0.02 0.08 0.18 0.25
1.28 (0.27–6.20) 0.50 (0.10–2.57)
0.21
0.98 (0.90–1.07) 0.63 (0.31–1.28) 3.47 (1.59–7.59)
0.66 0.20 <0.01
LF = local failure; RF = regional failure; LN vs PT = involved lymph nodes versus primary tumor; PS = performance status; SCC = squamous cell carcinoma; AC = adenocarcinoma.
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report on locoregional control [14]. In MVA, LNs had a reduced hazard ratio of 0.63 although not significant. This could suggest that LNs have a higher radiosensitivity or that their volume on PET-CT is overestimated. Additionally, not all LNs were pathologically proven and, as described in the methods section, also unproven nodes that were considered malignant, were irradiated. This could also explain the lower regional failure rate, since the percentage of uninvolved LNs in this analysis is unknown. It might be helpful to classify LNs based on clinicopathological features, such as discrete enlargement on CT and the close vicinity of involved LNs to the PT [15]. Although both features were associated with a more favorable PFS and OS, local relapses were frequently observed, as was the case in the subgroup of pathological proven LNs. Another solution might be to calculate the ratio of LNs SUV to PT SUV instead of the SUVmax, which was reported to be more reliable when assessing nodes of low to intermediate SUV [16]. A future analysis to assess the regional failure rate in pathologically proven versus unproven LNs could guide clinicians in selecting suspect lymph nodes. The SUVmax of a pre-RT 18FDG-PET-scan correlates with OS in locally advanced NSCLC patients, treated with definitive RT or CCRT [17]. Recently, the results of a secondary analysis of the ACRIN-study were published, showing that high residual FDGactivity in LNs on PET-scans is correlated with worse locoregional control [18]. Our results revealed a correlation between SUVmax and LRF in the univariate analysis, but no longer in the MVA when volume was accounted for (Table 2). This is explained by the correlation between log10(Volume) and log10(SUVmax), suggesting that SUVmax is not a strong prognostic factor in itself to predict LF or RF. Therefore, differentiating LNs metastases on PET might be complicated due to their smaller volume. In our analysis, the local and regional failure rate is primarily explained by the log10(Volume). This could be clarified by the proportionally higher number of clonogenic tumor cells in the PT than in LNs that need to be eradicated by chemoradiation. In the era of personalized treatment, the dose prescription could therefore be directed toward individual volumes of the PT and/or LNs. This is technically feasible using an integrated boost technique. Changing the dose to the PT and/or LNs might be a strategy to improve local control as well as a lower toxicity rate, e.g. acute esophagitis. An increase in grade 3 radiation-esophagitis is caused by a minimal radiotherapy dose of 50 Gy to an increasing volume of the esophagus (V50) [19,20]. Dose de-escalation to the mediastinum might therefore be considered. However, a concern is that higher RF rates may be encountered with this strategy and potentially translate in a reduced PFS and OS [21]. Therefore, dose-escalation to the PT only is an alternative based on the same rationale, as is currently being investigated in the international randomized phase II PETboost trial [22]. In conclusion, our regimen of hypofractionated radiotherapy combined with daily low-dose cisplatin results in relatively low LF and RF rates as first event in LA-NSCLC patients. With a median FU of 29 months, the recurrence rate in irradiated LNs was only 6%, whereas the recurrence rate of the PT was 16%. This is primarily explained by the difference in log10(Volume). Conflict of interest None.
Fig. 3. Proportion of failure at 1-year (a) and 2-year (b) for PT and LNs at different volume classes. The 4 volume subgroups for PT and LNs were defined by the 25%, 50%, 75% percentiles of the log10 transformed volume, and the points were plotted at the x-axis at the median volume of each subgroup. The y-axis gives the Kaplan– Meier estimates of the 1- and 2-year proportion of failure (with 95% confidence interval). Note that the 4th subgroup of the LNs is not plotted at 2-year since no events were observed after 15 months (either lost to FU or died within 2 year) (3b).
Appendix A. Supplementary data Supplementary data associated with this article can be found, in the online version, at http://dx.doi.org/10.1016/j.radonc.2016.02. 008.
Please cite this article in press as: van Diessen JNA et al. Differential analysis of local and regional failure in locally advanced non-small cell lung cancer patients treated with concurrent chemoradiotherapy. Radiother Oncol (2016), http://dx.doi.org/10.1016/j.radonc.2016.02.008
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Local and regional failure in advanced NSCLC
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Please cite this article in press as: van Diessen JNA et al. Differential analysis of local and regional failure in locally advanced non-small cell lung cancer patients treated with concurrent chemoradiotherapy. Radiother Oncol (2016), http://dx.doi.org/10.1016/j.radonc.2016.02.008