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P-annotatePDF-v11 INSTRUCTIONS ON THE ANNOTATION OF PDF FILES To view, print and annotate your article you will need Adobe Reader version 9 (or higher). This program is freely available for a whole series of platforms that include PC, Mac, and UNIX and can be downloaded from http://get.adobe.com/reader/. The exact system requirements are given at the Adobe site: http://www.adobe.com/products/reader/tech-specs.html. Note: if you opt to annotate the file with software other than Adobe Reader then please also highlight the appropriate place in the PDF file. PDF ANNOTATIONS Adobe Reader version 9 Adobe Reader version X and XI When you open the PDF file using Adobe Reader, the Commenting tool bar should be displayed automatically; if not, click on ‘Tools’, select ‘Comment & Markup’, then click on ‘Show Comment & Markup tool bar’ (or ‘Show Commenting bar’ on the Mac). 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Do not use this feature to make text edits. Click on the ‘Add Sticky Note’ icon on the Comment tool bar. Click to set the location of the note on the document and simply start typing. Do not use this feature to make text edits. the box by clicking on ‘_’ corner. in the top right-hand Replace text Remove text Highlight text/ make a comment Attach a file Leave a note/ comment HOW TO... Action Review Adobe Reader version 9 To review your changes, click on the ‘Show’ on the Commenting tool button bar. Choose ‘Show Comments List’. Navigate by clicking on a correction in the list. Alternatively, double click on any mark-up to open the commenting box. Undo/delete change To undo any changes made, use the right click button on your mouse (for PCs, Ctrl-Click for the Mac). Alternatively click on ‘Edit’ in the main Adobe menu and then ‘Undo’. You can also delete edits using the right click (Ctrl-click on the Mac) and selecting ‘Delete’. Adobe Reader version X and XI Your changes will appear automatically in a list below the Comment tool bar. Navigate by clicking on a correction in the list. Alternatively, double click on any mark-up to open the commenting box. To undo any changes made, use the right click button on your mouse (for PCs, Ctrl-Click for the Mac). Alternatively click on ‘Edit’ in the main Adobe menu and then ‘Undo’. You can also delete edits using the right click (Ctrl-click on the Mac) and selecting ‘Delete’. SEND YOUR ANNOTATED PDF FILE BACK TO ELSEVIER Save the annotations to your file and return as instructed by Elsevier. Before returning, please ensure you have answered any questions raised on the Query Form and that you have inserted all corrections: later inclusion of any subsequent corrections cannot be guaranteed. 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Our reference: JTHO 92 P-authorquery-v9 AUTHOR QUERY FORM Journal: JTHO Please e-mail your responses and any corrections to: E-mail: [email protected] Article Number: 92 Dear Author, Please check your proof carefully and mark all corrections at the appropriate place in the proof (e.g., by using on-screen annotation in the PDF file) or compile them in a separate list. Note: if you opt to annotate the file with software other than Adobe Reader then please also highlight the appropriate place in the PDF file. To ensure fast publication of your paper please return your corrections within 48 hours. For correction or revision of any artwork, please consult http://www.elsevier.com/artworkinstructions. Any queries or remarks that have arisen during the processing of your manuscript are listed below and highlighted by flags in the proof. Location in article Query / Remark: Click on the Q link to find the query’s location in text Please insert your reply or correction at the corresponding line in the proof If there are any drug dosages in your article, please verify them and indicate that you have done so by initialing this query Q1 Shortened title OK for running head? If not, please provide alternative with 45 or fewer characters. Q2 In author affiliation lines, please expand the following: IDIBELL in line a; ICO in lines b, c, d, and e; and ICREA in line g. Q3 Throughout manuscript, all abbreviations not used at least three times in abstract, text, or figure legends have been deleted from the respective sections per JTHO style. Also, throughout manuscript, "following" changed to "after" per JTHO usage rule. Q4 In sentence beginning "The European Organisation for Research and Treatment of Cancer Quality of Life QuestionnairedCore Questionnaire" (twice in abstract) and again in "Materials and Methods" section, is expansion of QLQ-C30 OK? Q5 In sentence beginning "These findings had a limited impact," is addition of "responses to the" OK? Q6 In sentence beginning “Patients were prospectively recruited,” please expand ICO (twice). Q7 In sentence beginning “Raw cognitive test scores were compared” and throughout, z-score changed to z value per Dorland's. Q8 In sentence beginning “Participants underwent imaging,” are addition of “M” before “B17” and location of Siemens OK? Q9 In sentence beginning “After omnibus testing, pairwise t tests,” is change to “baseline e 3 months” per “baseline minus 3 months” in Fig. 3 legend OK? Q10 In run-in head “DTI processing and analysis.” DTI was defined as “diffusion-weighted imaging,” but in abstract and in standard usage, DTI stands for “diffusion tensor imaging.” Should this head read (continued on next page) “T1-weighted and diffusion tensor imaging processing and analysis” or is head “DTI processing and analysis” OK? Q11 In sentence beginning “ Briefly, FA maps from all participants,” please define FNIRT. Q12 In sentence beginning “Once all skeletons were created” and in first sentence of next paragraph, is change to “baseline e 3 months” per “baseline minus 3 months” in Fig. 3 legend OK? Q13 In sentence beginning “Type 2 diabetes mellitus and dyslipidemia,” type 2 diabetes mellitis styled per Dorland's. Q14 Is head “Structural Neuroimaging: VBM” OK to get around problem of not being able to use two consecutive run-in heads? Q15 In sentence beginning “Specifically, patients with SCLC exhibited a significant decrease” and next sentence, are changes in word order and addition of “in GMV” twice OK? Q16 Is the sentence beginning “ Additionally, DM and dyslipidemia occurred at a higher incidence” OK as edited? Q17 Is sentence beginning “ In regard to quality of life measures and in line with previous literature,” OK as edited? Q18 In sentence beginning “This explanation is also supported by the fact,” is addition of “explanation” OK? If not, please add appropriate noun after “This.” Q19 In sentence beginning “In conclusion, the SCLC group exhibited cognitive deficits,” do you mean to say that the cognitive deficits and structural changes have a more limited impact on the quality of life of patients with SCLC than on the quality of life of HCs and patients with NSCLC? Q20 In ref 32, please provide date accessed. Q21 In Figure 1 legend, is expansion of CONSORT OK? Q22 Is Figure 2 legend OK as edited? In particular, are changes in word order for clarity and use of minus sign in "(at baseline e 3 months)" (per wording in Fig 3 legend) OK? Q23 In Fig. 4 legend, is expansion of QLC-C30 OK? Q24 In Tables 1 and 2 please provide explaination for use of boldface with some values. Q25 In Table 1, abbreviation for type 2 diabetes mellitus styled per Dorland's. Q26 Please confirm that given names and surnames have been identified correctly. Please check this box or indicate your approval if you have no corrections to make to the PDF file Thank you for your assistance. , 1 ORIGINAL ARTICLE 2 3 4 5 6 7 8 Q26 Marta Simó, PhD,a,b Lucía Vaquero, MSc,a Pablo Ripollés, MSc,a Ane Guturbay, MSc,a 9 Josep Jové, MD,c Arturo Navarro, MD,d Felipe Cardenal, PhD,e Jordi Bruna, PhD,b 10 Antoni Rodríguez-Fornells, PhDa,f,g,* 11 a 12 Cognition and Brain Plasticity Group, Bellvitge Biomedical Research Institute-IDIBELL, L’Hospitalet de Llobregat, 13 Q2 Barcelona, Spain b Neuro-Oncology Unit, Hospital Universitari de Bellvitge – ICO Hospital Duran i Reynals, L’Hospitalet del Llobregat, 14 Barcelona, Spain 15 c Radiation Oncology Department, Hospital Germans Trias i Pujol- ICO Badalona, Badalona, Barcelona, Spain d 16 Lung Cancer Unit, Radiation Oncology Department, ICO Duran i Reynals, L’Hospitalet del Llobregat, Barcelona, Spain e 17 Lung Cancer Unit, Medical Oncology Department, ICO Hospital Duran i Reynals, L’Hospitalet del Llobregat, Barcelona, Spain 18 f Department of Basic Psychology, Bellvitge Campus, University of Barcelona, L’Hospitalet de Llobregat, Barcelona, Spain 19 g Catalan Institution for Research and Advanced Studies, ICREA, Barcelona, Spain 20 21 Received 26 October 2015; revised 24 December 2015; accepted 27 December 2015 Available online - XXX 22 23 24 25 superior temporal gyrus in patients with SCLC compared ABSTRACT 26 with in both control groups. Additionally, patients with Introduction: The toxic effects of prophylactic cranial 27 SCLC showed decreases in GM over time in the aforemenirradiation (PCI) and platinum-based chemotherapy on 28 tioned regions plus in the right parahippocampal gyrus and cognition in the lung cancer population have not yet been hippocampus, together with changes in the WM micro29 well established. In the present study we examined the structure of the entire corpus callosum. These changes had 30 longitudinal neuropsychological and brain structural a limited impact on responses to the European Organisation 31 changes observed in patients with lung cancer who were for Research and Treatment of Cancer Quality of Life 32 undergoing these treatments. Questionnaire—Core Questionnaire, however. Patients with 33 NSCLC showed no cognitive or brain structural differences Methods: Twenty-two patients with small cell lung cancer 34 after chemotherapy. (SCLC) who underwent platinum-based chemotherapy and 35 PCI were compared with two control groups: an age- and 36 Conclusions: This longitudinal study documents moderate education-matched group of healthy controls (n ¼ 21) and a 37 neuropsychological deficits together with notable braingroup of patients with non-SCLC (NSCLC, n ¼ 13) who 38 specific structural changes (in GM and WM) in patients underwent platinum-based chemotherapy. All groups were 39 with SCLC after chemotherapy and PCI, suggesting that Q3 evaluated using a neuropsychological battery and multi40 chemotherapy and especially PCI are associated with the modal structural magnetic resonance imaging: T1-weighted development of cognitive and structural brain toxic effects. 41 and diffusion tensor imaging at baseline (before PCI for 42 SCLC and chemotherapy for NSCLC) and at 3 months after 43 treatment. T1 voxel-based morphometry and tract-based 44 spatial statistics (diffusion tensor imaging–tract-based *Corresponding author. 45 spatial statistics) were used to analyze microstructural Drs. Bruna and Rodríguez-Fornells are co–senior authors of this work. 46 changes in gray matter (GM) and white matter (WM). The Disclosure: The authors declare no conflicts of interest. 47 European Organisation for Research and Treatment of Address for correspondence: Antoni Rodríguez-Fornells, PhD, Cognition 48 Cancer Quality of Life Questionnaire—Core Questionnaire and Brain Plasticity Group, Bellvitge Biomedical Research InstituteIDIBELL, L’Hospitalet de Llobregat, Barcelona, Feixa Llarga s/n, 08097, 49 Q4 was also completed. Spain. E-mail: [email protected] 50 ª 2016 International Association for the Study of Lung Cancer. Results: Patients with SCLC exhibited cognitive deteriora51 Published by Elsevier Inc. All rights reserved. tion in verbal fluency over time. Structural magnetic reso52 ISSN: 1556-0864 nance imaging showed decreases in GM at 3 months in 53 http://dx.doi.org/10.1016/j.jtho.2015.12.110 the right subcortical regions, bilateral insular cortex, and Longitudinal Brain Changes Associated with Prophylactic Cranial Irradiation in Lung Cancer Journal of Thoracic Oncology FLA 5.4.0 DTD JTHO92_proof 4 February 2016 7:56 pm ce Vol. - No. -: --- Q5 54 55 56 57 58 59 60 61 62 63 64 65 66 67 68 69 70 71 72 73 74 75 76 77 78 79 80 81 82 83 84 85 86 87 88 89 90 91 92 93 94 95 96 97 98 99 100 101 102 103 104 105 106 2 Simó et al 107 108 109 110 111 112 113 114 115 116 117 118 119 120 121 122 123 124 125 126 127 128 129 130 131 132 133 134 135 136 137 138 139 140 141 142 143 144 145 146 147 148 149 150 151 152 153 154 155 156 157 158 159 160 Journal of Thoracic Oncology 2016 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved. Keywords: Radiotherapy; Chemotherapy; Cognition; Small cell lung cancer; Prophylactic cranial irradiation Introduction Small cell lung cancer (SCLC) constitutes nearly 15% of all newly diagnosed cases of lung cancer. Standard therapy for patients with SCLC includes platinum-based chemotherapy and thoracic radiation.1 Despite treatment advances, SCLC is difficult to cure as it has a high tendency toward development of distant metastasis, especially brain metastases. The use of prophylactic cranial irradiation (PCI) has reduced the incidence of brain metastases, prolonged disease-free survival, and improved overall survival (OS) in patients with SCLC who previously responded to chemoradiation therapy.2,3 Specifically, the addition of PCI to the standard therapy has an absolute benefit in prolonging survival without disease progression at 6 months (8.8% and 7.9% for limited and extensive SCLC, respectively) and in increasing OS (5.4% at 3 years for limited SCLC and 13.8% at 1 year for extensive SCLC).2,3 Thus, to date, only those patients with SCLC with a dismal prognosis are not eligible for PCI. Conversely, patients with nonSCLC (NSCLC) usually undergo similar platinum-based chemotherapy but not PCI.4 In the NSCLC population, PCI has been shown to increase disease-free survival without an improvement in OS.5 With recent increases in the number of long-term cancer survivors, the potential contribution of chemotherapy and radiotherapy to the development of neurocognitive deficits and its impact on quality of life are increasingly being recognized.6–8 However, chemotherapy-related cognitive research focused on the lung cancer population has been scarce. Early studies found that patients with NSCLC exhibited transient cognitive deficits soon after chemotherapy.9–14 Other studies, focusing exclusively on patients with SCLC, found that nearly 60% to 90% of patients were cognitively impaired 1 to 5 months after concluding chemotherapy.9–11,15,16 Although these results are suggestive, little is known about the underlying structural or functional brain alterations that might follow chemotherapy for lung cancer. Additionally, the cognitive toxic effects of PCI in patients with SCLC have not been well established. Studies focusing on PCI-associated cognitive neurotoxic effects are limited and contradictory.9,10,15,17–26 To the best of our knowledge, only a few short-term (1.5 months) prospective neuroimaging studies have been published, showing widespread changes in white matter (WM) Vol. - No. - shortly after PCI therapy.11,27 However, the impact of these neurotoxic effects on self-reported quality of life measures described in patients with SCLC is minor and not significant at 3 months after PCI. 6 The aim of our study was to examine the PCI-induced longitudinal cognitive toxic effects together with the structural changes in gray matter (GM) and WM in a group of patients with SCLC who were treated with platinum-based chemotherapy and PCI compared with those in an age- and education-matched group of healthy controls (HCs). Additionally, to control for the cognitive effects of chemotherapy, a group of patients with NSCLC who underwent the same platinum-based chemotherapy schedule were also recruited. Materials and Methods Patients Patients were prospectively recruited from December 2010 to January 2014 from the Lung Cancer Unit-ICO Duran i Reynals-Hospital Universitari de Bellvitge (n ¼ 28) and from the Radiation Oncology Department-ICO Badalona-Hospital Germans Trias i Pujol (n ¼ 7). Patients were eligible if they had a histologically proven diagnosis of either SCLC or NSCLC; were between 40 and 70 years of age; and had no severe concomitant systemic illness, psychiatric disorder with a negative impact on cognitive function, or contraindication to magnetic resonance imaging (MRI). Patients were excluded if they had antihuman antibodies in their serum (to exclude paraneoplastic antihuman encephalitis),28 evidence of brain metastasis on MRI, or disease progression. Patients with SCLC (n ¼ 22) eligible to receive PCI at a total dose of 25 Gy (2.5 Gy per fraction) were enrolled 1 month after completion of chemotherapy and before PCI (baseline assessment). Patients with NSCLC (n ¼ 13) eligible to receive platinum-based chemotherapy were enrolled in the study before the initiation of chemotherapy (baseline assessment). Both groups were evaluated at 3 months after completion of PCI in the group with SCLC and chemotherapy in the group with NSCLC (3-month assessment). The baseline analysis of this cohort (the group with SCLC 1 month after chemotherapy, the group with NSCLC before receiving chemotherapy, and the HC group) has been previously published.29 The NSCLC group was selected as a control for the evaluation of chemotherapy effects on patients with SCLC because patients with NSCLC presented a common organ location, had similar demographic and clinical features, and underwent the same platinum-based chemotherapy without PCI. Age- and education-matched HCs (n ¼ 21) meeting the same inclusion (except for cancer diagnosis) and exclusion criteria were recruited through community advertisements. Vascular risk factors were collected and FLA 5.4.0 DTD JTHO92_proof 4 February 2016 7:56 pm ce 161 162 163 164 165 166 167 168 169 170 171 172 173 174 175 176 177 178 Q6 179 180 181 182 183 184 185 186 187 188 189 190 191 192 193 194 195 196 197 198 199 200 201 202 203 204 205 206 207 208 209 210 211 212 213 214 --- 215 216 217 218 219 220 221 222 223 224 225 226 227 228 229 230 231 232 233 234 235 236 237 238 239 240 241 242 243 244 245 246 247 248 249 250 251 252 253 254 255 256 257 258 259 260 261 262 263 264 265 266 267 268 2016 Brain Changes with Irradiation in Lung Cancer patients were categorized as low-risk (no or one risk factor) or high-risk (two or more risk factors) groups.11 Platinum-based chemotherapy type (cisplatin or carboplatin) and dose (in mg/m2) received was also compiled. All statistical analyses were conducted using Statistical Package for the Social Sciences (SPSS) version 18.0 (SPSS Inc., Chicago, IL). One-way analysis of variance (ANOVA) and chi-square tests were used to test group differences with a critical p threshold of 0.05. Standard Protocol Approvals The study protocol was approved by the local ethical committee, and all participants were given and signed a written informed consent document. Neuropsychological and Quality of Life Assessment Q7 Patients were evaluated at baseline using the following instruments: the vocabulary subtest of the Spanish version of the Wechsler Adult Intelligence Scale-III to estimate intelligence quotient, a verbal memory test (the Rey Auditory Verbal Learning Test [AVLT]), a test to measure visuospatial abilities and visual memory (the copy and delayed recall measures of the Rey-Osterreith Complex Figure Test [ROCF]), the Verbal Fluency Test (phonemic and semantic), a processing speed test (parts A and B of the Trail Making Test [TMT]), and the Beck Depression Inventory (BDI). At the 3-month evaluation, a different version of the ROCF and the Rey AVLT, together with the Verbal Fluency Vest (phonemic and semantic), TMT A and B, and BDI, were administered. Quality of life measures included the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire—Core Questionnaire (QLQ-C30) and were administered at baseline and at the 3-month evaluations.30 Raw cognitive test scores were compared with the validated Spanish normative values, corrected for age and education, and converted into z values. The QLQ-C30 was scored according to methods described in the QLQ-C30 scoring manual (http://groups.eortc.be/qol/manuals). A repeated measures ANOVA with time (at baseline and at 3 months) as a within-subject factor and group (SCLC, HC, and NSCLC) as a between-subject factor was used to assess changes in cognitive test z values and quality of life results. Neuropsychological results are reported uncorrected for multiple testing, although the main group differences surviving a Bonferroni correction are also indicated (12 ANOVAs, p < 0.00416). Post hoc independent t tests between groups (calculated for those neuropsychological variables showing a main effect of group in the repeated measures ANOVA) are also reported after Bonferroni correction (three tests: SCLC versus NSCLC, SCLC versus HC, and HC versus NSCLC). 3 Q1 MRI Scan Acquisition Participants underwent imaging on a 3-tesla MRI scanner (the Siemens Magnetom Trio Tim Syngo MR B17, Siemens, Erlangen, Germany) with a 32-channel phasedarray head coil. High-resolution structural images were obtained using a T1-weighted magnetization-prepared, rapid-acquired gradient echo sequence (240 slices sagittal, repetition time [TR] ¼ 2300 ms, echo time [TE] ¼ 2.98 ms, 1 mm isotropic voxels). A whole brain diffusion MRI sequence using diffusion tensor spin echo planar imaging was acquired as well (voxel size: 2.5 2.5 2.5 mm, matrix: 96 96 55, 2.5-mm-thick slices, no gap, TE ¼ 98 ms, TR ¼ 9600 ms, echo planar imaging factor ¼ 96, field of view ¼ 240 mm, bandwidth ¼ 1022 Hz, echo spacing ¼ 1.08 ms, b value ¼ 1000 s/mm2) in one single run of 64 diffusion-weighted directions and one non– diffusion-weighted volume. Image data quality for both T1 and diffusion images was visually assessed and no artifacts were detected. Finally, a fluid-attenuated inversion recovery sequence was also acquired (64 slices, 2.0 mm thick, TE ¼ 145 ms, TR ¼ 9000 ms, voxel size 1.0 0.9 2.0 mm) to exclude asymptomatic brain metastasis. T1 Image Processing and Analysis. The methodology used was similar to that used in our previous works.29,31–33 Morphometric analysis was carried out using the longitudinal processing stream in the VoxelBased Morphometry 8 (VBM8) toolbox (http://dbm. neuro.uni-jena.de/vbm/) under the Statistical Parametric Mapping 8 (SPM8) software package (Version 8, Wellcome Department of Imaging Neuroscience, London, UK) and MATLAB (Version 7, Mathworks, Inc., Natick, MA). Follow-up T1 structural images were coregistered to baseline T1 images for each subject, bias-corrected, and segmented into GM, WM, and cerebrospinal fluid compartments using the Montreal Neurologic Institute (MNI) T1-weighted template and tissue probability maps. Then, the resultant subject-specific tissue probability maps (GM) were subjected to diffeomorphic anatomical registration using exponentiated Lie algebra to achieve spatial normalization by using a nonlinear registration to the MNI space. Diffeomorphic anatomical registration using exponentiated Lie algebra normalization alternates between computing an average template of GM segmentation from all subjects and warping all subjects’ GM tissue maps into a better alignment with the template created.31 Normalized images were modulated by their Jacobian determinants to identify regional differences in the volume of GM; “modulation” was used to try to compensate for the effect of spatial normalization.33 Normalized and modulated images were smoothed using an isotropic Gaussian spatial filter (full width at half maximum ¼ 8 mm) to accommodate for residual interindividual variability. FLA 5.4.0 DTD JTHO92_proof 4 February 2016 7:56 pm ce Q8 269 270 271 272 273 274 275 276 277 278 279 280 281 282 283 284 285 286 287 288 289 290 291 292 293 294 295 296 297 298 299 300 301 302 303 304 305 306 307 308 309 310 311 312 313 314 315 316 317 318 319 320 321 322 4 Simó et al 323 324 325 326 327 328 329 330 331 332 333 334 335 336 337 338 339 340 341 342 343 344 345 346 347 348 349 350 351 352 353 354 355 356 357 358 359 360 361 362 363 364 365 366 367 368 369 370 371 372 373 374 375 376 Q9 Q10 Q11 Journal of Thoracic Oncology The individual smoothed GM volume (GMV) images were entered into a second-level analysis, specifically a three groups (SCLC, HC, and NSCLC) two times (baseline and 3 months) flexible factorial design within SPM8. In this step, an explicit mask with a threshold of 0.4 (i.e., only those voxels having a 40% probability of being GM were included) was also used to select only the most homogeneous voxels. After omnibus testing, pairwise t tests were performed at the group level to analyze within-group changes over time (baseline – 3 months). For all contrasts, a p 0.05 familywise error (FWE)corrected threshold at the cluster level was used with an auxiliary threshold of p < 0.001 at the voxel level and 50 voxels of spatial extent. Additionally, to study the effect of cognitive deterioration on GMV, we carried out a Pearson’s correlation analysis between the neuropsychological testing scores showing significant differences (see the “Results” section) and the individual mean GMV maps of patients. Specifically, a mask for each significant cluster yielded by the GMV group analysis was defined and applied to each individual image. For each participant, the mean GMV value within the aforementioned mask was then calculated at baseline and at 3 months. Finally, four correlations were computed: the difference in GMV between the 3-month follow-up and baseline was correlated with the difference in the four neuropsychological variables of interest that showed significant main group effects (phonemic fluency, TMT A, AVLT immediate recall [A1], and ROCF first copy) (see the “Results” section). These correlations were Bonferroni-corrected for multiple comparisons. DTI Processing and Analysis. Diffusion tensor imaging (DTI) preprocessing was started by correcting for eddy current distortions and head motion using the Functional MRI of the Brain (FMRIB) group’s Diffusion Toolbox (FDT;FSL5.0.1, www.fmrib.ox.ac.uk/fsl/). The gradient matrix was rotated using the fdt_rotate_bvecs software included in the FMRIB Software Library distribution. Brain extraction was performed using the Brain Extraction Tool, which is also part of the FMRIB Software Library software. The analysis was continued, reconstructing the diffusion tensors by using the linear leastsquares algorithm included in Diffusion Toolkit 0.6.2.2 (Ruopeng Wang, Van Wedeen, trackvis.org/dtk, Martinos Center for Biomedical Imaging-Massachusetts General Hospital). Finally, fractional anisotropy (FA) maps for each subject were calculated at baseline and 3 months. Tract-based spatial statistics (TBSS) of FA was performed.34 Briefly, FA maps from all participants and sessions were recorded to the FMRIB58_FA template using the nonlinear registration tool FNIRT and then averaged to create a mean FA volume. A mean FA skeleton was Vol. - No. - derived, and each participant’s aligned FA data were then projected onto this skeleton. Once all skeletons were created, follow-up images were subtracted from the Q12 baseline images, creating baseline – 3 month skeletons. To compute voxelwise statistics, these baseline – 3 months skeletons were entered into a one-way ANOVA with group as the between factor (group ¼ SCLC, HC, NSCLC). The analysis implemented is equivalent to a three groups (SCLC, NSCLC, and HC) two times (baseline and 3 months) design. After interaction testing, pairwise t tests were performed at the group level to analyze within-group changes over time. Results are reported as an FWE-corrected value (p < 0.05) using threshold-free cluster enhancement and a nonparametric permutation test with 5000 permutations.35 Additionally, to study the effect of cognitive deficits on WM microstructure,30 we carried out a Pearson’s correlation analysis between the neuropsychological testing scores showing significant differences and individual mean FA values of the patients. Specifically, a mask covering the areas showing significant differences in the FA group analysis was defined (setting the threshold at a FWE-corrected p < 0.01; the mask included one cluster with maxima at the genu of the corpus callosum, see the “Results” section). For each participant, the mean FA value within the aforementioned mask was then calculated at baseline and at 3 months. Finally, as in the GMV analysis, four correlations were computed: the difference in FA between the 3-month follow-up and baseline was correlated with the difference in the neuropsychological variables of interest that showed significant main group effects (phonemic fluency, TMT A, AVLT A1, and ROCF first copy; see the “Results” section). These correlations were Bonferroni-corrected for multiple comparisons. Results Patient Characteristics The study design is graphically explained in Figure 1. The final groups consisted of 22 patients in the SCLC group, 13 in the NSCLC group, and 21 in the HC group (characteristics of the entire cohort are described in Table 1). There were no significant differences between groups in terms of age, gender, education, or grouped vascular risk factors. However, smoking history showed a significant difference between patients with lung cancer and the HCs (p < 0.0001), but no differences were observed between the two cancer groups (SCLC and NSCLC, p > 0.37). The rates of type 2 diabetes mellitus (DM) and dyslipidemia were significantly different be- Q13 tween groups. Type 2 DM showed a higher incidence in patients with NSCLC cancer compared with in both the SCLC (p < 0.03) and HC (p < 0.01) groups. Conversely, dyslipidemia showed a lower incidence in the SCLC FLA 5.4.0 DTD JTHO92_proof 4 February 2016 7:56 pm ce 377 378 379 380 381 382 383 384 385 386 387 388 389 390 391 392 393 394 395 396 397 398 399 400 401 402 403 404 405 406 407 408 409 410 411 412 413 414 415 416 417 418 419 420 421 422 423 424 425 426 427 428 429 430 --- 431 432 433 434 435 436 437 438 439 440 441 442 443 444 445 446 447 448 449 450 451 452 453 454 455 456 457 458 459 460 461 462 Q25 463 464 465 466 467 468 469 470 471 472 473 474 475 476 477 478 479 480 481 482 483 484 2016 Brain Changes with Irradiation in Lung Cancer 5 485 486 487 488 489 490 491 492 493 494 495 496 Q21 Figure 1. Consolidated Standards of Reporting Trials flow diagram. 497 498 group compared with in the NSCLC (p < 0.03) and HC Neuropsychological Assessment 499 (p < 0.02) groups. There were no significant differences No significant group time interaction in any of the 500 concerning disease- or treatment-related characteristics measures evaluated was found. However, there were 501 between the two lung cancer groups. main group effects for phonemic fluency [F(2,53) ¼ 6.02, 502 503 504 Table 1. Baseline Demographics and Vascular Risk Factors of the Entire Cohort and Disease- and Treatment-Related 505 Characteristics of the Patients 506 SCLC Group (n ¼ 22) NSCLC Group (n ¼ 13) HC Group (n ¼ 21) p Value Q24 507 Mean age ± SD, y 59.64 ± 4.84 59.92 ± 6.14 62.86 ± 7.91 0.22 508 Gender, n (%) 509 Male 16 (73) 12 (92) 19 (90.5) 0.18 510 Female 6 (27) 1 (8) 2 (9.5) 511 Median years of education (range) 8 (4–17) 10 (0–15) 8 (6–19) 0.61 512 Estimated mean verbal IQ ± SD 8.73 ± 3.55 9.54 ± 4.41 9.57 ± 3.94 0.22 513 Smoking, n (%) 22 (100) 12 (92) 11 (52) <0.01 Alcohol, n (%) 7 (32) 3 (23) 10 (48) 0.31 514 HT, n (%) 6 (27) 5 (38.5) 8 (38) 0.70 515 3 (14) 6 (46) 2 (9.5) 0.02 T2DM, n (%) 516 Dyslipidemia, n (%) 4 (18) 7 (54) 11 (52) 0.03 517 Vascular risk factors, n (%) 518 Low-risk (0–1) 12 (54.5) 2 (15) 9 (43) 0.07 519 High-risk (2) 10 (45.5) 11 (85) 12 (57) 520 Median KPS (range) 80 (70–100) 90 (80–100) 0.08 Histological diagnosis, n (%) 521 SCLC 22 (100) 522 NSCLC 523 Adenocarcinoma 7 (54) 524 Squamous cell carcinoma 5 (38) 525 Nonclassified 1 (8) 526 Tumor stage, n (%) 527 Limited disease 18 (82) Extensive disease 4 (18) 528 IIB 1 (8) 529 IIIA 5 (38) 530 IIIB 7 (54) 531 Chemotherapy type, n (%) 532 CDDP-based 18 (82) 11 (85) 0.41 533 CBDCA-based 4 (18) 2 (15) Median no. chemotherapy cycles (range) 4 (1–6) 4 (3–4) 0.11 534 287.5 ± 77 267.5 ± 45 0.44 Mean CDDP dose ± SD, mg/m2 535 Thoracic radiation therapy, n (%) 20 (91) 11 (85) 0.57 536 SCLC, small cell lung cancer; NSCLC, non–small cell lung cancer; HC, healthy control; SD, standard deviation; IQ, intelligence quotient; HT, 537 hypertension; T2DM, type 2 diabetes mellitus; KPS, Karnosfky Performance Scale; CDDP, cisplatin; CBDCA, carboplatin. 538 FLA 5.4.0 DTD JTHO92_proof 4 February 2016 7:56 pm ce 6 Simó et al 539 540 541 542 543 544 545 546 547 548 549 550 551 552 553 554 555 556 557 558 559 560 561 562 563 564 565 566 567 568 569 570 571 572 573 574 575 576 577 578 579 580 581 582 583 584 585 586 587 588 589 590 591 592 Journal of Thoracic Oncology p < 0.004], TMT A [F(2,51) ¼ 3.97, p < 0.025], AVLT A1 [F(2,53) ¼ 3.51, p < 0.037], and ROCF first copy [F(2,52) ¼ 9.85, p < 0.001]. The Bonferroni post hoc analysis revealed that the SCLC group performed worse than the HC group in verbal fluency (phonemic fluency), processing speed (TMT A), and verbal working memory (AVLT A1). Moreover, the SCLC group also performed worse than the HCs and patients with NSCLC in visuospatial abilities (ROCF first copy). Further paired t test comparisons in each group showed that patients with SCLC deteriorated over time in verbal fluency (semantic and phonemic fluency, p < 0.03), whereas no significant changes were observed in the NSCLC group. The HC group showed an improvement over time in visual memory and processing speed because of learning effects (see Table 2). Group effects for phonemic fluency and ROCF first copy were still significant after application of a Bonferronii correction (12 ANOVAs, p < 0.0041). Additionally, no significant differences between groups were found for the difference in BDI scores between the baseline and the follow-up sessions [KruskalWallis test, H(2) ¼ 0.10, p > 0.95]. Quality of Life Measures Overall, statistically significant group differences were observed for the QLQ-C30 in the corresponding ANOVA for most of the evaluated items (see Supplementary Table e-2 and Fig. 4). However, no significant group time interaction was encountered. Further explorative paired t test comparisons in each group showed that the SCLC group deteriorated over time in terms of cognitive functioning (p < 0.05) and nausea (p < 0.03) whereas no significant changes over time were observed in the NSCLC and HC groups. Q14 Structural Neuroimaging: VBM Q15 Longitudinal assessment: group 3 time interaction. The VBM analysis revealed a significant group time interaction for GMV in several brain regions (see Supplementary Table e-1 and Fig. 2). Specifically, patients with SCLC exhibited a significant decrease in GMV in the right thalamus, right caudate, bilateral insular cortex, and superior temporal gyrus at 3 months follow-up in comparison with the HC group. A significant decrease in GMV in the bilateral caudate and insula, left superior and middle temporal gyrus, and right cerebellum at 3 months follow-up was observed in patients with SCLC compared with in patients with NSCLC. No other significant results were found in the group time interaction analysis. Longitudinal Assessment: Within-Group Analysis. Within-group longitudinal analysis yielded significant results in the SCLC group. Those with SCLC showed a Vol. - No. - significant decrease in GMV over time in similar regions as in the aforementioned group time interaction (right thalamus, right caudate, bilateral insular cortex, and superior and middle temporal gyrus). Furthermore, GMV decreases in the right parahippocampal gyrus and hippocampus were also found for the SCLC group. No significant differences were observed in the within-group longitudinal analysis in the HC and NSCLC groups. Additionally, the correlations between the average GMV values of all the clusters showing differences over time in the SCLC group and the four cognitive tests showing a main group effect were not significant. Diffusion Tensor Imaging: TBSS Analysis Longitudinal Assessment: Group 3 Time Interaction. No significant differences were found in the group time interaction in the TBSS analysis. However, when using a more permissible p value (p ¼ 0.10 FWE-corrected) and also holding at a p ¼ 0.001 uncorrected threshold, we found a trend toward FA decreases mainly in the genu and body of the corpus callosum (CC) for the SCLC group compared with for both the HC and NSCLC groups at 3 months follow-up. These interactions should be taken with caution as, although plausible, they only reflect a trend that did not survive a corrected threshold. Longitudinal Assessment: Within-Group Analysis. The within-group longitudinal analysis showed a significant decrease (p < 0.05, FWE-corrected) in FA (changes in WM microstructure) in the CC at 3 months after PCI in the SCLC group. No significant differences were observed in the within-group longitudinal analysis for the HC or NSCLC groups. Additionally, the correlation between the average FA values of the only cluster at the CC in the SCLC group and the four cognitive tests showing a main group effect revealed a significant positive correlation (r ¼ 0.56, p < 0.007, Bonferroni-corrected for the four correlations computed) between FA decreases and deteriorated processing speed (TMT A). This correlation shows that slow processing speed was associated with changes in WM microstructure (lower FA values) in the CC (see Fig. 3). Discussion This is the first longitudinal study, to the best of our knowledge, to document neuropsychological and structural changes in the GM and WM of the brains of a group of patients with SCLC who were treated with PCI. Our results revealed that the SCLC group exhibited moderate cognitive worsening at 3 months after PCI treatment that was accompanied by large decreases in GM mainly in the caudate, insula, and superior temporal gyrus bilaterally in comparison with both the HC and NSCLC groups. FLA 5.4.0 DTD JTHO92_proof 4 February 2016 7:56 pm ce 593 594 595 596 597 598 599 600 601 602 603 604 605 606 607 608 609 610 611 612 613 614 615 616 617 618 619 620 621 622 623 624 625 626 627 628 629 630 631 632 633 634 635 636 637 638 639 640 641 642 643 644 645 646 647 648 649 650 651 652 653 654 655 656 657 658 659 660 661 662 663 664 665 666 667 668 669 670 671 672 673 674 675 676 677 678 679 680 681 682 683 684 685 686 687 688 689 690 691 692 693 694 695 696 697 698 699 700 --- 2016 Table 2. Neuropsychological Resultsa SCLC Group NSCLC Group HC Group BDI 13, n (%)b Verbal fluency Semantic fluency Phonemic fluency Processing speed and executive Trail Making Test A Trail Making Test B Visuospatial abilities ROCF first copy Visual memory ROCF delayed Verbal memoryb AVLT immediate recall (A1) AVLT immediate recall (B1) AVLT learning curve (A5–A1) AVLT short-delay recall (A6) AVLT long-delay recall (A7) p Value Paired t Test p Value Baseline 3 mo Paired t Test Baseline At 3 mo Baseline At 3 mo p Value p Value 6 (12) 4 (9) 0.89 1 (2) 2 (4) 0.72 3 (6) 3 (6) 0.75 0.95 0.06 (1.06) –0.32 (1.09) functions –0.33 (0.78) –0.55 (0.94) –0.41 (1.02) –0.83 (1.17) 0.03 0.03 0.18 (0.94) –0.03 (1) –0.26 (1.34) –0.54 (1.24) 0.32 0.20 0.40 (0.78) 0.51 (0.68) 0.16 (0.68) 0.21 (0.95) 0.18 0.06 0.19 0.004c,d –0.20 (1.14) –0.12 (1.53) 0.49 0.05 –0.18 (1.08) –0.37 (1.20) 0.09 (1.51) 0 (1.29) 0.61 0.52 0.35 (0.92) –0.03 (0.77) 0.62 (0.88) 0.35 (0.94) 0.06 0.02 0.025c 0.29 0.33 (0.76) 0.21 (1.18) 0.66 1.61 (1.22) 1.05 (1.45) 0.25 1.50 (1.04) 1.07 (1.14) 0.22 0.0001d,e 0.60 (0.81) 0.40 (1.04) 0.33 0.61 (0.72) 0.54 (0.88) 0.76 0.77 (0.71) 1.07 (1.14) 0.002 0.17 4.14 4.68 5.82 6.32 6.82 3.91 3.86 4.95 6.86 6.64 0.52 0.04 0.17 0.24 0.77 4.31 4.54 5.46 7.23 6.69 4.38 3.77 5.77 7.38 6.54 0.87 0.22 0.70 0.86 0.86 5.05 5 5.38 7.95 7.95 5.29 5 5.57 8.67 8.19 0.60 1 0.70 0.19 0.67 0.037c 0.08 0.94 0.11 0.18 (1.93) (1.21) (1.97) (2.51) (2.72) (1.72) (1.52) (2.48) (3.44) (3.06) (1.44) (2.26) (2.07) (3.47) (3.32) (1.32) (1.30) (2.49) (2.06) (2.40) (1.69) (1.30) (2.11) (3.04) (3.54) (1.79) (1.55) (2.46) (2.69) (2.44) a The paired t test and RM ANOVA between-group results are reported. Except for items marked with a b (raw score), all results are z values and presented as means (standard deviations). c Differences were significant between the SCLC and HC groups after Bonferroni correction. d p Values are reported uncorrected for multiple comparisons; main group differences that were significant after Bonferroni correction are marked with a d. e Differences were significant between the SCLC group and both the HC the NSCLC groups after Bonferroni correction. SCLC, small cell lung cancer; NSCLC, non–small cell lung cancer; HC, healthy control; RM ANOVA, repeated measures analysis of variance; mo, month; BDI, Beck Depression Inventory; ROCF, Rey-Osterrieth Complex Figure Test; AVLT, Auditory Verbal Learning Test. b Brain Changes with Irradiation in Lung Cancer FLA 5.4.0 DTD JTHO92_proof 4 February 2016 7:56 pm ce Paired t Test RM ANOVA Main Group Effect 7 701 702 703 704 705 706 707 708 709 710 711 712 713 714 715 716 717 718 719 720 721 722 723 724 725 726 727 728 729 730 731 732 733 734 735 736 737 738 739 740 741 742 743 744 745 746 747 748 749 750 751 752 753 754 755 756 757 758 759 760 761 762 763 764 765 766 767 768 769 770 771 772 773 774 775 776 777 778 779 780 781 782 783 784 785 786 787 788 789 790 791 792 793 794 795 796 797 798 799 800 801 802 803 804 805 806 807 808 Journal of Thoracic Oncology Vol. - No. - print & web 4C=FPO 8 Simó et al Figure 2. Regional gray matter volume (GMV) differences in the longitudinal voxel-based morphometry analysis. Results are displayed with a p < 0.05 familywise error–corrected threshold at the cluster level (using an auxiliary p < 0.001 threshold at the voxel level and 50 voxels of spatial extent) on a canonical T1 structural magnetic resonance imaging template. Neurological convention is used. Montreal Neurologic Institute coordinates are indicated at the bottom right of each slice. Bar plots show contrast estimates (amplitude of the effect at a given voxel) for all groups and times with standard error of the mean. Contrast estimates represent the mean-corrected parameter estimates of all effects of interest. Because of the mean correction, the bar plot shows the deviations of the contrast estimates from their mean. Therefore, a negative value does not necessarily mean that the contrast estimate is negative; rather, it may just be lower than the mean of all contrast estimates. (A) Group time interaction analysis comparing patients with small cell lung cancer (SCLC) with healthy controls. This analysis revealed that at 3 months, GMV decreases in the right thalamus, right caudate, bilateral insular cortex, and superior temporal gyrus of patients with SCLC compared with in healthy controls. (B) Group time interaction analysis comparing patients with SCLC with patients with non-SCLC. This analysis revealed that at 3 months, GMV decreases in the bilateral caudate and insula, left superior and middle temporal gyrus, and right cerebellum in patients with SCLC compared with in patients with non-SCLC. (C) Within-group longitudinal analysis of patients with SCLC. The analysis revealed differences in the GM in the right thalamus, right caudate, bilateral insular cortex, and superior and middle temporal gyrus, as well as in the right parahippocampal gyrus and hippocampus of patients with SCLC over time (at baseline – 3 months). FLA 5.4.0 DTD JTHO92_proof 4 February 2016 7:56 pm ce Q22 809 810 811 812 813 814 815 816 817 818 819 820 821 822 823 824 825 826 827 828 829 830 831 832 833 834 835 836 837 838 839 840 841 842 843 844 845 846 847 848 849 850 851 852 853 854 855 856 857 858 859 860 861 862 Brain Changes with Irradiation in Lung Cancer 9 Figure 3. Regional diffusion tensor imaging differences for fractional anisotropy (FA) in the longitudinal (at 3 months – baseline) tract-based spatial statistics analysis for the small cell lung cancer (SCLC) group. The within-group longitudinal analysis in the SCLC group revealed that FA decreases in the entire corpus callosum at 3 months compared with at baseline. Statistical maps (blue) showing reduced FA are displayed over a mean skeleton (green) and the FMRIB58_FA template for better visualization of the white matter pathways. The scatter plot displays the relationship between the areas showing differences in FA (maxima at the genu of the corpus callosum; baseline – 3 months) in the SCLC group and the Trail Making Test A (TMTA, 3 months – baseline). Bar plots show the mean difference (3 months – baseline) in FA within the main cluster at the corpus callosum for all groups with standard error of the mean. Results are shown at an FWE-corrected threshold (p < 0.05). Neurological convention and Montreal Neurologic Institute coordinates are indicated at the bottom right of each slice. Additionally, patients with SCLC showed GM decreases over time in the aforementioned regions and in the right parahippocampal gyrus and hippocampus. Regarding microstructural changes in WM, patients with SCLC showed less FA in the entire CC over time. These imaging findings were found only in patients with SCLC after radiation, suggesting that platinum-based chemotherapy and PCI therapy are associated with brain-specific structural changes in the SCLC population. Cranial radiation toxicity has often been associated with cognitive dysfunction and radiation-induced leukoencephalopathy in patients with brain metastases and primary central nervous system lymphoma. Cognitive symptoms related to cranial radiation include deficits in verbal memory and executive functions, together with a progressive subcortical dementia that usually accompanies gait alterations and extrapyramidal symptoms.36 Recent neuroimaging studies using DTI both in patients with brain tumors and in the SCLC population showed decreased FA in the CC after radiation.32,37 In fact, the CC has recently been described as one of the most radiation-sensitive structures of the brain,38 and the amount of microstructural damage to the WM fibers of the CC has been directly related to the cognitive deterioration found in long-term SCLC survivors.32 Hence, the WM changes in the CC exhibited in the present study are evidence that the damage to WM microstructure seen in long-term SCLC survivors occurs as early as 3 months after radiation therapy and that these WM changes also correlated with cognitive deficits in processing speed. Patients with SCLC present some of the potential risk factors that have been associated with the development of radiation-induced cognitive impairment: they are print & web 4C=FPO 863 864 865 866 867 868 869 870 871 872 873 874 875 876 877 878 879 880 881 882 883 884 885 886 887 888 889 890 891 892 893 894 895 896 897 898 899 900 901 902 903 904 905 906 907 908 909 910 911 912 913 914 915 916 2016 print & web 4C=FPO --- Figure 4. Quality of Life Questionnaire—Core Questionnaire (QLQ-C30) results. FLA 5.4.0 DTD JTHO92_proof 4 February 2016 7:56 pm ce Q23 917 918 919 920 921 922 923 924 925 926 927 928 929 930 931 932 933 934 935 936 937 938 939 940 941 942 943 944 945 946 947 948 949 950 951 952 953 954 955 956 957 958 959 960 961 962 963 964 965 966 967 968 969 970 10 Simó et al 971 972 973 974 975 976 977 978 979 980 981 982 983 984 985 986 987 988 989 990 Q16 991 992 993 994 995 996 997 998 999 1000 1001 1002 1003 1004 1005 1006 1007 1008 1009 Q17 1010 1011 1012 1013 1014 1015 1016 1017 1018 1019 1020 1021 1022 1023 1024 Journal of Thoracic Oncology usually elderly, have been previously treated with chemotherapy, and frequently carry vascular risk factors.11,36 To control for these risk factors, we included an age- and education-matched HC group as well as an NSCLC group. Concerning vascular risk factors, as expected, a higher proportion of patients with lung cancer had a history of smoking than in the HC group. Smoking has been associated with an increased risk of cognitive decline or even dementia, as well as with structural brain differences in both WM and GM, compared with in those who have never smoked.39 Additionally, smoking has also been associated with cerebrovascular damage induced by oxidative stress. This is of relevance especially because this pathological condition is also characterized by a loss of blood-brain barrier integrity. Both the increase in oxidative damage and the loss of bloodbrain barrier integrity have been related to the pathogenesis of chemotherapy- and cranial radiation–induced cognitive impairment.40,41 Additionally, DM and dyslipidemia occurred at a higher incidence in patients with NSCLC than in patients with SCLC, thus not appearing to be a confounding factor in the changes observed in SCLC. In agreement with some previous neuropsychological studies in patients with lung cancer,6,25,26,42–45 and although no significant group time interaction was found, the SCLC group did exhibit a moderate decrease in cognitive functioning at follow-up, especially in verbal fluency (no differences between time points were found for the other groups). These relevant but minor cognitive deficits observed in the SCLC group complement our previous results in the same cohort,28 in which almost 40% of the SCLC group examined 1 month after platinum-based chemotherapy and before PCI exhibited cognitive impairment. On the basis of these results, we hypothesize that significant cognitive changes may occur very soon after chemotherapy, leaving little room for further deterioration 3 months after PCI. In regard to quality of life measures and in line with previous literature,6 the main group differences between SCLC and both NSCLC and HC were found in relation to selected symptoms and functioning scales (see Fig. 4). Although there was no significant group time interaction, patients with SCLC exhibited a limited but significant self-reported cognitive worsening 3 months after PCI. These results are in concordance with the results of a previous longitudinal study comparing quality of life measures in a SCLC population treated with PCI with those in a group of patients with SCLC who did not receive PCI. The results of this study showed that both groups exhibited a global worsening in quality of life and cognitive functioning at 3 months follow-up, with small differences between groups.6 Concerning structural neuroimaging findings, we observed brain-specific structural damage after PCI that Vol. - No. - was not restricted to WM tracts but also involved GM structures. The GM alterations observed in this study were similar to those recently described by our group in an SCLC population 1 month after platinum-based chemotherapy and before PCI29 (see supplementary Fig e-1 for the imaging overlap between the studies). On the basis of these results, we suggest that the GM damage observed in the present study would be initially related to chemotherapy, especially affecting the bilateral insula, parahippocampal regions, and thalamus and would be then superimposed by PCI-specific damage in more medial and subcortical brain regions. Thus, PCI therapy seems to expand the cognitive and GM structural deficits already observed after chemotherapy in patients with SCLC, but adding brain-specific WM damage exclusively in the CC at 3 months follow-up. One possible explanation for this difference is that although chemotherapy may induce chronic changes in the GM of the brains of the SCLC population, it seems to trigger transient WM changes that are replaced by specific radiation-induced WM damage. Indeed, animal models have associated the lower capillary density and blood flow of the CC with severe WM degradation after radiation.46 This explanation is also supported by the fact that similar WM changes are seen in long-term SCLC Q18 survivors.32 Interestingly, these chemotherapy-related changes did not appear after platinum-based chemotherapy in the NSCLC group. We speculate that this distinct response to chemotherapy might be related to an increased susceptibility of SCLC to platinum-based toxicity. The mechanisms underlying these toxic adverse effects are not fully understood. We hypothesize that the inflammatory response induced by SCLC might facilitate the access into the brain of both cancer-related cytokines47 and platinum-based drugs by modifying some characteristics of the BBB.48 Brain-specific damage after cranial irradiation is a major issue, and many recent clinical trials have used selective sparing of critical brain regions in an effort to reduce late cognitive toxicities. One of the most frequently used strategies for reducing neurotoxicity while maintaining the efficacy of cranial radiation therapy is to avoid either the limbic circuit or the neural stem cell–specific areas, such as the subventricular zone and the subgranular zone within the hippocampus.49 Recently, conformal avoidance of the hippocampus during whole brain radiation therapy failed to prevent cognitive decline, although it did show a significant reduction of cognitive deficits.50 Yet, on the basis of our neuroimaging results, sparing only the limbic system or the neural stem cell areas may not prevent the development of neurocognitive deficits in patients with SCLC as the main affected areas appear to extend well beyond the aforementioned regions. FLA 5.4.0 DTD JTHO92_proof 4 February 2016 7:56 pm ce 1025 1026 1027 1028 1029 1030 1031 1032 1033 1034 1035 1036 1037 1038 1039 1040 1041 1042 1043 1044 1045 1046 1047 1048 1049 1050 1051 1052 1053 1054 1055 1056 1057 1058 1059 1060 1061 1062 1063 1064 1065 1066 1067 1068 1069 1070 1071 1072 1073 1074 1075 1076 1077 1078 --- 1079 1080 Q19 1081 1082 1083 1084 1085 1086 1087 1088 1089 1090 1091 1092 1093 1094 1095 1096 1097 1098 1099 1100 1101 1102 1103 1104 1105 1106 1107 1108 1109 1110 1111 1112 1113 1114 1115 1116 1117 1118 1119 1120 1121 1122 1123 1124 1125 1126 1127 1128 1129 1130 1131 1132 2016 Brain Changes with Irradiation in Lung Cancer In conclusion, the SCLC group exhibited cognitive deficits together with brain-specific structural changes after platinum-based chemotherapy and PCI, compared with both the HC and NSCLC groups with a limited impact on their quality of life. Although chemotherapy might have a role in the cognitive changes and changes in GM structure seen in patients with SCLC at baseline, our longitudinal results suggest that PCI-induced changes are mainly responsible for the brain structure and neuropsychological findings observed in the present study. On the basis of our results, patients with SCLC should be informed about the survival benefits of PCI and about the potential minor, but negative, effects of this therapy on cognitive functioning, with emphasis on their limited impact on quality of life. However, because of the permanent long-term cognitive and structural brain effects observed in our previous study of SCLC survivors treated with PCI,32 we think that it is crucial to better identify upfront those patients in whom brain metastases will develop and those patients in whom they will not develop, so that we can safely avoid PCI in subgroups of patients and thereby elude the brain-toxic effects of PCI. 6. 7. 8. 9. 10. 11. Acknowledgments This work was supported by Fundació Marató-TV3 (Acquired Spinal Cord and Brain Injuries Program [2012– 2014], grant awarded to Dr. Rodríguez-Fornells) and the Catalan Government (Generalitat de Catalunya, grant 2009 SGR 93 to Dr. Rodríguez-Fornells). Dr. Simó is a recipient of a Juan Rodés research contract from the Carlos III National Health Institute (Spanish government). 12. 13. Supplementary Data Note: To access the supplementary material accompanying this article, visit the online version of the Journal of Thoracic Oncology at www.jto.org and at http://dx.doi. org/10.1016/j.jtho.2015.12.110. 14. 15. References 1. Johnson BE, Grayson J, Makuch RW, et al. Ten-year survival of patients with small-cell lung cancer treated with combination chemotherapy with or without irradiation. J Clin Oncol. 1990;8:396–401. 2. Auperin A, Arriagada R, Pignon JP, et al. Prophylactic cranial irradiation for patients with small-cell lung cancer in complete remission. 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