Abstract Background Radiotherapy for lung cancer mayinduce pneumonit - PDF document

Abstract. Background: Radiotherapy for lung cancer mayinduce pneumonitis. However, histological effects ofradiotherapy on normal lung tissue are unknown.Transbronchial biopsy (TBB) is safe and accurate inmonitoring parenchymal lesions in lung-transplanted patients.The aim of this prospective study was to evaluate whetherhistological changes of the healthy lung parenchyma afterradiotherapy are present on TBB biopsies. Patients andMethods: Twelve patients with lung cancer necessitating 3119 Correspondence to:of Pneumonology, Medical School of Alexandroupolis, DemocritusUniversity of Thrace, 68100 Alexandroupolis, Greece. Tel: +302551075335, Fax: +30 2551030343, e-mail: mfroud@med.duth.grKey Words:Lung cancer, radiation therapy, transbonchial biopsy,bronchoscopy, pneumonitis, lung injury. Histological Changes fter Radiation Therapy in Patients with Lung Cancer: A Prospective Study GEORGIA KARPATHIOU, ALEXANDRA GIATROMANOLAKI, MICHAEL I. KOUKOURAKISVASILIS MIHAILIDIS1, EFTHIMIOS SIVRIDIS, DEMOSTHENES BOUROSand MARIOS E. FROUDARAKIS 0250-7005/2014 $2.00+.40 to study inclusion. Survival was calculated from the time oftreatment initiation (chemotherapy) until death. Characteristics ofthe 12 assessed patients (all male) are shown in Table I. Patientswith non-small cell lung cancer were classified according to theclinical TNM staging system (11). Eight patients were currentsmokers [range=40-110 packs per year (ppy), median=80 ppy]. Allpatients were treated with chemotherapy prior to radiation therapy.Treatment schedules consisted of cisplatin-vinorelbine (N=7) orcisplatin…etoposide (N=5). Radiotherapy was delivered to theaffected lung and mediastinal nodes. All patients were treated with18-MV photons and three-dimension conformal radiotherapy, whichspares healthy tissue as previously described (12). Nine fractions of3.5 Gy were applied, delivering a median biological (for /=4 Gydose) of 48 Gy to the mediastinum and the tumor mass, followedby five additional fractions of 3.5 Gy that increased the total�biological dose to 70 Gy to the gross tumor area. However, sincethe TBBs were taken from the distal lung parenchyma of thediagonally contralateral lobe, it is unlikely that biopsies were withinthe irradiated field.Patients were subjected to four serial TBS of thecontralateral lung. The rationale for the contralateral biopsy was tohave as much healthy tissue as possible and as less exposure toradiation therapy as possible to assess whether this minimalexposure led to demonstrable histological changes. The first biopsywas obtained after completion of the patients chemotherapeuticregimen and prior to the initiation of irradiation (pre-RT point), thesecond at the completion of the radiotherapy (time-point 0), themonths. However, none of our patients survived beyond 10 monthsfrom the initiation of radiation therapy to complete the last part oft

he study. All patients underwent a chest X-ray at each time point,evaluation. In cases of clinical or radiological suspicion ofpneumonitis, additional high-resolution tomography was mandatory.Bronchoscopy and biopsies. TBBs were performed during fiberopticbronchoscopy under local anesthesia only. In every case, TBBs weretaken from the distal lung parenchyma of the lobe diagonallycontralateral to the tumor. All biopsies were fixed in 10% formalinsolution and processed routinely to paraffin wax. They werehematoxylin and eosin and evaluated with an optical microscope.Tissue specimens were qualitatively evaluated for the followingpatterns: acute lung injury, chronic cellular infiltrates, fibrosis, andcellular or noncellular elements filling the alveoli. A scoring system(13) of four parameters, namely alveolar congestion, hemorrhage,leukocyte infiltration in airspace or the vessel wall, and thickness ofthe alveolar wall, was used as a semi-quantitative way of evaluatingchanges of lung parenchyma. The parameters were scored on a scaleof 0-4, as previously described (13): a score of 0 represented normallung; 1, mild, volvement; 2, moderate, 25-50%specimen involvement; 3, severe, 50-75% specimen involvement; and4, very sev%% ;&#xspec;&#ximen;&#x in4;�.10;ere, 75% specimen involvement. An overall score wasStatistics were performed using StatViewsoftware. Students -test was used to compare differences betweengroups. The differences were considered significant if -values wereResultsPatients.Patients overall survival (Table I) ranged from nineto 16 months (median=14.5 months); all deaths were cancer-related after disease progression. No patient exhibitedclinical or radiographic findings of radiation-induced lunginjury. Histopathological evaluation. fragments ranged from two to six per biopsy (median=4),Twelve cases were considered adequate, containing at leasttwo fragments of alveolated parenchyma at all three time-Semi-quantitative evaluation (Table II): Between the pre-RT0.048), as well as between the pre-RT0.014) (Figure 1), a significantincrease of the total score was observed [especiallyinterstitial fibrosis (thickness) and congestion] (Figure 2), but0.15) (Table II).Hemorrhage was not found in the biopsies studied, buthemosiderin-laden macrophages were present in eleven cases Table I. Patients characteristics (n=12). CharacteristicValueMedian age, years (range)55 (42-75)Male gender12Tumor cell typeSmall cell carcinoma4Adenocarcinoma2Squamous cell carcinoma3Large cell carcinoma2Large cell neuroendocrine carcinoma1IV5IIIb2IIIa1Limited3Unstaged (pleural effusion)1ChemotherapyCisplatin…vinorelbine7Cisplatin…etoposide5Survival, monthsMedian14.5 Range9-16 (91.6%), eight of them post-irradiation (Table III).Leucocytes were present in the biopsies of two patients atQualitative evaluation (Table III):indicative of acute lung injury, were prese

nt in two cases(16.6%), at the pre-RT point. No other findings of acute lunginjury, such as fibrin or type II cell hyperplasia, wereencountered. Two serial biopsies of the same patient and thespecimen of another patient (time-point 1) showed thepresence of eosinophils after irradiation. Lymphocytes werepresent in biopsies of two patients (time point 0 and 1)(Figure 2D). Intra-alveolar fibroblastic tissue (Figure 2A, Cand D), either mature or immature, was found in fourpatients (33.3%) at time-point 0; of these, two patients hadthe same findings at time-point 1. Two additional patients(16.6%) exhibited intra-alveolar fibroblastic growth at time-point 1. Overall, six patients (50%) exhibited intra-alveolarfibroblastic growth after radiotherapy.DiscussionOur study shows that radiotherapy for various types of lungcancer causes microscopic lesions, even in the absence ofcorresponding clinical manifestations of the non-cancerouslung, as monitored by serial TBBs. Septal fibrosis andalveolar congestion were the main findings at the time ofcompletion of the radiotherapy and at six months post-irradiation, showing statistically significant differences fromIn our study, six patients (50%) exhibited early features oforganizing pneumonia, such as intra-alveolar fibroblasticgrowth (Table III), occurring in the contralateral lung,without evidence of clinical/radiographic syndrome.Histological findings of our patients were consistent with thebiopsies of patients with breast cancer suffering frombronchiolitis obliteransorganizing pneumonia (4, 5).Organizing pneumonia, occurring in the early post-by fever, non-productive cough, mild dyspnea, and migratoryalveolar opacities on chest radiography and computedtomography (4, 5). We have not encountered any case ofbecause our study was prospective, enrolling few patients (1,2). It has been suggested that the increase of lymphocytesfound in BALF of patients with breast cancer followingunilateral irradiation mainly consisted of activated cluster ofdifferentiation 4+ cells (CD4We also found alveolar congestion, with inflammatorycells and fibrosis (Tables II and III). Furthermore, by serialTBBs, those histological features gradually increased overtime (Table II). Pathological events of the irradiated lungsuccessively consist of an acute exudative phase withsecondary infiltration of the interstitium by mononuclear andother inflammatory cells, with finally the development offibrosis (chronic phase) (1, 15). Findings such as hyalinemembranes, marked cytological atypia within hyperplasticpneumocytes, and prominent vascular changes are alsopresent (1, 5, 15). However, these histological features of thecontralateral non-irradiated lung have never been monitoredprospectively to our knowledge. Septum fibrosis was seen in our patients very early, raisingquestions regarding the underlying mechanism of thismanifestation. Studi

es on DNA damage induced byirradiation of rat lung showed the induction of chromosomalaberrations even in non-irradiated pulmonary regions,: Lung Lesions of Radiotherapy 3121 Score (mean±SD) of histopathological findings according totime-point of biopsy: a significant increase of total score between beforeradiation therapy (Before RT) and just after RT (After RT) (p=0.048),as well as between before radiation therapy and six months after RT (At Table II.Score (mean±SD) of histopathological findings according totime-point of biopsy relative to time of radiotherapy (RT). Time-pointParameterPre-RTAt RT After completion6 months (time-point 0)(time-point 1)Alveolar congestion1.8±1.612.11±0.742.16±1.16Hemorrhage0.09±0.300Leucocytes0.1±0.310.22±0.330.43±0.53Fibrosis2±1.83±0.93.3±0.95 Total score 3.18±3.185.09±1.37*6±1.89**Between Pre-RT and time-point 1: *deviation. possibly due to the action of superoxide radicals, activatedlymphocytes, and chromosomal-damaging factors producedregiondiffusion or blood circulation (16). Similarly,alveolar macrophages of both lungs exhibited functionalexperimental model (17). Another possible explanation for the early fibroticlesions observed in some of our patients might be previoustreatment by chemotherapy. In particular, hyalinemembranes, found in the alveoli of two patients, may beattributed to chemotherapy, as it is known to cause lunginjury (2, 18). Despite the classical diffused alveolardamage caused by many chemotherapeutic agents resultingin non-cardiogenic edema (18), the risk of developingcytostatic agent is applied, together with other factors suchas old age, low performance status, low baseline pulmonaryfunction and PaO(19). Finally, the process of acuteradiation pneumonitis is probably tightly linked to fibrosis, A: Transbronchial biopsy (TBB) at six months post-radiotherapy (RT) with severe septal thickening and intra-alveolar fibroblastic growth(×200). B: TBB at six months post-RT with severe septal thickening and leucocytes both in and outside the lumen of a vessel (×200). C: TBB atcompletion of RT with intra-alveolar fibroblastic growth (×200). D: TBB at six months post-irradiation with moderate septal thickening, intralveolarfibroblastic growth and lymphocytic infiltration (×200). Table III. Qualitative evaluation of histopathological findings. FindingsPre-RTAt RT completion (time-point 0) After 6 months (time-point 1)Total cases post-RT n (%)n (%)n (%)n (%)Hemosiderin-laden macrophages3 (25%)5 (41.6%)3 (25%)8 (66.6%)Fibroblastic growth-4 (33.3%)4 (33.3%)6 (50%)Hyaline membranes2 (16.6%)--0 (0%)Eoshinophils1 (8.3%)1 (8.3%)1 (8.3%)2 (16.6%) Lymphocytes-1 (8.3%)1 (8.3%)2 (16.6%)RT: Radiation therapy. involving complex molecular mechanisms (20). Yet, todesign such a study in patients with advanced-stage lungexternal beam irradiation as single treatment is notindicated. Therefore, all our patients

had previouslyundergone chemotherapy, after which the baseline biopsieswere considered for the study.In our study, eosinophils were found in the biopsies of twopatients after irradiation (Table III). Radiotherapy for breastcancer is known to cause a slightly elevated number ofeosinophils in BALF (21), or even the syndrome ofcharacterized by dyspnea, cough, alveolar or infiltrativepulmonary opacities, and marked alveolar and peripheraleosinophilia (6). Mild alveolar eosinophilia may alsoaccompany radiation-induced organizing pneumonia (4, 5).enrolled, and the short follow-up period. Indeed, patientswith breast cancer had a median follow-up period of 15Because such a long follow-up period is unlikely to beachieved in patients with lung cancer, due to poor survivalin those with advanced-stage disease, a minimum of 12months is necessary to fully-assess those patients likely topresent late lung injury (22). Although we designed thisstudy accordingly, we were unable to achieve this goal due toour patients rapidly deteriorating condition and death. Thisis probably why we did not observe changes in the chronicor late fibrotic phase comparing to the breast cancer series.Yet, as far as we are aware of, our study is the first reportingresults prospectively.In conclusion, our study shows that in patients with lungcarcinoma undergoing radiation therapy, healthy lungparenchyma presents early histological changes, even in theabsence of any clinical or radiographic finding, and theselesions can be monitored by serial TBB. The value of suchsurveillance of histological alterations in predicting theevolution of post-radiotherapy lung damage, and therefore inidentifying patients at risk of developing a clinical syndrome,requires further larger prospective studies. Clinical RelevanceThis prospective study of histological biopsies taken bytransbronchial way shows that, early lesions of the supposedcarcinoma after radiation therapy.Conflicts of InterestAll Authors state no conflict to discloseThis study was presented in part at the European Congress ofInterventional Pulmonology, Marseille 2011, and at the EuropeanRespiratory Society Congress, Amsterdam 2011.Funding SourceThis research was supported with a grant from FondationLancardisŽ, Martigny, Switzerland.References1 Movsas B, Raffin TA, Epstein AH and Link CJ Jr.: Pulmonaryradiation injury. Chest 2 Camus P, Fanton A, Bonniaud P, Camus C and Foucher P:3 Abratt RP and Morgan GW: Lung toxicity following chestirradiation in patients with lung cancer. Lung Cancer 4Bayle JY, Nesme P, Bejui-Thivolet F, Loire R, Guerin JC andCordier JF: Migratory organizing pneumonitis "primed" byradiation therapy. Eur Respir J 5Crestani B, Valeyre D, Roden S, Wallaert B, Dalphin JC andBronchiolitis obliteransorganizing pneumoniasyndrome primed by radiation therapy to the breast. The groupe(GERM"O"P). Am J Respir Crit Care Med 6

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