Prophylactic cranial irradiation versus observation in patients with extensive-disease small-cell lung cancer: a multicentre, randomised, open-label, phase 3 trial. Prophylactic cranial irradiation could improve overall survival in patients with extensive small cell lung cancer : A retrospective study. The Cochrane Collaboration’s tool for assessing risk of bias in randomised trials Diffusion Tensor Imaging Screening of Radiation-Induced Changes in the White Matter after Prophylactic Cranial Irradiation of Patients with Small Cell Lung Cancer: First Results of a Prospective Study Current Patterns of Care for Patients with Extensive‐Stage SCLC: Survey of U.S. Radiation Oncologists on Their Recommendations Regarding Prophylactic Cranial Irradiation Standard-dose versus higher-dose prophylactic cranial irradiation (PCI) in patients with limited-stage small-cell lung cancer in complete remission after chemotherapy and thoracic radiotherapy (PCI 99-01, EORTC 22003-08004, RTOG 0212, and IFCT 99-01): a randomised clinical trial. Decline in tested and self-reported cognitive functioning after prophylactic cranial irradiation for lung cancer: pooled secondary analysis of Radiation Therapy Oncology Group randomized trials 0212 and 0214. Neurocognitive function in patients with small cell lung cancer Positive Interaction between Prophylactic Cranial Irradiation and Maintenance Sunitinib for Untreated Extensive‐Stage Small Cell Lung Cancer Patients After Standard Chemotherapy: A Secondary Analysis of CALGB 30504 (ALLIANCE) Prophylactic cranial irradiation for patients with small-cell lung cancer in complete remission. Prophylactic cranial irradiation in elderly patients with small cell lung cancer: findings from a North Central Cancer Treatment Group pooled analysis.
BACKGROUND Results from a previous phase 3 study suggested that prophylactic cranial irradiation reduces the incidence of symptomatic brain metastases and prolongs overall survival compared with no prophylactic cranial irradiation in patients with extensive-disease small-cell lung cancer . However , because of the absence of brain imaging before enrolment and variations in chemotherapeutic regimens and irradiation doses , concerns have been raised about these findings . We did a phase 3 trial to reassess the efficacy of prophylactic cranial irradiation in the treatment of extensive-disease small-cell lung cancer . METHODS We did this r and omised , open-label , phase 3 study at 47 institutions in Japan . Patients with extensive-disease small-cell lung cancer who had any response to platinum-based doublet chemotherapy and no brain metastases on MRI were r and omly assigned ( 1:1 ) to receive prophylactic cranial irradiation ( 25 Gy in ten daily fractions of 2·5 Gy ) or observation . All patients were required to have brain MRI at 3-month intervals up to 12 months and at 18 and 24 months after enrolment . R and omisation was done by computer-generated allocation sequence , with age as a stratification factor and minimisation by institution , Eastern Cooperative Oncology Group performance status , and response to initial chemotherapy . The primary endpoint was overall survival , analysed in the intention-to-treat population . This trial is registered with the UMIN Clinical Trials Registry , number UMIN000001755 , and is closed to new participants . FINDINGS Between April 3 , 2009 , and July 17 , 2013 , 224 patients were enrolled and r and omly assigned ( 113 to prophylactic cranial irradiation and 111 to observation ) . In the planned interim analysis on June 18 , 2013 , of the first 163 enrolled patients , Bayesian predictive probability of prophylactic cranial irradiation being superior to observation was 0·011 % , result ing in early termination of the study because of futility . In the final analysis , median overall survival was 11·6 months ( 95 % CI 9·5 - 13·3 ) in the prophylactic cranial irradiation group and 13·7 months ( 10·2 - 16·4 ) in the observation group ( hazard ratio 1·27 , 95 % CI 0·96 - 1·68 ; p=0·094 ) . The most frequent grade 3 or worse adverse events at 3 months were anorexia ( six [ 6 % ] of 106 in the prophylactic cranial irradiation group vs two [ 2 % ] of 111 in the observation group ) , malaise ( three [ 3 % ] vs one [ < 1 % ] ) , and muscle weakness in a lower limb ( one [ < 1 % ] vs six [ 5 % ] ) . No treatment-related deaths occurred in either group . INTERPRETATION In this Japanese trial , prophylactic cranial irradiation did not result in longer overall survival compared with observation in patients with extensive-disease small-cell lung cancer .  Prophylactic cranial irradiation is therefore not essential for patients with extensive-disease small-cell lung cancer with any response to initial chemotherapy and a confirmed absence of brain metastases when patients receive periodic MRI examination during follow-up . FUNDING The Ministry of Health , Labour and Welfare of Japan OBJECTIVE To evaluate the effect of prophylactic cranial irradiation ( PCI ) on overall survival ( OS ) in patients with extensive small cell lung cancer ( ESCLC ) . METHODS Between April 2005 and May 2014 , 204 patients with ESCLC who had any response ( according to RECIST 1.1 ) to initial chemotherapy were review ed . All patients had undergone appropriate imaging tests to exclude brain metastases before initial chemotherapy . PCI was performed on 45 patients ( 22.1 % ) and the remaining patients ( 77.9 % ) received no such treatment ( control group ) . Primary endpoint was OS . The incidence of brain metastases , brain metastases-free survival ( BMFS ) , and adverse effects were also evaluated . RESULTS Survival data of the 204 patients were analyzed statistically . PCI significantly prolonged median OS from 12.6 to 16.5 months as compared to the control group ( hazard ratio , HR , 0.63 ; 95 % confidence interval , CI , 0.41 to 0.96 ; p = 0.033 ) . PCI significantly lowered the risk of brain metastases ( HR 0.48 ; 95 % CI 0.30 to 0.76 ; p = 0.001 ) . The 1‑year incidence of brain metastases was 17.1 and 55.9 % in the PCI and control group , respectively . PCI significantly correlated with the increased median BMFS ( p = 0.002 ) . Additionally , multivariate analyses demonstrated that PCI was a favorable independent predictor of OS , BMFS , and the incidence of brain metastases . Acute and chronic adverse effects were generally low grade and well tolerated in patients receiving PCI . CONCLUSION PCI after any response to initial chemotherapy significantly improved OS of ESCLC patients analyzed in this study Flaws in the design , conduct , analysis , and reporting of r and omised trials can cause the effect of an intervention to be underestimated or overestimated . The Cochrane Collaboration ’s tool for assessing risk of bias aims to make the process clearer and more BACKGROUND AND PURPOSE : Diffusion tensor imaging ( DTI ) will show abnormal fractional anisotropy ( FA ) in the normal-appearing brain after prophylactic cranial irradiation ( PCI ) . These abnormalities will be more accentuated in patients with underlying vascular risk factors . MATERIAL S AND METHODS : A prospect i ve study by use of DTI and conventional T2-weighted MR images was performed with a 1.5 T unit with 16 patients with small cell lung cancer and undergoing PCI .  All of the T2-weighted images were evaluated with respect to abnormalities in signal intensity of white matter as markers of radiation damage . Measurements of FA were performed before , at the end of , and 6 weeks after radiation therapy . On the FA maps , the bifrontal white matter , the corona radiata , the cerebellum , and the brain stem were evaluated . FA values were compared with respect to age , demographic , and vascular risk factors . Statistical analyses ( Friedman test , Wilcoxon test , and Mann-Whitney U test ) were performed . RESULTS : Fractional anisotropy decreased significantly in supratentorial and infratentorial normal-appearing white matter from the beginning to the end of PCI ( P < .01 ) . A further decline in FA occurred 6 weeks after irradiation ( P < .05 ) . A stronger reduction in FA was observed in patients with more than 1 vascular risk factor . There was an age-related reduction of white matter FA .  Patients 65 years and older showed a trend toward a stronger reduction in FA . CONCLUSION : During the acute phase , after PCI , patients with many vascular risk factors showed stronger damage in the white matter compared with patients with only 1 risk factor Introduction : Conflicting data from r and omized clinical trials incite the debate over the appropriate use of prophylactic cranial irradiation ( PCI ) for patients with extensive‐stage SCLC ( ES‐SCLC ) who achieve clinical response to systemic chemotherapy . The current pattern of practice among U.S. radiation oncologists is unknown . Methods : We surveyed practicing U.S. radiation oncologists through a short online question naire . Respondents ' characteristics and their self‐rated knowledge base were analyzed for association with their treatment recommendations . Results : We received 473 responses from practicing U.S. radiation oncologists . More than half of the respondents had been practicing for more than 10 years after completing residency training , and 70 % had treated more than 10 patients with lung cancer per year . Of the respondents , 90 % recommended  brain magnetic resonance imaging ( MRI )  before initiation of PCI and 98 % recommended PCI for patients with ES‐SCLC after systemic chemotherapy . Half of the respondents followed their patients with brain MRI after completion of PCI . One‐third of the respondents prescribed memantine to patients undergoing PCI . Among the respondents , recent graduates ( p = 0.004 ) and physicians practicing in academic centers ( p = 0.005 ) were more likely to prescribe memantine . Self‐rated knowledge base was not associated with any treatment recommendations . Conclusions : Our analysis revealed that among the respondents , there was a very high adherence to current National Comprehensive Cancer Network guidelines , which recommend providing universal PCI and obtaining brain MRI before initiation of PCI for patients with ES‐SCLC with clinical response to systemic chemotherapy . These guidelines and practice patterns are not supported by clinical evidence because patients in the European Organization for Research and Treatment of Cancer trial did not undergo brain MRI before PCI and the Japanese r and omized trial has shown a possible detrimental effect of PCI  on overall survival when brain MRI was incorporated . A critical reevaluation of current guidelines is essential to determine the appropriate management of these patients BACKGROUND The optimum dose of prophylactic cranial irradiation ( PCI ) for limited-stage small-cell lung cancer ( SCLC ) is unknown . A meta- analysis suggested that the incidence of brain metastases might be reduced with higher PCI doses . This r and omised clinical trial compared the effect of st and ard versus higher PCI doses on the incidence of brain metastases . METHODS Between September , 1999 , and December , 2005 , 720 patients with limited-stage SCLC in complete remission after chemotherapy and thoracic radiotherapy from 157 centres in 22 countries were r and omly assigned to a st and ard ( n=360 , 25 Gy in 10 daily fractions of 2.5 Gy ) or higher PCI total dose ( n=360 , 36 Gy ) delivered using either conventional ( 18 daily fractions of 2 Gy ) or accelerated hyperfractionated ( 24 fractions in 16 days with two daily sessions of 1.5 Gy separated by a minimum interval of 6 h ) radiotherapy . All of the treatment schedules excluded weekends . R and omisation was stratified according to medical centre , age ( < /=60 and > 60 years ) , and interval between the start of induction treatment and the date of r and omisation ( < /=90 , 91 - 180 , and > 180 days ) . Eligible patients were r and omised blindly by the data centre of the Institut Gustave Roussy ( PCI99 - 01 and IFCT ) using minimisation , and by the data centres of EORTC ( EORTC ROG and LG ) and RTOG ( for CALGB , ECOG , RTOG , and SWOG ) , both using block stratification . The primary endpoint was the incidence of brain metastases at 2 years . Analysis was by intention-to-treat . This study is registered with Clinical Trials.gov number NCT00005062 . FINDINGS Five patients in the st and ard-dose group and four in the higher-dose group did not receive PCI ; nonetheless , all r and omised patients were included in the effectiveness anlysis . After a median follow-up of 39 months ( range 0 - 89 months ) , 145 patients had brain metastases ; 82 in the st and ard-dose group and 63 in the higher-dose group . There was no significant difference in the 2-year incidence of brain metastases between the st and ard PCI dose group and the higher-dose group , at 29 % ( 95 % CI 24 - 35 ) and 23 % ( 18 - 29 ) , respectively ( hazard ratio [ HR ] 0.80 [ 95 % CI 0.57 - 1.11 ] , p=0.18 ) . 226 patients in the st and ard-dose group and 252 in the higher-dose group died ; 2-year overall survival was 42 % ( 95 % CI 37 - 48 ) in the st and ard-dose group and 37 % ( 32 - 42 ) in the higher-dose group ( HR 1.20 [ 1.00 - 1.44 ] ; p=0.05 ) . The lower overall survival in the higher-dose group is probably due to increased cancer-related mortality :  189 patients in the st and ard group versus 218 in the higher-dose group died of progressive disease . Five serious adverse events occurred in the st and ard-dose group versus zero in the higher-dose group . The most common acute toxic events were fatigue ( 106 [ 30 % ] patients in the st and ard-dose group vs 121 [ 34 % ] in the higher-dose group ) , headache ( 85 [ 24 % ] vs 99 [ 28 % ] ) , and nausea or vomiting ( 80 [ 23 % ] vs 101 [ 28 % ] ) . INTERPRETATION No significant reduction in the total incidence of brain metastases was observed after higher-dose PCI , but there was a significant increase in mortality . PCI at 25 Gy should remain the st and ard of care in limited-stage SCLC . FUNDING Institut Gustave-Roussy , Association pour la Recherche sur le Cancer ( 2001 ) , Programme Hospitalier de Recherche Clinique ( 2007 ) . The European Organisation for Research and Treatment of Cancer ( EORTC ) contribution to this trial was supported by grants 5U10 CA11488 - 30 through 5U10 CA011488 - 38 from the US National Cancer Institute PURPOSE To assess the impact of prophylactic cranial irradiation ( PCI ) on self-reported cognitive functioning ( SRCF ) , a functional scale on the European Organization for Research and Treatment of Cancer Core Quality of Life Question naire ( EORTC QLQ-C30 ) . METHODS AND MATERIAL S Radiation Therapy Oncology Group ( RTOG ) protocol 0214 r and omized patients with locally advanced non-small cell lung cancer to PCI or observation ; RTOG 0212 r and omized patients with limited-disease small cell lung cancer to high- or st and ard-dose PCI .  In both trials ,  Hopkins Verbal Learning Test (HVLT)-Recall and -Delayed Recall and SRCF were assessed at baseline ( after locoregional therapy but before PCI or observation ) and at 6 and 12 months . Patients developing brain relapse before follow-up evaluation were excluded . Decline was defined using the reliable change index method and correlated with receipt of PCI versus observation using logistic regression modeling . Fisher 's exact test correlated decline in SRCF with HVLT decline . RESULTS Of the eligible patients pooled from RTOG 0212 and RTOG 0214 , 410 ( 93 % ) receiving PCI and 173 ( 96 % ) undergoing observation completed baseline HVLT or EORTC QLQ-C30 testing and were included in this analysis . Prophylactic cranial irradiation was associated with a higher risk of decline in SRCF at 6 months ( odds ratio 3.60 , 95 % confidence interval 2.34 - 6.37 , P<.0001 ) and 12 months ( odds ratio 3.44 , 95 % confidence interval 1.84 - 6.44 , P<.0001 ) . Decline on HVLT-Recall at 6 and 12 months was also associated with PCI ( P=.002 and P=.002 , respectively ) but was not closely correlated with decline in SRCF at the same time points ( P=.05 and P=.86 , respectively ) . CONCLUSIONS In lung cancer patients who do not develop brain relapse , PCI is associated with decline in HVLT-tested and self-reported cognitive functioning . Decline in HVLT and decline in SRCF are not closely correlated , suggesting that they may represent distinct elements of the cognitive spectrum The use of prophylactic cranial irradiation ( PCI ) in patients with small cell lung cancer ( SCLC ) has been tempered by fears of detrimental effects on cognitive function . Neuropsychologic testing was prospect ively conducted before and after PCI to evaluate its effects on cognitive function in patients with SCLC Background : Prophylactic cranial irradiation ( PCI ) has become a st and ard option for patients with extensive‐stage small cell lung cancer ( ES‐SCLC ) . The Cancer and Leukemia Group B 30504 trial was a r and omized phase II study of the effect of sunitinib versus placebo in ES‐SCLC patients responding to platinum‐based systemic therapy . The study required preenrollment brain imaging . PCI was provided at the discretion of treating physicians . We performed a secondary analysis of the Cancer and Leukemia Group B trial to determine the impact of PCI on patients with ES‐SCLC . Methods : Fisher 's exact test and the Wilcoxon rank‐sum test were conducted to identify the differences between patients receiving PCI  and patients not receiving PCI  . Kaplan‐Meier analyses described progression‐free survival ( PFS ) and overall survival ( OS ) for patients in the PCI and non‐PCI groups . Results : A total of 85 patients received maintenance therapy ( 41 received placebo and 44 received sunitinib ) . Patient characteristics were balanced between the PCI and non‐PCI groups . The patients receiving PCI plus sunitinib had a nonsignificant 2.7‐month improvement in PFS ( 5.0 months versus 2.3 months , p = 0.14 , hazard risk [ HR ] = 0.62 , 95 % confidence interval [ CI ] : 0.33–1.18 ) trending toward improved OS ( 8.9 months versus 5.4 months , p = 0.053 , HR = 0.47 , 95 % CI : 0.22–1.03 ) . PCI was associated with a trend toward improved median PFS ( 2.9 months versus 2.2 months , p = 0.096 , HR = 0.69 , 95 % CI : 0.45–1.07 ) but not median OS ( 8.3 months in the PCI group versus 8.7 months in the non‐PCI group , p = 0.76 , HR = 1.07 , 95 % CI : 0.67–1.71 ) . The patients receiving placebo had no improvement in PFS or OS with PCI . Conclusions : Trends toward improved PFS and OS were seen in patients receiving PCI and sunitinib , thus supporting the need for further prospect i ve research evaluating the integration of maintenance systemic therapy and PCI for patients with ES‐SCLC . Improved outcomes for patients with ES‐SCLC after induction chemotherapy may require PCI , thoracic radiotherapy , and maintenance systemic therapy to achieve control of both intracranial and extracranial disease BACKGROUND Prophylactic cranial irradiation in patients with small-cell lung cancer decreases the overall rate of brain metastases without an effect on overall survival . It has been suggested that this treatment may increase neuropsychological syndromes and brain abnormalities indicated by computed tomography scans . However , other retrospective data suggested a beneficial effect on overall survival for patients in complete remission . PURPOSE Our purpose was to evaluate the effects of prophylactic cranial irradiation on brain metastasis , overall survival , and late-occurring toxic effects in patients with small-cell lung cancer in complete remission . METHODS We conducted a prospect i ve study of 300 patients who had small-cell lung cancer that was in complete remission . The patients were r and omly assigned to receive either prophylactic cranial irradiation delivering 24 Gy in eight fractions during 12 days ( treatment group ) or no prophylactic cranial irradiation ( control group ) . A neuropsychological examination and a computed tomography scan of the brain were performed at the time of r and om assignment and repeatedly assessed at 6 , 18 , 30 , and 48 months . Patterns of failure were analyzed according to total event rates and also according to an isolated first site of relapse , using a competing-risk approach . RESULTS Two hundred ninety-four patients who did not have brain metastases at the time of r and om assignment were analyzed . The 2-year cumulative rate of brain metastasis as an isolated first site of relapse was 45 % in the control group and 19 % in the treatment group ( P < 10(-6 ) ) . The total 2-year rate of brain metastasis was 67 % and 40 % , respectively ( relative risk = 0.35 ; P < 10(-13 ) ) . The 2-year overall survival rate was 21.5 % in the control group and 29 % in the treatment group ( relative risk = 0.83 ; P = .14 ) . There were no significant differences between the two groups in terms of neuropsychological function or abnormalities indicated by computed tomography brain scans . CONCLUSIONS Prophylactic cranial irradiation given to patients with small-cell lung cancer in complete remission decreases the risk of brain metastasis threefold without a significant increase in complications . A possible beneficial effect on overall survival should be tested with a higher statistical power . IMPLICATION S The results of the trial favor , at present , the indication of prophylactic cranial irradiation for patients who are in complete remission . A longer follow-up and confirmatory trials are needed to fully assess late-occurring toxic effects . The possible effect on overall survival needs to be evaluated with a larger number of patients in complete remission , and a meta- analysis of similar trials is recommended OBJECTIVES To examine the efficacy of prophylactic cranial irradiation ( PCI ) in elderly patients with small cell lung cancer ( SCLC ) ( ≥70 years of age ) from a pooled analysis of four prospect i ve trials . MATERIAL S & METHODS One hundred fifty-five patients with SCLC ( limited stage , LSCLC , and extensive stage , ESCLC ) participated in four phase II or III trials . Ninety-one patients received  PCI ( 30 Gy/15 or 25 Gy/10 ) and 64 patients did  not receive PCI .  Survival was compared in a l and mark analysis that included only patients who had stable disease or better in response to primary therapy . RESULTS Patients who received PCI  had better survival than patients who did not receive PCI ( median survival 12.0 months vs. 7.6 months , 3-year overall survival 13.2 % vs. 3.1 % , HR = 0.53 [ 95 % CI 0.36 - 0.78 ] , p = 0.001 ) . On multivariate analysis of the entire cohort , the only factor that remained significant for survival was stage ( ESCLC vs. LSCLC , p = 0.0072 ) . In contrast , the multivariate analysis of patients who had ESCLC revealed that PCI was the sole factor associated with a survival advantage ( HR = 0.47 [ 95 % CI 0.24 - 0.93 ] , p = 0.03 ) . Grade 3 or higher adverse events ( AEs ) were significantly greater in patients who received PCI ( 71.4 % vs. 47.5 % , p = 0.0031 ) , with non-neuro and non-heme being the specific AE categories most strongly correlated with PCI delivery . CONCLUSIONS PCI was associated with a significant improvement in survival for our entire elderly SCLC patient cohort on univariate analysis . Multivariate analysis suggested that the survival advantage remained significant in patients with ESCLC . PCI was also associated with a modest increase in grade 3 or higher AEs
Introduction : The role of prophylactic cranial irradiation ( PCI ) is controversial in patients with extensive stage small cell lung cancer .
The aim of this study was to determine the impact of PCI in these patients .