Cumulative Incidence Of Brain Metastases Research Articles

EGFR mutant locally advanced non-small cell lung cancer is at increased risk of brain metastasis

Background and purposeSmall studies of primarily metastatic non-small cell lung cancer (NSCLC) have suggested an association between EGFR mutation (EGFR+) and likelihood of brain metastasis. However, these studies are confounded by follow-up time bias. We performed a competing risk analysis of brain metastasis in a more uniform locally advanced NSCLC (LA-NSCLC) cohort with known tumor genotype. Materials and methodsBetween 2002 and 2014, 255 patients with LA-NSCLC underwent tumor genotyping for EGFR, ALK and/or KRAS (180 patients had follow-up brain imaging). Cumulative incidence and Fine-Gray regression were performed on clinical variables including genotype and risk of brain metastasis, with death as a competing event. ResultsThe proportion of tumors with aberrations in EGFR, ALK and KRAS were 17%, 4% and 28%, respectively. The median follow-up was 68 months. On multivariate analysis, EGFR+ was significantly associated with risk of brain metastasis in the full patient cohort (HR 2.04, 95% CI 1.22–3.39, p = 0.006) as well as in the subset of patients with brain follow-up imaging (HR 1.91. 95% CI 1.17–3.13, p = 0.01). This translated to a higher cumulative incidence of brain metastasis in EGFR+ patients at 3 and 5 years (33.3% vs. 23.2 and 43.8% vs. 24.2%, p = 0.006). ConclusionPatients with EGFR+ LA-NSCLC have a significantly higher likelihood of developing brain metastasis after standard combined modality therapy, independent of their longer overall survival. This high-risk genotypic subgroup may benefit from routine surveillance with brain MRI to allow early salvage with targeted systemic- and/or radiation-therapies.

The impact of systemic treatment on brain metastasis in patients with non-small-cell lung cancer: A retrospective nationwide population-based cohort study.

e20572 Background: We performed a large-scale, retrospective, nationwide, cohort study of the incidence of brain metastasis in patients with advanced non-small-cell lung cancer (NSCLC) according to the systemic treatment administered. Methods: The data were extracted from the Health Insurance Review and Assessment Service of Korea database from January 1, 2011 to November 30, 2016. Of the 29,224 patients newly diagnosed with stage IIIB or IV NSCLC who received first-line cytotoxic chemotherapy (CC group) or targeted therapy (TT group), 22,508 patients without brain metastasis were analyzed. Results: In total, 1,131 (5.0%) patients subsequently developed brain metastasis. The overall cumulative incidence of brain metastasis was significantly higher in the TT group than in the CC group (1-year cumulative incidence: 8.7 ± 0.6% vs. 3.8 ± 0.3%; 3-year: 17.2 ± 0.7% vs. 5.0 ± 0.3%, respectively; P < 0.001), despite the higher rate of brain metastasis in the CC group at < 3 years after diagnosis. Younger age, female sex, living in a rural area, anticoagulant use, and first-line TT (relative risk, 2.17 ± 0.03; 95% confidence interval, 1.92–2.50, P < 0.0001) retained significant associations with subsequent brain metastasis after adjusting for all variables. Conclusions: In the Korean population, the overall cumulative incidence of brain metastasis was significantly higher in patients in the TT group than in those in the CC group; the former could be regarded as having mutations in the EGFR or ALK gene.

Frequency of Brain Metastases and Multikinase Inhibitor Outcomes in Patients With RET-Rearranged Lung Cancers.

In ret proto-oncogene (RET)-rearranged lung cancers, data on the frequency of brain metastases and, in particular, the outcomes of multikinase inhibitor therapy in patients with intracranial disease are not well characterized. A global, multi-institutional registry (cohort A, n= 114) and a bi-institutional data set (cohort B, n= 71) of RET-rearranged lung cancer patients were analyzed. Patients were eligible if they had stage IV lung cancers harboring a RET rearrangement by local testing. The incidence of brain metastases and outcomes with multikinase inhibitor therapy were determined. The frequency of brain metastases at the time of diagnosis of stage IV disease was 25% (95% confidence interval [CI]: 18%-32%) in all patients from both cohorts. The lifetime prevalence of brain metastasis in stage IV disease was 46% (95% CI: 34%-58%) in patients for whom longitudinal data was available. The cumulative incidence of brain metastases was significantly different (p= 0.0039) between RET-, ROS1-, and ALK receptor tyrosine kinase (ALK)-rearranged lung cancers, with RET intermediate between the other two groups. Although intracranial response data was not available in cohort A, the median progression-free survival of multikinase inhibitortherapy (cabozantinib, vandetanib, or sunitinib) in patients with brain metastases was 2.1 months (95% CI: 1.3-2.9 months, n= 10). In cohort B, an intracranial response was observed in 2 of 11 patients (18%) treated with cabozantinib, vandetanib (± everolimus), ponatinib, or alectinib; the median overall progression-free survival (intracranial and extracranial) was 3.9 months (95% CI: 2.0-4.9 months). Brain metastases occur frequently in RET-rearranged lung cancers, and outcomes with multikinase inhibitor therapy in general are suboptimal. Novel RET-directed targeted therapy strategies are needed.

The role of prophylactic cranial irradiation in surgically resected combined small cell lung cancer: a retrospective study.

Combined small cell lung cancer (C-SCLC) is defined as small cell lung cancer (SCLC) combined with any of non-small cell lung cancer (NSCLC) histological types, such as large cell carcinoma, squamous cell carcinoma, or adenocarcinoma. Since C-SCLC is an increasingly recognized subtype of small cell carcinoma, we conducted a retrospective study in our institution to explore the value of prophylactic cranial irradiation (PCI) in patients with C-SCLC treated by surgery. Between 2005 and 2014, the records of all consecutive patients with pathologically diagnosed C-SCLC after surgery in our institution were reviewed. Overall survival (OS), disease-free survival (DFS), and brain metastasis free survival (BMFS) were estimated by Kaplan-Meier method. Survival differences were evaluated by log-rank test, while multivariate analysis was performed by a Cox proportional hazards model. Of the total 91 patients included in this analysis, 11 patients (12.1%) were in PCI group and 80 (87.9%) in non-PCI group. The 5-year cumulative incidence of brain metastasis in the whole group was 22.2% (26.3% in non-PCI group vs. 0% in PCI group), and 5-year OS rate was 44.1%. Patients treated with PCI had significantly longer OS (P=0.011) and DFS (P=0.013), also had the trend to live a longer BMFS with marginal significance (P=0.092) than non-PCI-treated patients. The multivariate analysis showed that PCI [hazard ratio (HR) =0.102, P=0.024] was one of independent prognostic factors of the OS in surgery-treated C-SCLC patients. C-SCLC patients have a relative high risk of developing brain metastases based on our study. These data showed that PCI could improve OS and DFS, as well as tend to decrease brain metastases in surgically resected C-SCLC. However, whether PCI could be part of comprehensive treatment modalities in C-SCLC should be assessed in prospective studies.

Patterns of Distant Failure by Intrinsic Breast Cancer Subtype in Premenopausal Women Treated With Neoadjuvant Chemotherapy

PurposeTo identify patterns of distant failure (DF) in premenopausal women receiving neoadjuvant chemotherapy (NAC) for breast cancer. Patients and MethodsPremenopausal patients treated with NAC between 2005 and 2015 at a single institution were retrospectively reviewed. Timing and location of local, regional, and distant metastases were described. Predictors for DF and overall survival (OS) were analyzed. ResultsOf 225 patients, there were 24 (10.7%) local, 30 (13.3%) regional, and 63 (28.0%) distant recurrences. Cumulative incidence of DF was higher in patients younger than age 40 (P = .01), in those with residual tumor size > 2 cm (P < .0001), in those with positive lymph nodes after NAC (P = .0003), and in those without pathologic complete response (P < .0001). Cumulative incidence of brain metastases was most common in patients with human epidermal growth factor receptor 2 (HER2)-positive disease (P = .05). Time from development of metastatic disease to death varied by breast cancer subtype (P = .019), as did 5-year OS (P = .024). Women with HER2-positive and triple-negative disease had the highest incidence of brain metastases and the shortest time from development of metastases to death. On multivariable analysis, luminal B subtype (P = .025), pathologic complete response (P = .0014), young age (P = .0008), lack of hormone therapy (P < .0001), lymphovascular space involvement (P < .0001), and pathologic size of the primary tumor (P < .0001) were all significant predictors for DF. ConclusionPatterns of DF after NAC in premenopausal women vary by breast cancer subtype, with DF more common than locoregional failure. Young age remains an independent poor prognostic factor, and OS differs by breast cancer subtype.

Incidence, pattern and prognosis of brain metastases in patients with metastatic triple negative breast cancer

BackgroundTo identify the incidence, recurrence pattern and prognosis of brain metastases (BM) among women with metastatic triple negative breast cancer (mTNBC) treated consecutively at a single institution during a 7-year period.MethodsPatients with histologically confirmed mTNBC were retrospectively identified. The incidence of BM as first site of recurrence and the cumulative BM incidence were computed. We used the Cox proportional hazards model to identify the univariate and multivariate factors associated with survival.ResultsFour hundred thirty three patients were included with a median overall survival (OS) of 21.6 months after median follow-up for 48.1 months. BM was found in 29% (127/433) of the patients and about a quarter (32/127) of BM was first recurrence. The cumulative incidence of BM at 1 and 2 years was 17 and 25%, respectively. The median time from the diagnosis of extracranial metastases to BM was 10 months. Median OS following a diagnosis of BM was 7.3 months. The longer median OS from time of first recurrent BM was noted compared with those of subsequent recurrent (17.3 vs 6.3 months, p = 0.008). However, patients with first recurrent BM were associated with shorter OS compared with those without BM (17.3 vs 22.1 months, p = 0.006). The independent factors that increased BM death risk were > 3 brain lesions, no BM-directed treatment, subsequent recurrent BM, symptomatic BM and uncontrolled extracranial metastasis.ConclusionsPatients with mTNBC have a high incidence of early BM with subsequent poor survival. The findings lend support to consideration of screening imaging of the brain for mTNBC patients.

Efficacy of prophylactic cranial irradiation in patients with limited-disease small-cell lung cancer who were confirmed to have no brain metastasis via magnetic resonance imaging after initial chemoradiotherapy.

BackgroundProphylactic cranial irradiation (PCI) is recommended for patients with limited-disease small-cell lung cancer (LD-SCLC) who achieved good response to definitive chemoradiotherapy. However, most clinical studies lacked brain imaging scans before PCI. Our study aimed to investigate whether PCI has a survival benefit in patients who have no brain metastases (BM) confirmed via magnetic resonance imaging (MRI) before PCI.ResultsEighty patients were included in this study. Sixty patients received PCI (PCI group) and 20 patients did not (non-PCI group). OS was not significantly different between the two groups. The median OS time was 4.3 years (95% CI: 2.6 years–8.6 years) in the PCI group and was not reached (NR) (95% CI: 1.9 years–NR) in the non-PCI group (p = 0.542). Moreover, no differences were observed in the 3-year rates of PFS (46.2% and 44.4%, p = 0.720) and cumulative incidence of BM (24.0% vs. 27%, p = 0.404).ConclusionsOur result suggests that PCI may not have a survival benefit in patients with LD-SCLC confirmed to have no BM after initial therapy, even if patients achieve a good response to definitive chemoradiotherapy.Patients and MethodsWe retrospectively evaluated patients with LD-SCLC who were confirmed to have no BM via MRI after initial chemoradiotherapy at the Shizuoka Cancer Center between September 2002 and August 2015. The overall survival (OS), progression-free survival (PFS), and cumulative incidence of BM were estimated using the Kaplan–Meier method between patients who received PCI and those who did not. Propensity score matching was used to balance baseline characteristics.

The impact of EGFR mutations on the incidence and survival of stages I to III NSCLC patients with subsequent brain metastasis.

Previous studies have demonstrated the association between EGFR mutations and distant metastasis. However, the association for subsequent brain metastasis (BM) in stages I-III non-small cell lung cancer (NSCLC) patients remains inconclusive. We conducted a retrospective analysis to clarify the impact of EGFR mutations on the incidence of BM and associated survival in patients with stage I-III NSCLC. A total of 491 patients screened for EGFR mutations were retrospectively enrolled. Brain MRI or CT was used to detect the BM. Cumulative incidence of subsequent BM and overall survival (OS) after diagnosis of BM were estimated by the Kaplan-Meier method and compared using log-rank test. We performed Cox proportional hazard regression for predictors of subsequent BM and determinants of OS after BM. The cumulative incidence of BM seemed higher in patients harboring EGFR mutations than those without EGFR mutations although it did not reach statistical significance (hazard ratio [HR] = 1.75, 95% confidence interval [CI] = 0.73~1.81). After adjusting possible confounders, including age, smoking, stage, and tumor size, EGFR mutation became one of the predictors for subsequent BM (HR = 1.89, 95% CI = 1.12~3.17, p = 0.017). Though there was no statistical difference in survival after BM between patients with EGFR mutations and wild-type EGFR (median survival: 17.8 vs. 12.2 months, HR = 0.79, 95% CI = 0.45–1.40), patients with EGFR 19 deletion (Del) tended to have a longer survival after BM than the non-EGFR 19 Del group (median survival: 29.4 vs. 14.3 months, HR 0.58, 95% CI = 0.32–1.09, p = 0.089). In conclusion, our data suggested EGFR mutation to be one of the predictors for subsequent BM in stage I-III patients. Given the small sample size, more studies are warranted to corroborate our results.

Abstract P6-03-06: Assessing occult brain metastasis with CT scan or MRI in HER2-positive breast cancer patients at initial diagnosis

Abstract Patients (pts) with HER2-positive breast cancer (BC) have a high risk of developing brain metastases (BM) that might be due to longer survival, low diffusion of Trastuzumab (T) in the CNS or an unknown incidence of occult BM at diagnosis. In a series of metastatic BC, occult metastasis was found in 15 % of the patients and Her2 over expression was an independent risk factor 1.In a series of early BC treated with T the cumulative incidence of BM at 12 and 24 months was 0.6 and 2 % respectively 2. Time to BM was 13.7 months in retrospective study 3 . Systematic cranial magnetic resonance imaging (MRI) in the staging of HER2-positive BC pts detected BM in 22 % of asymptomatic, metastatic pts versus 3.6 % in asymptomatic, non-metastatic pts 4. Early detection of BM decreases the cerebral death rate, but do not prolong survival in metastatic pts 4 . Therefore brain imaging is not recommended at diagnosis. However, retrospective trials assessing the incidence of BM in HER2-positive BC were mainly performed during follow up and not at the initial diagnosis. Pts treated for HER2-positive locally BC with adjuvant sequential chemotherapy including anthracycline and taxane associated with T, classified according to classical prognosis factor as histological subtype, TNM, SBR and hormonal receptor (HR), were systematically assessed for occult BM at initial diagnosis with CT scan or MRI. Retrospectively analyzed for the occurrence of BM was performed. Disease free metastatic survival (DFMS) and overall survival (OS) was estimated by Kaplan Meier estimation. Between March 2006 and July 2013 84 pts were included. The median follow up is 4.7 years. The characteristics pts were median age 57 years [30-86], ductal carcinoma 67 pts (93 %), lobular carcinoma 5 pts (7%), pT1 to 4 respectively 38 (48 %), 28 (36 %), 3 (4%), 9 pts (12%), pN 0 to 3 respectively 44 (54%), 27 (33%), 5 (6%), 5 pts (6%), SBR 1 to 3 respectively 1 (1%), 35 (43%), 43 pts (54%), RO positive 47 pts (59 %), RP positive 27 pts (63%). Thirty eight pts (45 %) had brain imaging at diagnosis or within 5 months of diagnosis. Only one pt with a pT4, pN2, ductal carcinoma, RO+, RP-, SBR 2 presented with BM (2.6 %) at initial diagnosis, with simultaneous lung, liver, bone and nodes metastasis. Four pts (4.8 %) presented BM during follow up, among those two symptomatic pts (2.4 %) as the only site of recurrence at 21 and 28 months. Median DFMS was 8.5 years and median OS was 16.7 years. This is the first report of systemic imaging at initial diagnosis of HER2 positive locally BC pts. The results did not support initial brain imaging in this subset of pts. Only pts with symptoms seems to benefit from brain imaging. Further prospective study should be launched to confirm this observation. Citation Format: Delbaldo C, Sarrade T, Brieau B, Billemont B, Denis J, Cojean-Zelek I, Bornier C, Vincens E. Assessing occult brain metastasis with CT scan or MRI in HER2-positive breast cancer patients at initial diagnosis [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr P6-03-06.

Commentary: Treatment Considerations for Patients With Epidermal Growth Factor Receptor-Mutated Non-Small Cell Lung Cancer Brain Metastases in the Era of Tyrosine Kinase Inhibitors

Brain metastasis is a serious complication of non-small cell lung cancer (NSCLC) affecting up to 40% of NSCLC patients. A subset of NSCLC tumors has mutations in the epidermal growth factor receptor (EGFR) gene, and determination of tumor EGFR mutation status is essential in guiding treatment decisions, as it directly affects the treatment approach. Patients with EGFR-mutated NSCLC have a higher cumulative incidence of brain metastases, and are especially sensitive to EGFR tyrosine kinase inhibitors (TKIs). Patients with newly diagnosed EGFR-mutated lung cancer presenting to a neurosurgeon with a new diagnosis of brain metastases now have a variety of treatment options available, including whole brain radiation therapy, stereotactic radiosurgery, surgical resection, chemotherapy, and targeted therapeutics such as the EGFR TKIs. In this review, we discuss the impact of EGFR mutation status on brain and leptomeningeal metastasis treatment considerations. Additionally, we present clinical cases of patients treated with EGFR TKIs alone and in combination with other therapies to highlight treatment alternatives.

Patterns of Metastatic Spread and Mechanisms of Resistance to Crizotinib in ROS1-Positive Non-Small-Cell Lung Cancer.

The ROS1 tyrosine kinase is activated through ROS1 gene rearrangements in 1-2% of non-small cell lung cancer (NSCLC), conferring sensitivity to treatment with the ALK/ROS1/MET inhibitor crizotinib. Currently, insights into patterns of metastatic spread and mechanisms of crizotinib resistance among ROS1-positive patients are limited. We reviewed clinical and radiographic imaging data of patients with ROS1- and ALK-positive NSCLC in order to compare patterns of metastatic spread at initial metastatic diagnosis. To determine molecular mechanisms of crizotinib resistance, we also analyzed repeat biopsies from a cohort of ROS1-positive patients progressing on crizotinib. We identified 39 and 196 patients with advanced ROS1- and ALK-positive NSCLC, respectively. ROS1-positive patients had significantly lower rates of extrathoracic metastases (ROS1 59.0%, ALK 83.2%, P=0.002), including lower rates of brain metastases (ROS1 19.4%, ALK 39.1%; P = 0.033), at initial metastatic diagnosis. Despite similar overall survival between ALK- and ROS1-positive patients treated with crizotinib (median 3.0 versus 2.5 years, respectively; P=0.786), ROS1-positive patients also had a significantly lower cumulative incidence of brain metastases (34% vs. 73% at 5 years; P<0.0001). Additionally, we identified 16 patients who underwent a total of 17 repeat biopsies following progression on crizotinib. ROS1 resistance mutations were identified in 53% of specimens, including 9/14 (64%) non-brain metastasis specimens. ROS1 mutations included: G2032R (41%), D2033N (6%), and S1986F (6%). Compared to ALK rearrangements, ROS1 rearrangements are associated with lower rates of extrathoracic metastases, including fewer brain metastases, at initial metastatic diagnosis. ROS1 resistance mutations, particularly G2032R, appear to be the predominant mechanism of resistance to crizotinib, underscoring the need to develop novel ROS1 inhibitors with activity against these resistant mutants.

Factors influencing the utilization of prophylactic cranial irradiation in patients with limited-stage small cell lung cancer

PurposeBrain metastases are common in patients with limited-stage small cell lung cancer (LS-SCLC) due to the inability of most chemotherapeutics to penetrate the blood–brain barrier. Prophylactic cranial irradiation (PCI) is therefore recommended for use in patients with a good response to concurrent chemoradiotherapy. However, PCI is not always delivered; therefore, we investigated the reasons for PCI omission in patients who underwent therapy with curative intent. Methods and materialsWe retrospectively reviewed all patients with LS-SCLC who were treated with curative intent at our institution. Overall survival and cumulative incidence of brain metastasis were estimated by the Kaplan-Meier method. The Pearson χ2 test and Mann-Whitney U test were used to examine factors associated with PCI use, and prognostic factors were analyzed with Cox proportional hazards modeling. ResultsWe examined 208 patients who were treated for LS-SCLC at our institution. A total of 115 patients (55%) received PCI. The most common documented reason for PCI omission was patient refusal due to neurotoxicity concerns (38%). Physician assessment of being medically unfit (33%) and of advanced age (8%) were the second and third most common reasons, respectively. Karnofsky performance status and clinical American Joint Committee on Cancer stage but not PCI were significantly associated with overall survival. Only clinical stage remained an independent factor on multivariate analysis. ConclusionsApproximately half of patients with LS-SCLC ultimately receive PCI, generally for guideline-recommended reasons. The most common reason for PCI omission was patient concerns regarding neurotoxicity. Efforts to decrease PCI neurotoxicity, including hippocampal-sparing radiation and memantine use, may increase the use of this survival-improving intervention in eligible patients with LS-SCLC.

Patterns of failure in limited-stage small cell lung cancer: Implications of TNM stage for prophylactic cranial irradiation

Background and purposeThe relationship between tumor-node-metastasis (TNM) stage and patterns of failure in limited-stage small cell lung cancer (LS-SCLC) remains unclear. We hypothesized that TNM stage predicts brain metastasis risk, and could inform the use of prophylactic cranial irradiation. Material and methodsWe reviewed 283 patients with stage I–IIIB SCLC. Competing-risks regression was used to analyze local, distant, and brain failure. Multivariate analysis was used to evaluate the effect of treatment and clinical factors on failure and OS. ResultsPatients with stage I or II SCLC (35% of cohort) had significantly better survival and lower risk of distant and brain metastasis, compared with stage III patients. The 5-year cumulative incidence of brain metastasis for stage I/II and III were 12% and 26%, respectively. Stage had no correlation with local failure. On multivariate analysis, stage was independently prognostic for survival, distant metastasis risk, and brain metastasis risk. ConclusionsTNM staging predicts likelihood of distant metastasis, brain metastasis, and survival in LS-SCLC. This supports the routine use of TNM staging in clinical practice. The lower risk of brain metastasis in stage I and II SCLC suggests that prophylactic cranial irradiation could play a more limited role in treatment of early-stage disease.

Impacts of EGFR mutation and EGFR-TKIs on incidence of brain metastases in advanced non-squamous NSCLC

ObjectiveBrain metastases remain lethal in lung cancer patients. The impacts of epidermal growth factor receptor (EGFR) mutations and EGFR tyrosine kinase inhibitors (TKIs) on the incidence of brain metastases in patients with advanced non-squamous non-small cell lung cancer (NSCLC) are still uncertain. Patients and methodsA total of 1672 patients with advanced non-squamous NSCLC with a definitive report on EGFR mutation status between January 2005 and June 2013 were retrospectively analyzed. The impacts of EGFR mutation status and EGFR TKIs use on the incidence of brain metastases and survival were investigated. ResultsOf the 1672 patients, 465 (27.8%) had an EGFR mutation, and 1207 (72.2%) did not. Four hundred and eighteen (25.0%) patients had baseline brain metastases. The cumulative incidence of brain metastases for patients in EGFR+ group was significantly higher than patients in EGFR- group (HR, 1.27; 95% CI 1.06–1.52; P=0.008). The cumulative incidence of brain metastases was also higher for patients who received an EGFR-TKI as their first-line treatment than those who received other first-line treatment (HR, 1.36; 95% CI 1.14–1.64; P=0.001). Patients harboring EGFR mutations had prolonged overall survival (OS) than patients with wild-type EGFR (HR, 0.47; 95% CI 0.41–0.54; P<0.001; median, 25.2 vs. 12.9 months). ConclusionsBoth the EGFR mutation-positive status and the use of a TKI are associated with higher incidence of brain metastases for patients with advanced non-squamous NSCLC.

Patterns of initial and intracranial failure in metastatic EGFR-mutant non-small cell lung cancer treated with erlotinib

ObjectivesPatients with metastatic EGFR-mutant (mEGFRmt) NSCLC have favorable survival when treated with erlotinib. We hypothesized that treatment failure in most patients is limited to initial sites of disease, in which case incorporating local therapy such as radiation might further delay progression. We therefore analyzed patterns and predictors of failure in a large cohort of such patients. Materials and methodsWe reviewed 189 patients treated with erlotinib for mEGFRmt NSCLC. We classified first pattern of failure as involving initial sites only (ISF), new sites only (NSF), or the combination (CSF), and used competing-risks regression to identify factors associated with ISF, progression and overall survival (OS). We also separately analyzed intracranial and intrathoracic failure. ResultsOf 171 patients who progressed, 103 (60.2%) had ISF, 30 (17.5%) had NSF, and 38 (22.2%) had CSF. Younger age and lack of initial CNS involvement independently correlated with ISF, with a trend for higher T and N stage. Higher T and N stage was also a significant predictor of progression. Factors predicting shorter OS were female gender, weight loss, initial intracranial involvement, and ≥4 extracranial metastases. Intrathoracic progression was a component of first failure in 61%, and three-year cumulative incidence of brain metastasis was 30%. ConclusionThe main pattern of progression in mEGFRmt NSCLC on erlotinib is in the initial sites of disease. Younger patients and those without brain involvement are particularly likely to develop ISF. This suggests a role for incorporating local therapy into treatment of selected patients with mEGFRmt NSCLC.

P1.07-018 Incidence of Brain Recurrence and Survival Outcomes in High-Grade Neuroendocrine Carcinomas of the Lung: Implications for Clinical Practice

Among patients with advanced high-grade neuroendocrine carcinoma (HGNEC) of the lung, the optimal therapeutic management is much less established for large cell neuroendocrine carcinomas (LCNECs) than for small cell lung cancers (SCLCs). We evaluated the survival outcomes and incidence of brain recurrence of advanced LCNECs, and compared them with those of a population of SCLCs matched by stage. Forty-eight unresected stage III HGNECs (16 LCNECs and 32 SCLCs) and 113 stage IV HGNECs (37 LCNECs and 76 SCLCs) were eligible for the analysis. The efficacy of platinum-etoposide chemotherapy with or without thoracic radiotherapy (TRT) and/or prophylactic cranial irradiation (PCI) was investigated. Overall response was significantly lower for LCNECs compared with SCLCs for both stage III (43.8% vs 90.6% respectively, P=0.004) and stage IV (43.3% vs 64.5%, respectively, P=0.04). Similarly, an inferior outcome was observed in terms of progression-free survival (PFS), and overall survival (OS) for LCNECs compared with SCLCs, which, however, reached significance only for stage III disease (median: 5.6 vs 8.9 months, P=0.06 and 10.4 vs 17.6 months, P=0.03 for PFS and OS, respectively), (Figure 1). Histologic subtype (LCNEC vs SCLC) was an independent prognosticator in multivariate analysis. In the lack of PCI, LCNECs showed a high cumulative incidence of brain metastases, as 58% and 48% of still living stage III and IV patients, respectively, developed brain metastases at 18 mo. Patients with advanced LCNECs are at high risk for brain recurrence. Unresected stage III LCNECs treated with platinum-etoposide with or without TRT bear a dismal prognosis, when compared indirectly with SCLC counterparts. Randomized trials should evaluate whether PCI could improve survival of advanced LCNECs.

PUB062 Risk Factors of Brain Metastasis during the Course of EGFR-TKIs Therapy for Patients with EGFR-Mutated Advanced Lung Adenocarcinoma

Brain metastasis (BM) remains a therapeutically challenging issue, which often predicts poor prognosis. Moreover, there are still some patients developing BM during the course of EGFR-TKIs therapy, although EGFR-TKIs are effective for EGFR-mutated NSCLC patients with BM. Therefore, controversial value of prophylactic cranial irradiation (PCI) in NSCLC in terms of survival benefit prompted us to explore the possible risk factors for BM during the course of EGFR-TKIs therapy from EGFR-mutated advanced lung adenocarcinoma and identify the potential population most likely to benefit from PCI. We retrospectively reviewed the records of 134 patients with EGFR-TKIs therapy from EGFR-mutated advanced lung adenocarcinoma between 2008 and 2012. Among them, 78 patients (58.2 %) were confirmed to have EGFR exon 19 point mutations, while 56 patients (41.8%) had EGFR exon 21 point mutations. The cumulative incidence of BM was calculated by the Kaplan–Meier method and differences between the groups were analyzed using the log-rank test. Multivariate Cox regression analysis was used to assess the independent risk factors of BM. Thirty-four patients (34/134, 25.4%) developed BM during the course of EGFR-TKIs therapy. Multivariate analysis indicated that age ≤ 53 years (HR: 2.751, 95% CI: 1.326-5.707; p = 0.007), serum carcinoembryonic antigen (CEA) ≥ 23 ng/mL (HR: 3.197, 95% CI: 1.512-6.758; p = 0.002) and EGFR exon 21 point mutations (HR: 2.769, 95 % CI: 1.355-5.659; p= 0.005) were the independent high-risk factors for developing BM, which could offer important insights into the individualized treatment. Patients, with age ≤ 53 years, CEA ≥ 23 ng/mL and exon 21 point mutations from EGFR-mutated advanced lung adenocarcinoma, are at the highest risk for developing BM during the course of EGFR-TKIs therapy, and are most likely to benefit from PCI. Additionally, further studies are warranted to validate our findings.

An analysis of risk factors for brain metastases after prophylactic cranial irradiation for limited-stage small-cell lung cancer

Objective To evaluate the high-risk factors for brain metastases after prophylactic cranial irradiation (PCI), and to provide a basis for personalized treatment. Methods A retrospective analysis was performed in 188 patients with limited-stage small-cell lung cancer who received PCI in our hospital from 2005 to 2010. The Kaplan-Meier method was used to calculate the cumulative rate of brain metastases. The log-rank test and the Cox model were used for the univariate and multivariate analyses of the potential factors for the cumulative incidence of brain metastases, respectively. Results In the 188 patients, 31(16.5%) had brain metastases. The 1-, 2-, and 3-year cumulative incidence rates of brain metastases were 4%, 15%, and 20%, respectively. The univariate analysis showed that staged Ⅲ disease before treatment, elevated levels of tumor markers, incomplete remission after chemoradiotherapy, and local-regional relapse were risk factors for high incidence of brain metastases (P=0.044, 0.037, 0.005, 0.007). The multivariate analysis revealed that incomplete remission after chemoradiotherapy and local-regional relapse after chemoradiotherapy were risk factors for high incidence of brain metastases after PCI (P=0.003, 0.040). Conclusions Patients with incomplete remission or local-regional relapse after chemoradiotherapy have high incidence of brain metastases after PCI. For those patients, a frequent follow-up of the central nervous system plus salvage cranial irradiation might provide an alternative to PCI. Key words: Small cell carcinoma, lung/prophylactic cranial irradiation; Brain metastasis; Risk factor

Risk factors of brain metastasis during the course of EGFR-TKIs therapy for patients with EGFR-mutated advanced lung adenocarcinoma

Controversial value of prophylactic cranial irradiation (PCI) in NSCLC in terms of survival benefit prompted us to explore the possible risk factors for brain metastasis (BM) during the course of EGFR-TKIs therapy from EGFR-mutated advanced lung adenocarcinoma and identify the potential population most likely to benefit from PCI, because BM remains a therapeutically challenging issue. We retrospectively reviewed the records of 134 patients with EGFR-mutated advanced lung adenocarcinoma between 2008 and 2012. The cumulative incidence of BM was calculated by the Kaplan-Meier method, and Multivariate Cox regression analysis was used to assess the independent risk factors for BM. Thirty-four patients (34/134, 25.4%) developed BM during the course of EGFR-TKIs therapy. Moreover, the Multivariate analysis indicated that age ≤ 53 years (HR: 2.751, 95 % CI: 1.326-5.707; p = 0.007), serum carcinoembryonic antigen (CEA) ≥ 23 ng/mL (HR: 3.197, 95 % CI: 1.512-6.758; p = 0.002) and EGFR exon 21 point mutations (HR: 2.769, 95 % CI: 1.355-5.659; p= 0.005) were the independent high-risk factors for developing BM, which could offer important insights into the individualized treatment. Further studies are warranted to validate our findings.

163: Cumulative Incidence of Brain Metastasis after Diagnosis of Non-Small Cell Lung Cancer: Estimates from a Regional Cancer Centre Cohort

163: Cumulative Incidence of Brain Metastasis after Diagnosis of Non-Small Cell Lung Cancer: Estimates from a Regional Cancer Centre Cohort