Small Cell Lung Cancer Brain Metastases Research Articles

PD-L1 inhibitors combined with whole brain radiotherapy in patients with small cell lung cancer brain metastases: Real-world evidence.

Numerous studies have demonstrated that brain metastases patients may benefit from intracranial radiotherapy combined with immune checkpoint inhibitors (ICIs). However, it is unclear whether this treatment is effective for patients with small cell lung cancer brain metastases (SCLC-BMs). We conducted a retrospective study by analyzing medical records of patients with SCLC-BMs from January 1, 2017 to June 1, 2022. Data related to median overall survival (mOS), median progression-free survival (mPFS), and intracranial progression-free survival (iPFS) were analyzed. A total of 109 patients were enrolled, of which 60 received WBRT and 49 received WBRT-ICI. Compared to the WBRT alone cohort, the WBRT-ICI cohort showed longer mOS (20.4 months vs. 29.3 months, p = 0.021), mPFS (7.9 months vs. 15.1 months, p < 0.001), and iPFS (8.3 months vs. 16.5 months, p < 0.001). Furthermore, WBRT-ICI cohort had a better response rate for both BMs. (p = 0.035) and extracranial diseases (p < 0.001) compared to those receiving WBRT alone. Notably, the use of WBRT before ICI was associated with longer mOS compared to the use of WBRT after ICI (23.3 months for the ICI-WBRT group vs. 34.8 months for the WBRT-ICI group, p = 0.020). Our results indicated that WBRT combined with immunotherapy improved survival in SCLC-BMs patients compared to WBRT monotherapy. Administering WBRT prior to ICI treatment is associated with improved survival outcomes compared to WBRT following ICI treatment, for patients with SCLC-BMs. These findings highlight the significance of conducting further prospective researches on combination strategies of intracranial radiotherapy and ICI in SCLC-BMs patients.

Predictive importance of systemic inflammation response index in de novo brain metastatic small cell lung cancer patients

Aims: The subtype of lung cancer, known as small cell lung cancer (SCLC), tends to have a highly fatal course, especially in advanced stages. In particular, the overall survival durations further decrease in cases of brain metastases in SCLC. There is increasing evidence for the role of systemic inflammation parameters in predicting cancer prognosis, and they appear likely to become potential target markers for clinical treatments in the future. We aimed to evaluate the systemic inflammation response index (SIRI), a novel inflammatory laboratory marker that could predict long-term survival and serve as a potential target marker for clinical treatment, in patients with de novo brain metastatic small cell lung carcinoma (DNBM SCLC)."&#x0D; Methods: Clinicopathological features of adult patients diagnosed with DNBM SCLC were recorded from the patient registry of the hospital. Patients without medical records were not included in the study. Investigations were carried out to assess the prognostic effect of the SIRI parameter in predicting the 12-month overall survival (OS12) in DNBM SCLC patients, by determining a cut-off value and conducting appropriate statistical analyses, considering p-values (

Incidence and Risk Factors for Brain Metastases in Patients with Lung Cancer: A Systematic Review and Meta-Analysis

Brain metastases (BM) are a very common metastatic site in lung cancer, but the exact rate of metastasis is still controversial. Risk factors for BM development are also largely lacking, hampering personalized treatment strategies. This study aimed to identify the incidence and possible risk factors for BM in lung cancer. A systematic review, based on the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guide-lines, was conducted using PubMed, Medline databases and Cochrane Library databases from inception until February 2023. Two investigators independently searched and selected literature, included in randomized controlled trials and cohort studies. Heterogeneity was assessed using the χ2 test and the I2 statistic. Significant heterogeneity was indicated by P <0.05 in Cochrane Q tests and a ratio greater than 40% in I2 statistics. The review is registered on PROSPERO, number: CRD42022370173. Forty-nine studies were included in the meta-analysis. The results showed that the incidence rate of BM in non-small cell lung cancer (NSCLC) was 0.24 (95% confidence interval [CI]: 0.23-0.25; I2 = 97.1%). The incidence rate in early NSCLC was 0.11 (95% CI: 0.10-0.13), locally advanced NSCLC was 0.32 (95% CI: 0.29-0.34), and advanced NSCLC was 0.37 (95% CI: 0.35-0.38). Lung adenocarcinoma was more prone to BM in NSCLC (risk ratio [RR] = 3.59, 95% CI: 1.97-6.54; P<0.001). The BM rate of NSCLC with EGFR mutation was also higher (hazard ratio [HR] = 1.49, 95% CI: 1.14-1.94; P = 0.004). Sex and smoking had no significant effect on the incidence of BM in NSCLC. Prophylactic Cranial Irradiation (PCI) could significantly reduce BM in NSCLC (HR = 0.36, 95% CI: 0.23-0.56; P<0.001), but chemotherapy had no obvious effect on decreasing the rate of BM (HR = 0.91, 95% CI: 0.54-1.54; P = 0.73). The incidence rate of BM in small cell lung cancer (SCLC) was 0.28 (95% CI: 0.27-0.30; I2 = 95.9%), and 0.23 (95% CI: 0.20-0.25) in the limited-stage SCLC. Older age (≥65) (HR = 0.70, 95% CI: 0.54-0.92; P = 0.01) were associated with less BM in SCLC. A higher T stage (≥T3) (HR = 1.72, 95% CI: 1.16-2.56; P = 0.007) was a significant risk factor for BM, while sex, smoking dose were not. PCI could also significantly decreased BM in SCLC (HR = 0.47, 95% CI: 0.38-0.58; P<0.001). This study is the first meta-analysis of BM incidence rate in lung cancer, and further explores the factors affecting BM, providing some suggestions for clinical decision-making of BM prevention in patients with lung cancer.

Magnetic resonance imaging characteristics of brain metastases in small cell lung cancer.

Lung is the most common primary site of brain metastases (BMs). For different pathological types of BMs have some similar characteristics, it is still a challenge to confirm the origin based on their characteristics directly. BMs of small cell lung cancer (SCLC) have favorable therapeutic expectations due to their high sensitivity to radiotherapy. This study sought to identify unique characteristics of BMs in SCLC, aiming to assist in clinical decision-making. Patients diagnosed with BMs of lung cancer who received radiotherapy from January 2017 to January 2022 were reviewed (N = 284). Definitive diagnosis of BMs of SCLC was reached for 36 patients. All patients underwent head examination using magnetic resonance imaging. The number, size, location, and signal characteristics of lesions were analyzed. There were 7 and 29 patients with single focus and non-single focus, respectively. Ten patients had diffuse lesions, and the remaining 26 patients had a total of 90 lesions. These lesions were divided into three groups according to size: <1, 1-3, and >3 cm (43.33%, 53.34%, and 3.33%, respectively). Sixty-six lesions were located in the supratentorial area, primarily including cortical and subcortical lesions (55.56%) and deep brain lesions (20%). Moreover, 22 lesions were located in the infratentorial area. According to diffusion-weighted imaging and T1-weighted contrast enhancement, the imaging characteristics were classified into six patterns. Hyperintensity in diffusion-weighted imaging and homogeneous enhancement was the most common pattern of BMs in SCLC (46.67%), while partial lesions showed hyperintensity in diffusion-weighted imaging without enhancement (7.78%). The manifestations of BMs in SCLC were multiple lesions (diameter: 1-3 cm), hyperintensity in diffusion-weighted imaging, and homogeneous enhancement. Interestingly, hyperintensity in diffusion-weighted imaging without enhancement was also one of the characteristics.

Syphilis mimetic nanoparticles for cuproptosis-based synergistic cancer therapy via reprogramming copper metabolism

Small cell lung cancer (SCLC) is one of the most devastating type of human lung cancer and has a high propensity to metastasize into the brain. Cuproptosis recently has been defined as a copper dependent cell death, offers a new lens to develop the novel copper-based nanostructure inducing cuproptosis for suppressing tumor growth and metastasis. Here, we report a syphilis mimetic TP0751-peptide decorated stem cell membrane-coated copper-based metal organic framework (Cu-MOF) nanodelivery system for SCLC brain metastasis. The Cu-MOF is employed as nanocarrier to support siRNA with high loading efficiency, and its pH sensitivity facilitates endosomal disruption upon cellular uptake. Furthermore, the cell membrane coating Cu-MOF presents a good biocompatibility, high BBB transcytosis, and specific uptake by tumor cells within the brain. In vitro and in vivo trials have shown that TP-M−Cu−MOF/siATP7a exhibited high silencing efficiency against target gene, specifically blocked copper trafficking, increased copper intake, triggered cuproptosis, and improved therapeutic efficacy in SCLC brain metastasis tumor-bearing mice. Overall, the biomimetic nanodelivery platform presented here further offers a promising way of orchestrating gene therapy to target copper-dependent signalling for reprogramming copper metabolism and cuproptosis-based synergistic therapy in mice bearing brain metastases.

Abstract 931: Comprehensive analysis of 3,600 small cell lung cancer cases reveals rare genetic subtypes and multiple mechanisms of histological transformation

Abstract Background: Small cell lung cancer (SCLC) is an aggressive neuroendocrine carcinoma with limited treatment options and extremely poor survival outcomes. A major barrier in the field has been the relative paucity of human tumors studied and lack of access to longitudinal samples to understand tumor evolution. Methods: Here we provide a comprehensive analysis of 3,600 patients with SCLC who underwent targeted genomic profiling of at least 324 cancer-related genes as part of routine clinical care, including 678 cases with additional clinical and treatment information obtained from a US-based de-identified SCLC clinico-genomic database that originated from approximately 280 US cancer clinics. This large cohort allowed us to examine for new genetic subtypes, ancestry-associated genomic alterations, biopsy site-specific patterns, survival trends and histological transformation of SCLC from non-small cell lung cancer (NSCLC). Results: Consistent with prior studies, SCLCs were predominantly TP53/RB1 altered. Yet, 5.5% of the cases in our cohort were TP53/RB1 wild-type tumors. These tumors often lacked a tobacco mutational signature, exhibited alternate mechanisms of p53/Rb pathway inactivation (e.g., CDKN2A, CCND1, MDM2), and had a high fraction of human papillomavirus-positive cases (12.7%). Another rare subtype of SCLCs included STK11-altered tumors (1.7%), which were observed more frequently in patients of African ancestry, and were associated with a decreased overall survival (OS) compared with the STK11 wild-type cohort. In our cohort, gene amplifications on 4q12 (KDR, KIT, PDGFRA) were associated with increased OS while CCNE1 amplification was associated with decreased OS. Interestingly, alterations in PTEN were more common in brain metastases compared to lung biopsies and liver metastases, suggesting its potentially unique role in brain metastases of SCLCs. Profiling of over 100 putative transformed SCLCs demonstrated that lineage plasticity may occur at variable lengths of time from the original NSCLC diagnosis and include multiple distinct molecular cohorts of NSCLC, beyond EGFR-mutant NSCLC (e.g., kinase fusion+ tumors: RET, ALK, ROS1, NTRK1). Conclusion: Our work underscores the existence of genetic subtypes in SCLC, including rare subtypes with potential clinical utility. Findings from this study provide an improved understanding of genetic subtypes in SCLC and better inform mechanisms of transformation to SCLC from NSCLC, that may further guide the development of personalized therapies for subsets of patients with this fatal tumor. Citation Format: Smruthy Sivakumar, Jay A. Moore, Meagan Montesion, Douglas I. Lin, Zoe Fleischmann, Ericka M. Ebot, Justin Newberg, Jennifer M. Mills, Priti S. Hegde, Garrett M. Frampton, Julien Sage, Christine M. Lovly. Comprehensive analysis of 3,600 small cell lung cancer cases reveals rare genetic subtypes and multiple mechanisms of histological transformation [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 931.

EP14.01-014 Risk Factors for Brain Metastasis in Patients with Small Cell Lung Cancer: A Systematic Review and Meta-analysis

The use of prophylactic cranial irradiation (PCI) for small cell lung cancer (SCLC) is controversial. Risk factors for brain metastasis (BM) are largely unknown, hampering personalized treatment strategies. This study aimed to identify possible risk factors for BM in SCLC.

Stereotactic radiosurgery for patients with small-cell lung cancer brain metastases

Despite the continuous implementation of stereotactic radiosurgery (SRS) for patients with limited (≤4) brain metastases from various solid tumours1 and despite the increasing evidence of neurocognitive toxicity from whole brain radiotherapy (WBRT),2 patients with brain metastases from small-cell lung cancer (SCLC) are still considered typical candidates for WBRT. International guidelines and surveys on care patterns still regard WBRT as a standard of care for this setting in clinical practice. Several studies in various cancers have shown that postoperative SRS instead of additional WBRT can be associated with high control and survival rates and could preserve neurocognitive functioning;3,4 therefore, SRS has replaced WBRT as the standard of care for patients with limited brain metastases from most solid tumours, and its safety and efficacy is suggested for as many as ten targetable lesions.

Organoids as a Systems Platform for SCLC Brain Metastasis.

Small Cell Lung Cancer (SCLC) is a highly aggressive, neuroendocrine tumor. Traditional reductionist approaches have proven ineffective to ameliorate the uniformly dismal outcomes for SCLC – survival at 5 years remains less than 5%. A major obstacle to improving treatment is that SCLC tumor cells disseminate early, with a strong propensity for metastasizing to the brain. Accumulating evidence indicates that, contrary to previous textbook knowledge, virtually every SCLC tumor is comprised of multiple subtypes. Important questions persist regarding the role that this intra-tumor subtype heterogeneity may play in supporting the invasive properties of SCLC. A recurrent hypothesis in the field is that subtype interactions and/or transition dynamics are major determinants of SCLC metastatic seeding and progression. Here, we review the advantages of cerebral organoids as an experimentally accessible platform for SCLC brain metastasis, amenable to genetic manipulations, drug perturbations, and assessment of subtype interactions when coupled, e.g., to temporal longitudinal monitoring by high-content imaging or high-throughput omics data generation. We then consider systems approaches that can produce mathematical and computational models useful to generalize lessons learned from ex vivo organoid cultures, and integrate them with in vivo observations. In summary, systems approaches combined with ex vivo SCLC cultures in brain organoids may effectively capture both tumor-tumor and host-tumor interactions that underlie general principles of brain metastasis.

Brain Metastasis in Patients with Small Cell Lung Cancer.

PurposeTo characterize the risk factors for brain metastasis (BM) at presentation and analyze the prognostic factors for patients with small cell lung cancer (SCLC).Patients and MethodsPatients were recruited from the SEER database between 2010 and 2016. They were divided into two groups according to BM status. The incidence trends of SCLC and its BM were analyzed by joinpoint software. The risk factors for BM in SCLC were identified by binary logistic regression models. The prognostic factors for SCLC patients with BM were identified by Cox proportional hazard models.ResultsThe incidence of SCLC and its BM significantly decreased after 2010. Totally 11,093 patients were collected, including 1717 (15.5%) patients with BM and 9376 (84.5%) patients without BM. In multivariate logistic regression analysis, age, male and higher T stage were independent risk factors for BM in SCLC patients at presentation. SCLC patients with BM showed inferior survival to those without BM. In multivariate Cox regression analysis, increasing age, large tumor size, and higher N stage were risk factors for poor prognosis, while other race, surgery, adjuvant radiotherapy, and chemotherapy were protective factors for SCLC patients with BM. A nomogram was developed for prognosis evaluation of such patients.ConclusionAge, male and higher T stage were risk factors for BM in SCLC patients at presentation. Increasing age, large tumor size, and advanced N stage may predict poor survival for SCLC patients with BM. Multidisciplinary therapies may provide clinical benefits. This study will help identify patients with higher BM risk and hopefully improve their clinical outcome.

JIES01.04 Prophylactic Cranial Irradiation in Lung Cancer: Where We Are

Prophylactic cranial irradiation (PCI) has been used in small cell lung cancer (SCLC) to reduce the high risk (∼60%) of brain metastases in these patients. Early trials on PCI have focused on patients in complete remission after treatment for limited stage (LS). Individual studies showed unequivocally a significant reduction in the risk of brain metastases, but a survival benefit was only seen in a meta-analysis [1]. In this analysis. An absolute increase in survival rate of 5.4% at 3 years [1]. The vast majority of patients in these studies had a complete remission (often based on chest radiographs) after chemotherapy. Based on these studies, PCI became part of standard treatment of LS-SCLC patients with a complete response. To reduce the risk of neurocognitive toxicity, PCI was not simultaneously given with chemotherapy and started within 6 weeks after last chemotherapy. A study on the effectiveness of higher dose PCI (36 Gy) showed no benefit over standard dose (25 Gy) PCI [2]. Since most patients with SCLC present with extensive stage (ES) disease, and the risk of brain metastases is even higher in this group of patients, the EORTC performed a study on PCI in patients with any response after chemotherapy for ES-SCLC. In this trial, PCI not only significantly reduced the risk of symptomatic brain metastases (15 vs 40%), but also significantly improved survival (1 year survival 27 vs 13%) [3]. This study was pragmatic and in line with existing guidelines not to repeat brain imaging and to focus on symptomatic disease. It was argued that some individuals with asymptomatic, but radiologically detectable brain metastases may have been included in the study and that could, at least partially, have contributed to the outcome. In a Japanese study on PCI in ES-SCLC patients, all patients had a brain MRI to excluded presence of asymptomatic brain metastases [4]. In addition, regular brain MR imaging was performed during follow-up and when appropriate, brain metastases that appeared were treated. The study showed a significant reduction in the rate of brain metastases when using PCI (33 vs 59%), but no survival benefit. In the observation arm that did not receive PCI, many patients (83%) who developed brain metastases were treated with radiotherapy [4]. A SWOG trial (SWOG 1827/”MAVERICK”) has opened in 2020 to compare a strategy of MRI surveillance with early treatment to MRI surveillance with PCI. Interestingly, this study is not only enrolling patients with ES-SCLC but also with LS-SCLC. In it well known that the disease SCLC and PCI can be associated with cognitive decline. Studies aiming at sparing brain regions involved in memory and cognitive functions, esp. hippocampal region, led to attempt of using hippocampal avoiding PCI (HA-PCI). Whole brain radiotherapy with hippocampal avoidance was associated with better preservation of memory and quality of life [5]. Studies on the benefit of HA-PCI are less conclusive [6,7] and the results of an ongoing trails (NRG CC003) are awaited. In conclusion, PCI is very effective in reducing the risk of brain metastases in SCLC. There are questions whether the beneficial effect on survival is maintained in the era of MR screening and MR surveillance with early treatment of (asymptomatic) brain metastases. Studies to re-evaluate the role of PCI in the current era of immunotherapy are underway. In the meantime, PCI or MRI surveillance should be considered guideline-recommended treatment. In NSCLC, the role of PCI was also addressed in a number of studies. In a recent trial with long term follow-up (NRG/RTOG0214) and a meta-analyses, earlier findings of a significant reduction in the rate of brain metastases, improvement in diseasefree survival, but absence of improved overall survival after PCI, were confirmed [8,9]. Literature 1. Auperin A, Arriagada R, Pignon JP, et al. N Engl J Med 341, 476-84, 1999. 2. Le Pechoux C, Dunant A, Senan S, et al. Lancet Oncol 10, 467-74, 2009. 3. Slotman BJ. Faivre-Finn C, Kramer G, et al. N Engl J Med 357, 664-72, 2007. 4. Takahashi T, Yamanaka T, Seto T, et al. Lancet Oncol 18, 663-71, 2017. 5. Gondi V, Pugh SL, Tome WA. J Clin Oncol 3, 3810-6, 2014. 6. De Dios ND, Counago F, Lopez JL, et al., Int J Radiat Oncol Biol Phys 105, S35-6, 2019. 7. Belderbos JS, De Ruysscher DK, de Jaeger K, et al. T Thor Oncol 16, 840-9, 2021. 8. Sun A, Hu C, Wong SJ. JAMA Oncol 5, 847-55, 2019. 9. Witlox WJA, Ramaekers BLT, Lacas B, et al., Radiother Oncol. 158, 40-7. 2021. brain metastases, PCI, prophylactic cranial irradiation

Care Patterns for Stereotactic Radiosurgery in Small Cell Lung Cancer Brain Metastases

IntroductionThe historical standard of care for brain metastases (BMs) from small cell lung cancer (SCLC) has been whole-brain radiotherapy (WBRT). However, there is growing interest in upfront stereotactic radiosurgery (SRS) for select SCLC patients. Materials and MethodsWe invited United State-based Radiation Oncologists (ROs) via email to answer an anonymous survey using a branching logic system addressing their use of SRS and WBRT for SCLC BMs. Wilcoxon rank-sum test and Fisher's exact test were used to compare differences in continuous and categorical variables, respectively. Multivariable logistic regression analyses were fitted for outcome variables including covariates with P < .10 obtained on univariable analysis. ResultsIn total, 309 ROs completed the survey and 290 (95.7%) reported that they would consider SRS for SCLC BMs under certain clinical circumstances. Across patient characteristics, the number of BMs was the most heavily weighted factor (mean 4.3/5 in importance), followed by performance status, cognitive function, and response to prior therapy. Fewer BMs were correlated with increased SRS use (55.8% offered SRS “very frequently” [>75% of cases] or “often” [51%-75% of cases] for 1 BM vs. 1.1% for >10 BM, P < .001). In situations where WBRT was preferred, concern for rapid intracranial progression (45.3%) and lack of high-level data (36.9%) were the most important factors. The majority (60.6%) were aware of a large recent international retrospective analysis (the FIRE-SCLC study) reporting similar OS between upfront SRS and WBRT; awareness of this study was the only respondent variable predictive of SRS use for limited BMs (19.2% of those aware of the study preferring SRS for limited [≤4] BMs before vs. 61% preferring SRS after the publication, P < .001). The majority of respondents (88.2%) expressed a willingness to enroll patients on a recently opened recently opened randomized trial, NRG-CC009, comparing SRS versus hippocampal-avoidance WBRT. ConclusionsIn the first survey of SRS for SCLC BMs, we observed a high level of physician openness to upfront SRS in SCLC, particularly for patients with limited numbers of BMs, as well as significant interest in generating prospective randomized data to clarify the role of SRS in this population.

Differentiation of brain metastases from small and non-small lung cancers using apparent diffusion coefficient (ADC) maps

BackgroundBrain metastases are particularly common in patients with small cell lung cancer (SCLC) and non-small cell lung cancer (NSCLC), with NSCLC showing a less aggressive clinical course and lower chemo- and radio sensitivity compared to SCLC. Early adequate therapy is highly desirable and depends on a reliable classification of tumor type. The apparent diffusion coefficient is a noninvasive neuroimaging marker with the potential to differentiate between major histological subtypes. Here we determine the sensitivity and specificity of the apparent diffusion coefficient to distinguish between NSCLC and SCLC.MethodsWe enrolled all NSCLC and SCLC patients diagnosed between 2008 and 2019 at the University Medical Center Göttingen. Cranial MR scans were visually inspected for brain metastases and the ratio of the apparent diffusion coefficient (ADC) was calculated by dividing the ADC measured within the solid part of a metastasis by a reference ADC extracted from an equivalent region in unaffected tissue on the contralateral hemisphere.ResultsOut of 411 enrolled patients, we detected 129 patients (83 NSCLC, 46 SCLC) with sufficiently large brain metastases with histologically classified lung cancer and no hemorrhage. We analyzed 185 brain metastases, 84 of SCLC and 101 of NSCLC. SCLC brain metastases showed an ADC ratio of 0.68 ± 0.12 SD, and NSCLC brain metastases showed an ADC ratio of 1.47 ± 0.31 SD. Receiver operating curve statistics differentiated brain metastases of NSCLC from SCLC with an area under the curve of 0.99 and a 95% CI of 0.98 to 1, p < 0.001. Youden's J cut-point is 0.97 at a sensitivity of 0.989 and a specificity of 0.988.ConclusionsIn patients with lung cancer and brain metastases with solid tumor parts, ADC ratio enables an ad hoc differentiation of SCLC and NSCLC, easily achieved during routine neuroradiological examination. Non-invasive MR imaging enables an early-individualized management of brain metastases from lung cancer.Trial registration: The study was registered in the German Clinical Trials Register (DRKS00023016).

Differentiating Small-Cell Lung Cancer From Non-Small-Cell Lung Cancer Brain Metastases Based on MRI Using Efficientnet and Transfer Learning Approach.

Differentiation between small-cell lung cancer (SCLC) from non-small-cell lung cancer (NSCLC) brain metastases is crucial due to the different clinical behaviors of the two tumor types. We propose the use of a deep learning and transfer learning approach based on conventional magnetic resonance imaging (MRI) for non-invasive classification of SCLC vs. NSCLC brain metastases. Sixty-nine patients with brain metastasis of lung cancer origin were included. Of them, 44 patients had NSCLC and 25 patients had SCLC. Classification was performed with EfficientNet architecture on crop images of lesion areas and based on post-contrast T1-weighted, T2-weighted and FLAIR imaging input data. Evaluation of the model was carried out in a 5-fold cross-validation manner, and based on accuracy, precision, recall, F1 score and area under the receiver operating characteristic curve. The best classification results were obtained with multiparametric MRI input data (T1WI+c+FLAIR+T2WI), with a mean overall accuracy of 0.90 ± 0.04, and F1 score of 0.92 ± 0.05 for NSCLC and 0.87 ± 0.08 for SCLC for the validation data and an accuracy of 0.87 ± 0.05, with an F1 score of 0.88 ± 0.05 for NSCLC and 0.85 ± 0.05 for SCLC for the test dataset. The proposed method provides an automatic noninvasive method for the classification of brain metastasis with high sensitivity and specificity for differentiation between NSCLC vs. SCLC brain metastases. It may be used as a diagnostic tool for improving decision-making in the treatment of patients with these metastases. Further studies on larger patient samples are required to validate the current results.

Combined Immunotherapy and Stereotactic Radiotherapy Improves Neurologic Outcomes in Patients with Non–small-cell Lung Cancer Brain Metastases

BackgroundThe purpose of this study was to compare the outcomes of patients with non-small cell lung cancer (NSCLC) brain metastases treated with stereotactic radiotherapy (SRT) alone versus SRT and immune checkpoint inhibitors (ICIs). Patients and MethodsPatients treated for their first diagnosis of intracranial metastases with SRT or SRT plus ICI were retrospectively identified. Overall survival (OS), local control (LC), distant brain failure (DBF), neurologic death, and rates of radiation necrosis were calculated. Univariate (UVA) and multivariable (MVA) analyses with competing risk analysis were performed. ResultsSeventy-seven patients with 132 lesions were analyzed, including 44 patients with 68 lesions in the SRT group and 33 patients with 64 lesions in the SRT plus ICI group. There were no differences in baseline factors between groups. Use of ICI predicted for decreased DBF (hazard ratio [HR], 0.45; 95% confidence interval [CI], 0.24-0.84; P = .01), decreased rates of neurologic death (HR, 0.29; 95% CI, 0.10-0.85; P = .02), and better OS (HR, 0.46; 95% CI, 0.23-0.91; P = .03). Two-year LC was 97% for the SRT + ICI group, and 86% for the SRT-alone group (P = .046). Actuarial 2-year DBF was 39% for the SRT + ICI group and 66% for the SRT alone group (P = .016). On MVA, ICI use persisted in predicting lower incidence of neurologic death (HR, 0.25; 95% CI, 0.09-0.72; P = .01) and DBF (HR, 0.47; 95% CI, 0.25-0.85; P = .01) when adjusted for competing risk of death. ConclusionIn this cohort of patients with NSCLC brain metastases, ICI use combined with SRT predicted for improved LC and OS and decreased DBF and risk of neurologic death.

Radiosurgery for small-cell lung cancer brain metastases: a review.

First-line stereotactic radiosurgery (SRS) is now considered the preferred treatment over whole brain radiation therapy (WBRT) for limited brain metastases arising from most tumor histologies. This standard was reached following the consistent results of multiple phase III studies which demonstrated that, despite improved CNS control, the addition of WBRT to SRS does not improve overall survival (OS) and is associated with a reduction in cognitive function. Thus, it may be reasonable to consider the benchmark necessary to favor a paradigm of SRS alone over strategies incorporating WBRT as the demonstration of comparable OS in the context of decreased treatment-related side effects. However, patients with small-cell lung cancer (SCLC) brain metastases were excluded from the landmark trials that established SRS alone for limited brain metastases, largely due to concerns for short-interval CNS progression in SCLC as well the historic role of prophylactic cranial irradiation (PCI) in SCLC in the absence of known brain metastases. As a result, WBRT has remained the standard for SCLC for limited and even solitary brain lesions. With shifting SCLC care patterns including increased MRI surveillance, decreased PCI delivery, and emerging systemic agents, interest in first-line SRS for SCLC is likely to continue to increase over time. Herein we will review the emerging data for first-line SRS in the management of SCLC brain metastases and the potential for its increasing role in the setting of a greater utilization of MRI surveillance and improving systemic therapies.

Survival outcomes after whole brain radiotherapy for brain metastases in older adults with newly diagnosed metastatic small cell carcinoma: A national cancer database (NCDB) analysis.

Small cell lung cancer (SCLC) is an aggressive malignancy with a tendency to affect older adults and also metastasize to the brain. Older adults tolerate whole brain radiotherapy (WBRT) poorly with marginal survival benefit. We utilized the national cancer database (NCDB) to evaluate the survival outcomes following WBRT in older adults with SCLC and brain metastases. We identified 1615 patients ≥75 years old diagnosed with SCLC and brain metastases. Patients were categorized by type of therapy: chemotherapy + WBRT (n = 576), chemotherapy alone (n = 238), WBRT alone (n = 360) and no chemotherapy or WBRT (n = 441). Clinical and demographic characteristics were reported for each treatment cohort with a subsequent multivariable regression analysis for survival. Median patient age was 79 years. WBRT median dose was 30 Gy. At time of analysis, 1530 of the cohort had died, yielding a median OS of 2.9 months and 6 month survival of 31% for patients that received chemotherapy. For patients treated without chemotherapy, median OS with WBRT was 1.9 months compared to 1.2 months without (p < .0001). For patients receiving chemotherapy with, and without WBRT, median OS was 5.6 months and 6.4 months, respectively (p = .43). Multivariable cox regression revealed age > 80, extracranial disease, male sex, and rural location as predictors of increased risk of death. In older adult patients with SCLC brain metastasis, WBRT was associated with a modest increase in survival in patients not fit for chemotherapy, and there was no association with increased survival over chemotherapy alone.

Stereotactic radiosurgery for brain metastases from newly diagnosed small cell lung cancer: practice patterns and outcomes

Background: Up-front stereotactic radiosurgery (SRS) has been historically thought of as inadequate for brain metastases (BM) from newly diagnosed small cell lung cancer (SCLC). This study evaluates national practice patterns and clinical outcomes for BM from SCLC.Material and methods: The National Cancer Database was queried (2004–2013) for patients with newly diagnosed metastatic SCLC receiving intracranial radiotherapy. Patients were grouped into three categories: upfront SRS, whole-brain radiotherapy (WBRT) alone, or WBRT with boost (SRS or fractionated radiotherapy). Statistics included temporal trend assessment by annual percent change (APC), logistic regression, exploratory Kaplan–Meier overall survival (OS) analysis without and with propensity matching, and Cox proportional hazards modeling.Results: A total of 14,722 patients met selection criteria, of whom 487 (3.3%), 13,657 (92.8%), and 578 (3.9%) received upfront SRS, WBRT and WBRT with boost, respectively. Utilization of SRS showed a slight increasing trend from 2004 to 2013 (2.7–4.3%). In addition to socioeconomic factors, other variables associated with SRS use included diagnosis after 2010, treatment at academic centers, and residing in higher-educated regions. SRS was less often delivered to patients with node-positive disease (p < .05). On exploratory analysis, SRS cohort was observed to have a higher overall survival (OS) than WBRT-based groups (p < .001), namely in patients without extracranial metastases.Conclusions: Utilization of up-front SRS for SCLC BM has been increasing over time but is driven by socioeconomic disparities. Although there are likely numerous biases associated with the OS findings herein, further research is needed to validate this finding as well as the role of SRS on patients with brain metastases due to SCLC.

Application of magnetic resonance diffusion-weighted imaging combined with serum tumor markers in brain metastases of small cell lung cancer

Objective To investigate the value of magnetic resonance diffusion-weighted imaging (DWI) in combination with peripheral serum tumor markers in the diagnosis and therapeutic evaluation of small cell lung cancer (SCLC) brain metastases. Methods Retrospective analysis of 368 SCLC cases diagnosed by histopathology or cytology from February 2009 to February 2012 in Shanxi Provincial Cancer Hospital was made. All patients underwent pathological examination of progastrin-releasing peptide (ProGRP), neuron-specific enolase (NSE) and brain DWI, and measured the apparent diffusion coefficient (ADC) of DWI sequences of brain metastases. The difference between the positive rates of ProGRP and NSE in patients with or without brain metastases was compared by the χ 2 test, and the diagnostic efficiency of ProGRP, NSE, DWI and combined detection for brain metastases were analyzed. The Kruskal-Wallis H test was used to compare the changes of ADC value, ProGRP and NSE before and after brain irradiation therapy in brain metastases of SCLC. Pearson correlation analysis was made to evaluate the correlation between the changes of ADC value and the levels of ProGRP and NSE in SCLC patients with brain metastases before and after treatment. Results The median expression of serum ProGRP in 169 SCLC patients was 2 664.7 pg/ml (98.4-4 876.8 pg/ml), with a positive rate of 98.2% (166/169). The median expression of NSE was 41.9 μg/L(9.4-264.3 μg/L), with a positive rate of 70.4% (119/169). The median expression of serum ProGRP level was 514.3 pg/ml (3.9-2 899.3 pg/ml) in 199 SCLC patients without brain metastasis, the positive rate was 89.4% (178/199). The median expression of NSE was 40.4 μg/L (0.3-176.1 μg/L), with a positive rate of 64.8% (129/199). The difference of ProGRP level between the two groups was statistically significant (u = 121.47, P < 0.001), but there was no significant difference in NSE level (u = 1.35, P = 0.12). The sensitivities of ProGRP, NSE, DWI, ProGRP+DWI and NSE+DWI were 68.4%, 41.2%, 66.7%, 92.2%, and 82.4%, and the specificities were 52.9%, 35.3%, 76.5%, 94.1%, and 88.2%. The sensitivity and specificity of ProGRP+DWI and NSE+DWI were higher than those of single test, and the differences were statistically significant (all P < 0.001). One hundred and fifty-six SCLC patients with brain metastases were treated with whole brain radiotherapy. Pearson correlation analysis showed that ADC values were negatively correlated with ProGRP and NSE levels (r = -0.945, P < 0.001; r = -0.995, P < 0.001). Conclusion DWI combined with ProGRP and NSE can provide objective evidence and clinical guidance for the diagnosis of SCLC brain metastases and the evaluation of whole brain radiotherapy. Key words: Small-cell lung carcinoma; Brain metastases; Progastrin-releasing peptide; Neuron-specific enolase; Magnetic resonance imaging

Stereotactic Radiosurgery for Brain Metastases of Small Cell Lung Cancer at Diagnosis: Local Management Patterns

Retrospective reports have suggested up-front stereotactic radiosurgery (SRS) to be a potentially effective treatment option for brain metastases (BM) from small cell lung cancer (SCLC). However, due to the likelihood of multiple microscopic intracranial metastases and distant brain failure, SRS has not typically been deemed to be an appropriate stand-alone treatment for these patients, as it is in patients with BM due to non-small cell lung cancer. The purpose of the present study is to evaluate national practice patterns and clinical outcomes for SCLC patients with BM receiving up front SRS. The National Cancer Data Base was queried (2004-2013) for patients with metastatic SCLC receiving intracranial radiotherapy for management of BM. Patients were grouped into categories based on the radiation treatment selected for the brain: upfront SRS, whole-brain radiotherapy(WBRT) or WBRT with concomitant boost (SRS or fractionated radiotherapy). Univariable and multivariable logistic regression were performed to evaluate factors associated with SRS administration. Temporal trends were analyzed graphically. Survival was analyzed with the Kaplan-Meier method and Cox proportional hazards modeling was used to evaluate predictors of overall survival (OS). To account for indication bias, survival analysis was repeated following and propensity score matching. A total of 14,722 patients met the selection criteria, of whom 487 (3.3%), 13,657 (92.8%) and 578 (3.9%) received upfront SRS, WBRT and WBRT with boost, respectively. The utilization of upfront SRS showed a slight increase from 2004 to 2013 (2.7% to 4.3%). Diagnosis in more recent time periods (2011-2013) was predictive of SRS use (p=0.004). Other socioeconomic factors associated with upfront SRS use included receiving therapy at academic centers and residing in higher-educated regions. SRS was less likely to be used in patients with node positive disease (p<0.05). The upfront SRS cohort was found to have a higher overall survival (OS) than WBRT-based groups before and after propensity matching (p<0.001). Younger patients, female gender, Charlson Deyo Score of 0, treatment at an academic center, higher-income, private insurance, recent years at diagnosis, early T stage, node negative disease and receipt of chemotherapy independently predicted for higher OS. This NCDB analysis demonstrates that utilization of upfront SRS for SCLC BMs has been increasing over time. Socioeconomic disparities exist with regards to SRS utilization. Use of SRS was associated with improved OS, though this could partially be due to selection bias. Further research is required to further elucidate the role of SRS in BMs due to SCLC.