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Background: Cognitive decline is an arising concern in patients who need cranial irradiation. We used the pooled longitudinal individual patient data of two phase III trials: NCT01780675 and PREMER to investigate whether hippocampal avoidance (HA)-PCI is associated with improved self-reported cognitive functioning (SRCF) compared with PCI without increasing brain metastases (BM) development within the HA area., Methods: Patients with stage I-IV small cell lung cancer (SCLC) were randomized to PCI or HA-PCI. SRCF was assessed and contrast enhanced brain magnetic resonance imaging (MRI) was performed at baseline and up to 24 months follow-up. SRCF and BM incidence after (HA)-PCI were compared between arms. Self reported cognitive impairment was defined as SCRF < 75., Results: In total, 318 patients were randomized. Longitudinal generalized estimating equation (GEE) analysis showed that HA-PCI neither had a significant impact on SRCF (β = 1.41, p = 0.52) nor on cognitive impairment (OR 0.81, 95 %CI 0.53-1.25, p = 0.34). The median follow up was 41.7 (95 %CI 35.7-47.6) months, during which 61 patients developed BM (PCI arm: 30, HA-PCI arm: 31, p = 0.9). BM site was solitary in 15 patients (PCI arm: 7, HA-PCI arm: 8, p = 0.8). Nine of the 61 patients had BM within the HA area (PCI arm: 4, HA-PCI arm: 5, p = 1.0). The BM incidence was not significantly different between arms (subdistribution hazard ratio [sHR] 1.03, 95 %CI 0.62-1.70, p = 0.91)., Conclusion: HA-PCI did not preserve longitudinal SRCF but did also not increase the risk of BM. Additional strategies should be investigated to further improve the therapeutic ratio of PCI., Trials Registration: ClinicalTrials.gov (NCT01780675) ClinicalTrials.gov (NCT02397733)., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: N Rodríguez de Dios: Consulting or Advisory Role: AstraZeneca Spain. Speakers' Bureau: AstraZeneca Spain, Siemens Healthineers. F Couñago: Honoraria: AstraZeneca, Astellas Pharma. L Hendriks: No related COI. Outside of this manuscript personal fees as an invited speaker from Benecke, Medtalks and VJOncology; personal fees for participation in mentorship programme funded by AstraZeneca; personal fees for travel support from Roche; personal fees as member of the committee that revised the Dutch guidelines on NSCLC, brain metastases and leptomeningeal metastases; fees paid to her institution for an educational webinar from Janssen; fees paid to her institution for advisory board membership from Amgen, BMS, Boehringer Ingelheim, Janssen, Lilly, Merck, MSD, Novartis, Pfizer, Roche and Takeda; fees paid to her institution as an invited speaker from AstraZeneca, Bayer, high5oncology, Lilly and Merck Sharp & Dohme (MSD); fees paid to her institution for interview sessions from Roche; fees paid to her institution for podcast appearance from Takeda; institutional research grants from AstraZeneca, Boehringer Ingelheim, Roche, Takeda, Merck and Pfizer (Novartis under negotiation); institutional funding as a local principal investigator (PI) from AbbVie, AstraZeneca, Blueprint Medicines, Gilead, GlaxoSmithKline (GSK), Merck Serono, Mirati, MSD, Novartis, Roche and Takeda; non-remunerated roles as chair for metastatic NSCLC of the lung cancer group for EORTC (European Organisation for Research and Treatment of Cancer) and as the secretary of the studies foundation for NVALT (Nederlandse Vereniging van Artsen voor Longziekten en Tuberculose). The other authors declare no conflicts of interest., (Copyright © 2024. Published by Elsevier B.V.)

Introduction: Few data is available on whether brain metastases (BM) influence survival in patients with stage IV KRAS G12C mutated (KRAS G12C+ ) non-small cell lung cancer (NSCLC) treated with first-line immune checkpoint inhibitor (ICI) +/- chemotherapy ([chemo]-ICI)., Methods: Data was retrospectively collected from the population-based Netherlands Cancer Registry. The cumulative incidence of intracranial progression, overall survival (OS) and progression free survival (PFS) was determined for patients with KRAS G12C+ stage IV NSCLC diagnosed January 1 - June 30, 2019, treated with first-line (chemo)-ICI. OS and PFS were estimated using Kaplan-Meier methods and BM+ and BM- groups were compared using log-rank tests., Results: Of 2489 patients with stage IV NSCLC, 153 patients had KRAS G12C+ and received first-line (chemo)-ICI. Of those patients, 35% (54/153) underwent brain imaging (CT and/or MRI), of which 85% (46/54) MRI. Half of the patients with brain imaging (56%; 30/54) had BM, concerning one-fifth (20%; 30/153) of all patients, of which 67% was symptomatic. Compared to BM-, patients with BM+ were younger and had more organs affected with metastasis. Around one-third (30%) of patients with BM+ had ≥5 BM at diagnosis. Three quarters of patients with BM+ received cranial radiotherapy prior to start of (chemo)-ICI. The 1-year cumulative incidence of intracranial progression was 33% for patients with known baseline BM and 7% for those without (p = 0.0001). Median PFS was 6.6 (95% CI 3.0-15.9) and 6.7 (95% CI 5.1-8.5) months for BM+ and BM- (p = 0.80), respectively. Median OS was 15.7 (95% CI 6.2-27.3) and 17.8 (95% CI 13.4-22.0) months for BM+ and BM- (p = 0.77), respectively., Conclusion: Baseline BM are common in patients with metastatic KRAS G12C+ NSCLC. During (chemo)-ICI treatment, intracranial progression was more frequent in patients with known baseline BM, justifying regular imaging during treatment. In our study, presence of known baseline BM did not influence OS or PFS., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023. Published by Elsevier B.V.)

Aim: To identify risk factors for self-reported cognitive impairment in radically treated stage III non-small cell lung cancer (NSCLC)., Methods: Cognitive functioning was assessed using the EORTC-QLQ-C30 at seven pre-specified time points in the phase III NVALT-11 trial (observation versus prophylactic cranial irradiation [PCI] in stage III NSCLC treated with chemo-radiotherapy ± surgery). Cognition was analyzed as binary (impairment or not) and continuous outcome, respectively, using generalized estimating equation (GEE) before and after multiple imputation. A score < 75 was defined as cognitive impairment. A mean difference by < 10, 10-<20, ≥ 20 points was regarded as of no, moderate, and large clinical effect, respectively. We categorized the cognitive impairment into four types based on changes over time: sustained, reversible, recurring, and alternating., Results: In the no-PCI arm, 43/84 [51.2%] reported cognitive impairment at least once, of which 31.4% were sustained, 25.7% reversible, 28.6% recurring, and 14.3% alternating. Results were similar in the PCI arm. Cognitive functioning at baseline was comparable in two arms and a score < 75 was a significant risk factor with large effect for subsequent cognitive impairment (no-PCI: β = -23.30, p < 0.001; PCI arm: β = -22.34, p < 0.001; All: β = -23.47, p < 0.001). Younger age (≤60y), squamous histology, and PCI were risk factors without clinical relevance (β > -10, p < 0.05). Cognitive functioning declined over time (β = -0.26, p = 0.001) except for patients with cognitive impairment at baseline (β = 0.141, p = 0.33)., Conclusion: Cognitive impairment is dynamic over time with four types. Baseline cognitive impairment (score < 75) is the most important risk factor for subsequent cognitive impairment in stage III NSCLC. Note: This work has been partly reported as an oral presentation at the ESTRO 2021 meeting (OC-0176)., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier B.V. All rights reserved.)

The guideline on brain metastasis from the Netherlands Society of Neurology has been updated. Important changes have been made, particularly with regard to treatment of brain metastases. Treatment of patients with brain metastases is complex and requires a multidisciplinary approach to formulate an optimal, individualized treatment plan. Neurosurgical resection may also be considered in patients with multiple brain metastases and one dominant, symptomatic lesion, if the patient is in good clinical condition. Stereotactic radiosurgery is a treatment option for patients with a maximum of 10 brain metastases, depending on the size and number of metastases. The indication for whole brain radiotherapy is relatively limited. Doctors should be cautious with whole brain radiotherapy in patients with a Karnofsky Performance Status <70. In patients with small, asymptomatic brain metastases, targeted therapy or immune therapy may be considered without locoregional therapy.

Background: Prophylactic cranial irradiation (PCI) reduces brain metastasis incidence in lung cancer, however with risk of neurocognitive decline. Nevertheless, risk factors for neurocognitive decline after PCI remain unclear., Methods: We systematically reviewed the PubMed database according to the PRISMA guideline. Inclusion criteria were: randomized clinical trials (RCTs) and observational/single arm trials evaluating PCI, including ≥20 patients, reporting neurocognitive test results for lung cancer. Primary aim: evaluate risk factors associated with neurocognitive decline after PCI., Results: Twenty records were eligible (8 different RCTs, 8 observational studies), including 3553 patients in total (858 NSCLC, 2695 SCLC) of which 73.6% received PCI. Incidence of mild/moderate cognitive decline after PCI varied from 8 to 89% (grading not always provided); for those without PCI, this was 3.4-42%. Interestingly, 23-95% had baseline cognitive impairment. Risk factors were often not reported. In one trial, both age (>60 years) and higher PCI dose (36 Gy) including twice-daily PCI were associated with a higher risk of cognitive decline. In one trial, white matter abnormalities were more frequent in the concurrent or sandwiched PCI arm, but without significant neuropsychological differences. One trial identified hippocampal sparing PCI to limit the neurocognitive toxicities of PCI and another reported an association between hippocampal dose volume effects and memory decline. As neurocognition was a secondary endpoint in most RCTs, and was assessed by various instruments with often poor/moderate compliance, high-quality data is lacking., Conclusions: Age, PCI dose, regimen and timing might be associated with cognitive impairment after PCI in lung cancer patients, but high-quality data is lacking. Future PCI trials should collect and evaluate possible risk factors systematically., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Introduction: Although frequent in NSCLC, patients with brain metastases (BMs) are often excluded from immune checkpoint inhibitor (ICI) trials. We evaluated BM outcome in a less-selected NSCLC cohort., Methods: Data from consecutive patients with advanced ICI-treated NSCLC were collected. Active BMs were defined as new and/or growing lesions without any subsequent local treatment before the start of ICI treatment. Objective response rate (ORR), progression-free survival, and overall survival (OS) were evaluated. Multivariate analyses were performed by using a Cox proportional hazards model and logistic regression., Results: A total of 1025 patients were included; the median follow-up time from start of ICI treatment was 15.8 months. Of these patients, 255 (24.9%) had BMs (39.2% active, 14.3% symptomatic, and 27.4% being treated with steroids). Disease-specific Graded Prognostic Assessment (ds-GPA) score was known for 94.5% of patients (35.7% with a score of 0-1, 58.5% with a score of 1.5-2.5, and 5.8% with a score of 3). The ORRs with BM versus without BM were similar: 20.6% (with BM) versus 22.7% (without BM) (p = 0.484). The intracranial ORR (active BM with follow-up brain imaging [n = 73]) was 27.3%. The median progression-free survival times were 1.7 (95% confidence interval [CI]: 1.5-2.1) and 2.1 (95% CI: 1.9-2.5) months, respectively (p = 0.009). Of the patients with BMs, 12.7% had a dissociated cranial-extracranial response and two (0.8%) had brain pseudoprogression. Brain progression occurred more in active BM than in stable BM (54.2% versus 30% [p < 0.001]). The median OS times were 8.6 months (95% CI: 6.8-12.0) with BM and 11.4 months (95% CI: 8.6-13.8) months with no BM (p = 0.035). In the BM subgroup multivariate analysis, corticosteroid use (hazard ratio [HR] = 2.37) was associated with poorer OS, whereas stable BMs (HR = 0.62) and higher ds-GPA classification (HR = 0.48-0.52) were associated with improved OS., Conclusion: In multivariate analysis BMs are not associated with a poorer survival in patients with ICI-treated NSCLC. Stable patients with BM without baseline corticosteroids and a good ds-GPA classification have the best prognosis., (Copyright © 2019 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved.)

Introduction: Non-small-cell lung cancer (NSCLC) guidelines advise to screen stage III NSCLC patients for brain metastases (BMs), preferably by magnetic resonance imaging (MRI) or when contraindicated or not accessible a dedicated contrast enhanced-computed tomography (dCE-CT), which can be incorporated in the staging 18 Fluodeoxoglucose-positron emission tomography ( 18 FDG-PET-CE-CT). In daily practice, often a dCE-CT is performed instead of a MRI. The aim of the current study is to evaluate the additive value of MRI after dCE-CT, incorporated in the 18 FDG-PET-CE-CT., Patients and Methods: It is an observational prospective multicentre study (NTR3628). Inclusion criteria included stage III NSCLC patients with a dCE-CT of the brain incorporated in the 18 FDG-PET and an additional MRI of the brain. Primary end-point is percentage of patients with BM on MRI without suspect lesions on dCE-CT. Secondary end-points are percentage of patients with BM on dCE-CT and percentage of patients with BM ≤ 1 year of a negative staging MRI., Results: Sixteen (7%) patients with extracranial stage III had BM on dCE-CT and were excluded. One hundred forty-nine patients were enrolled. 7/149 (4.7%) had BM on MRI without suspect lesions on dCE-CT. One hundred eighteen patients had a follow-up of at least 1 year (four with BM on baseline MRI); eight of the remaining 114 (7%) patients developed BM ≤ 1 year after a negative staging brain MRI., Conclusion: Although in 7% of otherwise stage III NSCLC patients, BMs were detected on staging dCE-CT, MRI brain detected BMs in an additional 4.7%, which we consider clinically relevant. Within 1 year after a negative staging MRI, 7% developed BM., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

The incidence of brain metastases of solid tumors is increasing. Local treatment of brain metastases is generally straightforward: cranial radiotherapy (e.g., whole-brain radiotherapy or stereotactic radiosurgery) or resection when feasible. However, treatment becomes more complex when brain metastases occur while other metastases, outside of the central nervous system, are being controlled with systemic therapy (chemotherapeutics, molecular targeted agents, or monoclonal antibodies). It is known that some anticancer agents can increase the risk for neurotoxicity when used concurrently with radiotherapy. Increased neurotoxicity decreases quality of life, which is undesirable in this predominantly palliative patient group. Therefore, it is of utmost importance to identify the compounds that should be temporarily discontinued when cranial radiotherapy is needed.This review summarizes the (neuro)toxicity data for combining systemic therapy (chemotherapeutics, molecular targeted agents, or monoclonal antibodies) with concurrent radiotherapy of brain metastases. Because only a limited amount of high-level data has been published, a risk assessment of each agent was done, taking into account the characteristics of each compound (e.g., lipophilicity) and the microenvironment of brain metastasis. The available trials suggest that only gemcitabine, erlotinib, and vemurafenib induce significant neurotoxicity when used concurrently with cranial radiotherapy. We conclude that for most systemic therapies, the currently available literature does not show an increase in neurotoxicity when these therapies are used concurrently with cranial radiotherapy. However, further studies are needed to confirm safety because there is no high-level evidence to permit definitive conclusions. The Oncologist 2017;22:222-235 Implications for Practice: The treatment of symptomatic brain metastases diagnosed while patients are receiving systemic therapy continues to pose a dilemma to clinicians. Will concurrent treatment with cranial radiotherapy and systemic therapy (chemotherapeutics, molecular targeted agents, and monoclonal antibodies), used to control intra- and extracranial tumor load, increase the risk for neurotoxicity? This review addresses this clinically relevant question and evaluates the toxicity of combining systemic therapies with cranial radiotherapy, based on currently available literature, in order to determine the need to and interval to interrupt systemic treatment., (© AlphaMed Press 2017.)

Objectives: Symptomatic brain metastases (BM) occur frequently after chemoradiotherapy (CRT) for stage III NSCLC. Aim of the current study was to determine whether the specific chemotherapy used in a CRT regimen influences BM development., Materials and Methods: Retrospective multicenter study including all consecutive stage III NSCLC who completed CRT. Primary endpoints: symptomatic BM development, whether this was the only site of first relapse. Differences between regimens were assessed with a logistic regression model including known BM risk factors and the specific chemotherapy: concurrent versus sequential (cCRT/sCRT), within cCRT: daily low dose cisplatin (LDC)-cyclic dose polychemotherapy; LDC-(non-)taxane cyclic dose; LDC-polychemotherapy subgroups of ≥50 patients., Results: Between January 2006 and June 2014, 838 patients were eligible (737 cCRT, 101 sCRT). 18.2% developed symptomatic BM, 8.0% had BM as only site of first relapse. BM patients were significantly younger, female, had more advanced N-stage and had adenocarcinoma histology. In both cCRT and sCRT BM were found in 18% (p=0.904). In cyclic dose cCRT (N=346) and LDC (N=391) BM were found in 18.8% and 17.9%, respectively (p=0.757). In 7.2% and 8.7%, respectively, BM were the only site of first relapse (p=0.463). The chemotherapy used (cCRT versus sCRT) had no influence on BM development, not for all brain relapses nor as only site of first relapse (OR 0.88 (p=0.669), OR 0.93 (p=0.855), respectively). LDC versus cyclic dose cCRT was not significantly different: neither for all brain relapses nor as only site of first relapse (OR 0.96 (p=0.819), OR 1.21 (p=0.498), respectively). Comparable results were found for LDC versus cyclic dose non-taxane (N=277) and cyclic dose taxane regimens (N=69) and for cCRT regimens with ≥50 patients (LDC versus cisplatin/etoposide (N=188), cisplatin/vinorelbin (N=65), weekly cisplatin/docetaxel (N=60))., Conclusion: approximately 18% developed symptomatic BM after stage III diagnosis, not dependent on type of chemotherapy regimen used within a CRT treatment., (Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.)

Background: Median survival after diagnosis of brain metastases is, depending on the Recursive Partitioning Analysis (RPA) classes, 7.1 (class I) to 2.3 months (class III). In 2011 the Dutch guideline on brain metastases was revised, advising to withhold whole brain radiotherapy (WBRT) in RPA class III. In this large retrospective study, we evaluated the guideline's use in daily practice., Material and Methods: Data of 428 lung cancer patients undergoing WBRT for brain metastases (2004-2012) referred from three Dutch hospitals were retrospectively analyzed. Details on Karnofsky performance score (KPS), age, control of primary tumor, extracranial metastases, histology, and survival after diagnosis of brain metastases were collected. RPA class was determined using the first four items., Results: In total 327 patients had non-small cell lung cancer (NSCLC) and 101 small cell lung cancer (SCLC). For NSCLC, 6.1%, 71.9%, and 16.2% were classified as RPA I, II, and III, respectively, and 5.8% could not be classified. For SCLC this was 8.9%, 66.3%, 14.9%, and 9.9%, respectively. Before the revised guideline was implemented, 11.3-21.3% of WBRT patients were annually classified as RPA III. In the year thereafter, this was 13.0% (p = 0.646). Median survival (95% CI) for NSCLC RPA class I, II, and III was 11.4 (9.9-12.9), 4.0 (3.4-4.7), and 1.7 (1.3-2.0) months, respectively. For SCLC this was 7.9 (4.1-11.7), 4.7 (3.3-6.1), and 1.7 (1.5-1.8) months., Conclusions: Although it is advised to withhold WBRT in RPA class III patients, in daily practice 11.3-21.3% of WBRT-treated patients were classified as RPA III. The new guideline did not result in a decrease. Reasons for referral of RPA III patients despite a low KPS were not found. Despite WBRT, survival of RPA III patients remains poor and this poor outcome should be stressed in practice guidelines. Therefore, better awareness amongst physicians would prevent some patients from being treated unnecessarily.

Introduction: Stage III NSCLC patients are candidates for treatment with curative intent. Current guidelines advise post contrast magnetic resonance imaging (MRI) or contrast enhanced computed tomography (CE-CT) of the brain in these patients to exclude brain metastases (BM). In previous small studies MRI was reported to be superior to CE-CT. However, CT and MR technology have evolved and 18F-deoxyglucose-positron-emission-tomography (18FDG-PET) has been implemented in staging of NSCLC. If CE-CT, performed together with 18FDG-PET-CT shows the same yield of BM detection as an additionally performed MRI, substantial gain in time and resources is expected., Methods: All NSCLC patients who underwent a staging 18FDG-PET-CT between January 2008 and September 2011 were reviewed. Neurological asymptomatic patients with stage III NSCLC who were eligible for treatment with curative intent were selected, without taking into account the results of brain MRI. CT was compared to MRI to investigate whether additional BM were detected on MRI. Development of BM within a year after negative MRI was recorded., Results: 97/429 NSCLC patients who underwent a PET-CT had stage III disease. Three otherwise stage III patients already had occult BM on CE-CT. 77/97 (79%) patients underwent MRI, 45/77 (58%) CE-CT and 32/77 (42%) LD-CT. In none of the CE-CT, but in 5/32 (16%) LD-CT patients BM were detected on MRI. 9/72 patients (13%) without BM on MRI at diagnosis developed BM within a year., Conclusions: This retrospective study suggests that there is no additive value of MRI to 18FDG-PET-CT with CE-CT in screening for BM in neurological asymptomatic patients with stage III NSCLC., (Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.)

In a patient with a medical history of cancer, the most probable diagnosis of an 18FDG-avid pulmonary mass combined with intracranial abnormalities on brain imaging is metastasized cancer. However, sometimes a differential diagnosis with an infectious cause such as aspergillosis can be very challenging as both cancer and infection are sometimes difficult to distinguish. Pulmonary aspergillosis can present as an infectious pseudotumour with clinical and imaging characteristics mimicking lung cancer. Even in the presence of cerebral lesions, radiological appearance of abscesses can look like brain metastasis. These similarities can cause significant diagnostic difficulties with a subsequent therapeutic delay and a potential adverse outcome. Awareness of this infectious disease that can mimic lung cancer, even in an immunocompetent patient, is important. We report a case of a 65-year-old woman with pulmonary aspergillosis disseminated to the brain mimicking metastatic lung cancer. [ABSTRACT FROM AUTHOR]