Non-small cell lung cancer intracranial metastases case series

A total of 110 patients with 1386 brain metastases from primary NSCLC were included in this study. Gray matter density at the tumor center peaked at ~0.6 for all mutations. The median depths of tumors were 7.9 mm, 8.7 mm, and 9.1 mm for EGFR, ALK, and KRAS mutation groups, respectively (p = 0.044). Brain metastases for the EGFR mutation-positive group were more frequently located in the left cerebellum, left cuneus, left precuneus, and right precentral gyrus. In the ALK mutation-positive group, brain metastases were more frequently located in the right middle occipital gyrus, right posterior cingulate, right precuneus, right precentral gyrus, and right parietal lobe. In the KRAS mutation-positive patient group, brain metastases were more frequently located in the posterior left cerebellum. The study showed differential spatial distribution of brain metastases in patients with NSCLC according to their mutation status. Information regarding the distribution of brain metastases is clinically relevant as it could be helpful to guide treatment planning for targeted therapy, and for predicting prognosis ¹⁾.

A retrospective study was conducted through the International Radiosurgery Research Foundation. Logistic regression models and competing risk analyses were utilized to identify predictors of any grade radiation necrosis (RN) and symptomatic RN (SRN).

The study included 395 patients with 2,540 brain metastases treated with single fraction SRS and ICI across 11 institutions in four countries with a median follow-up of 14.2 months. The median age was 67 years. The median margin SRS dose was 19 Gy; 36.5% of patients had a V12 Gy ≥ 10 cm3. On multivariable analysis, V12 Gy ≥ 10 cm3 was a significant predictor of developing any grade RN (OR: 2.18) and SRN (OR: 3.95). At 1-year, the cumulative incidence of any grade and SRN for all patients was 4.8% and 3.8%, respectively. For concurrent and non-concurrent groups, the cumulative incidence of any grade RN was 3.8% versus 5.3%, respectively (p = 0.35); and for SRN was 3.8% vs. 3.6%, respectively (p = 0.95).

The risk of any grade radiation necrosis and symptomatic radiation necrosis following single fraction SRS and Immune checkpoint inhibitors (ICI) for NSCLC brain metastases increases as V12 Gy exceeds 10 cm3. Concurrent Immune checkpoint inhibitors (ICI) and SRS do not appear to increase this risk. Radiosurgical planning techniques should aim to minimize V12 Gy ²⁾.

Among 1078 Non-small cell lung cancer intracranial metastases patients diagnosed/treated between January 1, 2000 and December 31, 2015, three hundred and forty-eight with known EGFR/ALK status were analyzed. Overall survival (OS) and intracranial progression-free survival (PFS) were measured from the time of BM.

Ninety-one patients had either ALK (n = 23) alterations or EGFR (n = 68) mutation and 257 were wild-type (WT; negative actionable mutations/alterations). The median age of EGFR/ALK+ NSCLC BM patients was 60 years (range 29.8-82.6 y) and ~50% (n = 44) had Karnofsky performance status (KPS) score >80. Median number of BM was 2 (1 to ≥99). The median OS for the ALK/EGFR+ NSCLC BM was 19.9 versus 10.1 months for the WT (P = 0.028). The number of BM in the EGFR/ALK+ group did not impact OS (BM = 1 with 21.1 months vs 2-3 with 19.1 months and >3 with 23.7 months, P = 0.74), whereas fewer BM in the WT cohort had significantly better OS (BM = 1 with 13.8 mo, 2-3 with 11.0 mo and >3 with 8.1 mo; P = 0.006) with the adjustment of age, KPS, symptoms from BM and synchronicity.

The number of BM does not impact outcomes in the EGFR/ALK+ NSCLC patients, implying that targeted therapy along with surgery and/or radiation may improve OS irrespective of the number of BM. The number of BM, extracranial metastases (ECM), and KPS independently affected OS/PFS in WT NSCLC BM, which was consistent with the known literature ³⁾.

A study included 264 patients (1069 BMs) who underwent GKRS treatment and for whom EGFR mutation status, demographics, performance status, and tumor characteristics were available. Radiological images were obtained at 3 months after GKRS and at 3-month intervals thereafter. Kaplan-Meier plots and Cox regression analysis were used to correlate EGFR mutation status and other clinical features with tumor control and overall survival.

The tumor control rates and overall 12-month survival rates were 87.8% and 65.5%, respectively. Tumor control rates in the EGFR mutant group versus the EGFR wild-type group were 90.5% versus 79.4% at 12 months and 75.0% versus 24.5% at 24 months. During the 2-year follow-up period after SRS, the intracranial response rate in the EGFR mutant group was approximately 3-fold higher than that in the wild-type group (p < 0.001). Cox regression multivariate analysis identified EGFR mutation status, extracranial metastasis, primary tumor control, and prescribed margin dose as predictors of tumor control (p = 0.004, p < 0.001, p = 0.004, and p = 0.026, respectively). Treatment with a combination of GKRS and tyrosine kinase inhibitors (TKIs) was the most important predictor of overall survival (p < 0.001).

The study demonstrated that, among patients with non-small cell lung cancer intracranial metastases, EGFR mutations were independent prognostic factors of tumor control. It was also determined that a combination of GKRS and TKI had the most pronounced effect on prolonging survival after SRS. In select patient groups, treatment with SRS in conjunction with EGFR-TKIs provided effective tumor control for NSCLC-BMs ⁴⁾.

Lee et al. analyzed 33 patients with 40 lesions who underwent Fractionated Gamma Knife surgery (FGKS) for Non-small cell lung cancer intracranial metastases (NSCLC; 25 patients with 32 lesions) and breast cancer (8 patients with 8 lesions). FGKS was performed in 3-5 fractions. A baseline MRI was performed before the first fraction. MRI was repeated after 1 or 2 fractions. Adaptive planning was executed based on new images. The median prescription dose was 8 Gy (range 6-10 Gy) with a 50% isodose line.

On follow-up MRI, 18 of 40 lesions (45.0%) showed decreased tumor volumes (TVs). A significant difference was observed between baseline (median 15.8 cm3) and follow-up (median 14.2 cm3) volumes (p < 0.001). A conformity index was significantly decreased when it was assumed that adaptive planning was not implemented, from baseline (mean 0.96) to follow-up (mean 0.90, p < 0.001). The average reduction rate was 1.5% per day. The median follow-up duration was 29.5 weeks (range 9-94 weeks). During the follow-up period, local recurrence occurred in 5 lesions.

The TV showed changes with a high dose of radiation during the course of FGKS. Volumetric change caused a significant difference in the clinical parameters. It is expected that adaptive planning would be helpful in the case of radiosensitive tumors such as NSCLCs or breast cancer to ensure an adequate dose to the target area and reduce unnecessary exposure of normal tissue to radiation ⁵⁾.

Between January 2010 and December 2016, 66 patients with 74 lesions ≥10 cm3 from large brain metastases from only Non small cell lung cancer (NSCLC) were included. Fifty-five patients with 60 lesions were treated with single-session radiosurgery (S-GKS); 11 patients with 14 lesions were treated with multisession radiosurgery (M-GKS). Median doses were 16 Gy (range, 11-18 Gy) for the S-GKS group and 8 Gy (range, 7-10 Gy) in three fractions for the M-GKS group.

With a mean follow-up period of 13.1 months (range, 1.3-76.4 months), the median survival duration was 21.1 months for all patients. Median tumor volume was 14.3 cm3 (range, 10.0-58.3 cm3). The local control rate was 77.0% and the progression free survival rate was 73.6% at the last follow-up. There were no significant between-group differences in terms of local control rate (p = 0.10). Compared with S-GKS, M-GKS did not differ significantly in radiation-induced complications (38.1 vs. 45.4%, p =0.83). While 8 patients who underwent S-GKS experienced major complications of grade ≥3, no toxicity was observed in patients treated with M-GKS.

Multisession radiosurgery (M-GKS) may be an effective alternative for large brain metastases from Non small cell lung cancer (NSCLC). Specifically, severe radiation-induced toxicity (≥grade 3) did not occur in M-GKS for large-volume metastases. Although the long-term effects and results from larger samples remain unclear, M-GKS may be a suitable palliative treatment for preserving neurological function ⁶⁾.

The National Cancer Database was queried for patients with NSCLC diagnosed from 2004 to 2013 that received brain irradiation for metastases and patients grouped into having had received fractionated brain radiotherapy (5-15 fractions with or without radiosurgery) or intracranial radiosurgery alone (1-5 fractions). Univariable and multivariable (MVA) analyses were performed to investigate factors associated with the receipt of SRS alone, and temporal/regional trends.

47,746 patients met inclusion criteria, of which 42,148 received fractionated brain irradiation (88%) and 5,598 received radiosurgery (12%). 345 patients received fractioned brain irradiation with a radiosurgical boost (0.8%). The utilization of radiosurgery-alone increased over time owing to increases in each radiosurgery modality. On MVA, several factors were associated with increased odds of receiving intracranial radiosurgery-alone over fractionated brain radiotherapy including more recent year of diagnosis, increased median income, eastern U.S. regions, further distance to the hospital, and the receipt of chemotherapy (each p<0.001). Patients of Asian descent were less likely to receive radiosurgery alone (p=0.044).

In the management of brain metastases from NSCLC, overall utilization of an intracranial radiosurgery alone treatment strategy has increased over the past decade. Despite this, there appear to be significant geographic variations and disparities remain based on patient income level and race. Further study is needed to define the reasons for these disparities and appropriate actions to mitigate them ⁷⁾.

During the 2-year period, 91 of 878 patients (10.4%) developed brain metastases. Median age in this cohort was 64 years. In 45, brain metastases were present at initial diagnosis, and in 46, brain metastases developed later in the course of the illness. Median survival in the entire cohort was 7.8 months. Survival after the diagnosis of brain metastases was similar for patients with brain metastases at diagnosis and later in the illness (4.8 months vs. 3.7 months, p = 0.53). As a result, patients who developed brain metastases later in their illness had a longer overall survival than did patients with brain metastases at diagnosis (9.8 months vs. 4.8 months). Among patients who received chemotherapy, the survival of patients with brain metastases at diagnosis was still poor (6.2 months) ⁸⁾.

Figlin et al. retrospectively analyzed the risk of intracranial recurrence of cancer in 1532 patients who were surgically treated between 1977 and 1986 for Stage I, II, or III non small cell lung cancer, after rigorous surgical and pathological staging. This analysis was undertaken as a background for a possible randomized clinical trial of prophylactic cranial irradiation in such patients. One hundred four patients (6.8 percent) had documented first recurrences involving the brain, including 98 patients (6.4 percent) in whom the brain was the sole site of first recurrence. Sixty patients (3.9 percent) had only intracranial involvement at the time of death. Prognostic variables that had a significant effect on the time to recurrence in the brain were histologic features of the carcinoma (patients with nonsquamous-cell cancers were more at risk than those with squamous-cell cancer), the T1N1/T2N0 and T2N1 staging subsets (T1, tumor less than or equal to 3 cm in diameter; T2, tumor greater than 3 cm; N0, no regional lymph-node metastasis; N1, ipsilateral hilar-lymph-node metastasis), and initial weight loss of more than 10 percent. We conclude that prophylactic cranial irradiation would at best benefit only a very small subset of these patients. We believe, therefore, that neither prophylactic cranial irradiation nor a randomized trial is indicated in patients with non-small-cell lung cancer who have undergone complete resection ⁹⁾.