Fiveash, John B.

2008 Background: For non-small cell lung cancer (NSCLC) with brain metastases (BM) stereotactic radiosurgery (SRS) is the current preferred therapy. Due to frequent intracranial failures, there is a high unmet need for salvage therapies. Whole brain radiotherapy (WBRT) reduces intracranial failure but used less frequently due to cognitive consequences. Tumor Treating Fields (TTFields) are electric fields that disrupt cancer cell division and have shown improved survival and safety in patients with glioblastoma and metastatic NSCLC. Phase 3 METIS trial [NCT02831959] aimed to evaluate the efficacy and safety of TTFields therapy in NSCLC patients with BM treated with SRS, specifically in terms of lengthening time to intracranial progression without cognitive decline. Methods: Mutation negative (M-) NSCLC patients with 1–10 BM were randomized 1:1 to receive stereotactic radiosurgery (SRS) followed by Tumor Treating Fields (TTFields; 150 kHz) therapy with best supportive care (BSC) or SRS followed by BSC. Patients with Karnofsky Performance Status (KPS) ≥70, newly diagnosed with one inoperable or 2–10 supra-/infratentorial brain metastases suitable for SRS and receiving optimal extracranial disease therapy were included. Exclusions were prior WBRT and single operable or recurrent brain metastases. Primary endpoint was time to first intracranial progression (RANO-BM) based on cumulative risk. Patients were followed every two months until second intracranial progression. Cognition and patient quality of life (QoL) were evaluated. Results: Between July 2016 and September 2022, 298 patients were randomized. Baseline characteristics were balanced: median age was 63.5 (range 37-84) years, 37.6% females, majority of patients had a KPS ≥ 80, median time from initial NSCLC diagnosis was 1.8 months (range: 0.2-55.7), 77% had adenocarcinoma. Median treatment duration of TTFields was 16 weeks, with a median usage time of 67%. Primary endpoint, time to intracranial progression from SRS, was significantly prolonged with SRS followed by TTFields therapy with BSC vs. BSC alone arm (median of 21.9 vs. 11.3 months); HR=0.67 [0.48-0.93], p=0.02. TTFields-related AEs were mainly dermatological, and Grade ≤2. TTFields therapy also improved deterioration-free survival of global health status, physical functioning, and fatigue according to QoL, and did not negatively impact cognition. Conclusion: METIS study met its primary endpoint, demonstrating that TTFields therapy following SRS in mutation negative NSCLC patients with BM, significantly prolongs time to intracranial progression and could postpone WBRT, without QoL and cognition decline. Clinical trial information: NCT02831959 .

2524 Background: Postoperative radiosurgery (SRS) has been associated with up to 30% risk of subsequent leptomeningeal disease (LMD). We previously demonstrated that radiographic pattern of LMD (classical “sugarcoating” [cLMD] vs. nodular [nLMD]) in this setting is prognostic. The association between radiographic pattern of LMD, type of salvage treatment (tx), and neurologic death (ND) has not been well described. Methods: The records of patients (pts) with brain metastases (BM), of which 1 was resected and treated with adjunctive SRS, and who subsequently developed LMD were combined from 7 tertiary care centers. Pts with classically radiosensitive tumors or prior or planned whole brain radiotherapy (WBRT) were excluded. ND was defined as symptomatic CNS progression around the time of death without life threatening systemic symptoms or progression. Salvage radiotherapy (RT) for LMD was categorized according to use of WBRT vs. focal cranial RT. Results: The study cohort consisted of 147 pts, of which 125 had died with known cause, 107 also received LMD salvage tx, and 82 also had cranial MRI follow-up. The ND rate in the 125 pts who died with known cause was 79%; the rate in pts who underwent LMD salvage tx (n = 107) was 76%. Univariate logistic regression demonstrated radiographic pattern of LMD (cLMD vs. nLMD, odds ratio [OR] 2.9, p = 0.04) and 2nd LMD failure after salvage tx (OR 3.9, p = 0.02) as significantly associated with ND. The ND rate was 86% for cLMD vs. 68% for nLMD pattern. WBRT was used in 95% of pts with cLMD vs. 52% of pts with nLMD. In the nLMD cohort (n = 58), there was no difference in ND rate based on type of salvage RT (WBRT: 67% vs. focal cranial RT: 68%, p = 0.92). Second LMD failure (vs. not) was associated with higher ND in the nLMD cohort (77% vs. 52%, p = 0.02). Of the 26 pts with nLMD who experienced 2nd LMD failure, 7 had classical 2nd LMD, of which 100% experienced ND, and 19 had nodular 2nd LMD, of which 68% experienced ND (p = 0.09). Conclusions: LMD after surgery and SRS for brain metastases is a clinically significant event with high rates of neurologic death. Classical LMD pattern (vs. nodular) and 2nd LMD failure after salvage tx were significantly associated with higher risk of neurologic death. In the nodular LMD cohort, radiographic pattern of 2nd LMD may be associated with risk of subsequent neurologic death. Pts with nodular LMD treated with salvage focal cranial RT or WBRT had similar risk of neurologic death. Methods to decrease LMD and the subsequent high risk of neurologic death in this setting warrant investigation.

Abstract Background Radiographic leptomeningeal disease (LMD) develops in up to 30% of patients following postoperative stereotactic radiosurgery (SRS) for brain metastases. However, the clinical relevancy of this finding and outcomes after various salvage treatments are not known. Methods Patients with brain metastases, of which 1 was resected and treated with adjunctive SRS, and who subsequently developed LMD were combined from 7 tertiary care centers. LMD pattern was categorized as nodular (nLMD) or classical (“sugarcoating,” cLMD). Results The study cohort was 147 patients. Most patients (60%) were symptomatic at LMD presentation, with cLMD more likely to be symptomatic than nLMD (71% vs. 51%, P = 0.01). Salvage therapy was whole brain radiotherapy (WBRT) alone (47%), SRS (27%), craniospinal radiotherapy (RT) (10%), and other (16%), with 58% receiving a WBRT-containing regimen. WBRT was associated with lower second LMD recurrence compared with focal RT (40% vs 68%, P = 0.02). Patients with nLMD had longer median overall survival (OS) than those with cLMD (8.2 vs 3.3 mo, P < 0.001). On multivariable analysis for OS, pattern of initial LMD (nodular vs classical) was significant, but type of salvage RT (WBRT vs focal) was not. Conclusions Nodular LMD is a distinct pattern of LMD associated with postoperative SRS that is less likely to be symptomatic and has better OS outcomes than classical “sugarcoating” LMD. Although focal RT demonstrated increased second LMD recurrence compared with WBRT, there was no associated OS detriment. Focal cranial RT for nLMD recurrence after surgery and SRS for brain metastases may be a reasonable alternative to WBRT.