By Jason K. Molitoris, MD, PhD, Anthony D. Nehlsen, MD, and Minesh P. Mehta, MD
Posted: October 2017
Up to 40% of patients with advanced non-small cell lung cancer (NSCLC) will develop brain metastases (BM); this contributes significantly to decrement in survival and quality of life. Optimal BM treatment in patients with targetable rearrangements in ALK and mutations in EGFR is in a state of dramatic flux because of the underlying disease biology, availability of effective, blood-brain barrier penetrant targeted agents, new evidence on therapeutic outcomes after stereotactic radiosurgery (SRS), wholebrain radiation therapy (WBRT), and ongoing evaluation of cognitive preservation strategies.
Large retrospective data cohorts of NSCLC patients with BM demonstrate an overall “improvement” in median survival (MS) from 7 to 12 months in patients treated between 1985–2005 and 2006–2014; whether this is a genuine improvement or a function of selection bias and earlier detection remains speculative. Dramatically longer survival times are seen in patients harboring actionable mutations, with a MS of 14 months in non-mutated patients, 23 months for EGFR-mutated patients, and 45 months for ALK-rearranged patients.1 An update to the NSCLC disease-specific graded prognostic assessment (ds-GPA) now includes mutational status, with a median survival of nearly 4 years for the most favorable patients.2 As survival increases in general, and specifically in mutationdriven tumors, there are competing priorities in the management strategies for BM: improving survival and achieving durable intracranial control while minimizing toxicity.
In the US and increasingly around the world, there is a clear trend towards the utilization of SRS and delayed use of WBRT. The recently reported NCCTG-N0574 trial, which randomized patients with 1 to 4 BM to SRS+/− WBRT, demonstrated similar OS, and WBRT was associated with worse cognition at 3 months, which persisted for long-term survivors at 1 year.3 However, this came at the cost of a significantly shorter time to intracranial failure with SRS, compared to SRS+WBRT. As SRS alone increases in utilization, the risk of intracranial progression increases, the time-to-intracranial failure shortens, and the need for more reliable followup increases, usually entailing more frequent surveillance MRIs; each of these considerations must be balanced for individual patients. Alternative strategies to preserve cognitive function while instituting WBRT include the use of the N-methyl-D-aspartate (NMDA)-receptor agonist, memantine, with WBRT, which has led to a delay in cognitive deterioration. 4 In a recently published phase II trial, hippocampal-avoidance WBRT also preserved cognition, compared to historical controls.5 An ongoing phase III trial is evaluating the addition of hippocampalavoidance in combination with WBRT and memantine.
The prolonged survival and availability of well-tolerated tyrosine kinase inhibitors (TKI), most of which cross the blood-brain barrier, has led investigators to question whether radiotherapy now has any upfront role in the management of BM in ALK-rearranged or EGFR-mutated NSCLC, particularly in patients with minimal symptomatology. A recent multi-institutional review of EGFR-mutated NSCLC with BM compared patients treated with upfront SRS or WBRT followed by TKI or TKI with delayed radiation. MS was significantly longer for patients receiving either upfront SRS (46 months) or WBRT (30 months), compared to TKI with delayed radiation (25 months).6 While patients in the SRS and TKI groups were similar, patients in the WBRT group had poor prognostic features, and still outperformed upfront TKI treatment alone. While these findings are retrospective, they are cautionary and underscore the potential for increased importance of early intracranial control in patients, thereby ensuring prolonged survival.
Recent data have demonstrated intriguing evidence for the intracranial activity of TKIs in ALK-rearranged NSCLC BM. Crizotinib initially demonstrated mild CNS penetration and responses in a study evaluating 275 patients with asymptomatic BM who received either RT+crizotinib or crizotinib alone.7 Patients who did not receive RT had significantly shorter time to intracranial progression (7 vs 13 months). More recently second- and third-generation TKIs have demonstrated superior intracranial response rates. In a pooled analysis, alectinib demonstrated a 64% CNS response.8 The recently presented ALEX study reported that, compared to crizotinib, alectinib had improved CNS response (81% vs 50%) and decreased 12-month incidence of BM (9% vs 41%).9 Similarly, ceritinib has demonstrated responses in 34% to 61% of patients, and intracranial PFS of 8.3 months.10,11 Several retrospective studies evaluating outcomes for upfront vs delayed CNS RT have largely failed to demonstrate survival differences.12,13 However, caution is warranted in over-interpreting these data, as the patients who underwent delayed CNS RT typically had lower disease burden and better prognosis.
Therefore, in patients with EGFR mutations, until more evidence is obtained, it is our preference to treat BMs in these patients similarly to non-mutated patients. We are more inclined to treat those patients with a “limited” number of lesions with SRS, provided close followup is achievable, and those with “numerous” lesions with WBRT, both in concert with an EGFR TKI. In those with ALK fusion proteins, the choice of BM treatment currently is more challenging. We believe that prospective clinical trial data are required prior to recommending therapeutic de-escalation, and we therefore would caution against withholding CNS RT outside of a clinical trial environment. We are hopeful that the newer agents with increased CNS penetration may lead to situations where early response to targeted therapy could “down stage” patients from treatment with WBRT to SRS, alter dose fractionation of WBRT, and/or allow for increased use of cognitive-sparing WBRT techniques. We might learn from these clinical trials that perhaps, in some well-selected patient subsets, RT could even be withheld or postponed. At present, however, without additional data, making this leap is somewhat dangerous, and therapeutic de-escalation outside a clinical trial context places the patient at risk. These risks putatively include an increased risk of intracranial failure, shorter time to intracranial failure, worsening cognitive function and neurologic sequelae from increased intracranial failure, and possibly even a decrement in survival. ✦
Expert Comment
The authors provide a well-written summary of the current status of brain metastases in mutation-positive NSCLC. The newer TKI appear more effective but the improved survival may be due to better control of systemic disease, not the brain metastases. Until randomized data show otherwise, SRS for CNS metastases remains the standard of care.
—Paul W. Sperduto, MD, MPP, FASTRO
References
1. Sperduto PW, Yang TJ, Beal K, et al: The effect of gene alterations and tyrosine kinase inhibition on survival and cause of death in patients with adenocarcinoma of the lung and brain metastases. Int J Radiat Oncol Biol Phys. 2016; 96:406-413.
2. Sperduto PW, Yang TJ, Beal K, et al: Estimating survival in patients with lung cancer and brain metastases: An update of the graded prognostic assessment for lung cancer using molecular markers (lung-molGPA). JAMA Oncol. 2017; 3:827-831.
3. Brown PD, Jaeckle K, Ballman KV, et al: Effect of radiosurgery alone vs radiosurgery with whole brain radiation therapy on cognitive function in patients with 1 to 3 brain metastases: A randomized clinical trial. JAMA. 2016; 316:401-409.
4. Brown PD, Pugh S, Laack NN, et al: Memantine for the prevention of cognitive dysfunction in patients receiving whole-brain radiotherapy: A randomized, double-blind, placebo-controlled trial. Neuro Oncol. 2013; 15:1429-1437.
5. Gondi V, Pugh SL, Tome WA, et al: Preservation of memory with conformal avoidance of the hippocampal neural stem-cell compartment during whole-brain radiotherapy for brain metastases (RTOG 0933): A phase II multi-institutional trial. J Clin Oncol. 2014; 32:3810-3816.
6. Magnuson WJ, Lester-Coll NH, Wu AJ, et al: Management of brain metastases in tyrosine kinase Inhibitor–Naïve epidermal growth factor Receptor–Mutant Non–Small-cell lung cancer: A retrospective multi-institutional analysis. J Clin Oncol. 2017; 35:1070-1077.
7. Costa DB, Shaw AT, Ou SI, et al: Clinical experience with crizotinib in patients with advanced ALK-rearranged non–small-cell lung cancer and brain metastases. J Clin Oncol. 2015; 33:1881-1888.
