Brain Metastases: The Changing Landscape

April 15, 2015

It is time to put aside the pessimism of the past when it comes to brain metastases and embrace the wide array of clinical investigational opportunities arising in this field.

In this issue of ONCOLOGY, Lin and colleagues provide an elegant review of the clinical approach to patients with brain metastases.[1] They highlight key directions that are emerging in this field, including a nascent, but promising, understanding of underlying tumor biology; recognition of the limitations (with associated mechanistic causes) of systemic therapies, as well as the emergence of the blood-brain barrier–penetrating targeted therapeutics aimed at specific oncogenic driver mutations, which are beginning to demonstrate early, albeit modest, activity; the increasing utilization of focally directed therapies, both radiotherapeutic and otherwise; and the changing role of whole-brain radiation therapy (WBRT).

In this commentary, I wish to highlight four key issues: the role of WBRT, especially as a neuroprotective strategy; the increasing role-but also limitations-of focal therapies, especially given the implications of compartmental failure; a tempered view of targeted therapeutics; and the need for the identification of high-risk patient subgroups in order to develop prophylactic strategies.

WBRT is a well-accepted treatment modality for brain metastases, with two key goals-the control of the obviously visible metastases, and the control of microscopic seeding of the brain, which occurs at an inordinately high frequency, estimated to exceed at least 60%.[2] In association with focal therapies, WBRT categorically and dramatically decreases local failure, reduces leptomeningeal dissemination (especially in the postoperative context), and dramatically decreases subsequent compartmental failure in the brain. Focal therapies yield very high local control rates, but these sometimes cloud the existence of level 1 data demonstrating further enhancement of local control with WBRT.[3]

The potential of cognitive decline associated with the use of WBRT has led to a reduction in the utilization of this approach. As valid as this concern is, a more granular analysis reveals two other key points whose importance needs to be underscored. First, omission of WBRT is almost universally associated with subsequent compartmental brain failure. Second, an abundance of data demonstrate that cognitive decline is also associated with progressive disease/failure in the brain. In fact, in at least one randomized trial, the incidence of decline in mini-mental status examination scores and the time to such decline were both greater in the arm in which WBRT was withheld, underscoring that recurrence in the brain is not “cost-free” in terms of cognition.[4,5] This issue was evaluated in a recently completed randomized trial (North Central Cancer Treatment Group [NCCTG]-N0574/Radiation Therapy Oncology Group [RTOG] 0671), the results of which are awaited. A second ongoing trial (RTOG 1270) of postoperative stereotactic radiosurgery (SRS) vs WBRT will shed further light on this question.

A controversial issue is the impact of WBRT on survival. Based on a handful of retrospective reviews, substantially underpowered trials, and a meta-analysis based on these underpowered trials,[6] it has been widely concluded that the omission of WBRT does not decrease overall survival (OS). However, other factors contributing to the lack of a survival difference include the effectiveness of salvage therapies, and the fact that systemic progression is a significant competing cause of mortality. Moreover, while it may perhaps be true that omitting WBRT does not decrease OS, a diligent review of the available data would caution against jumping to such a conclusion, since the supporting data are relatively weak and contradictory data have recently emerged. An analysis of three other pieces of data in the literature should induce a degree of interpretive caution. As early as 1998, Pirzkall et al reported a single-institution, 236-patient retrospective study of SRS with or without WBRT, demonstrating a trend for superior OS in favor of WBRT (1-year OS, 30% vs 19%; 2-year OS, 14% vs 8%). Much more impressive was the recognition that in patients without extracranial disease-in whom systemic progression as a competing cause of mortality is largely diminished-the median survival (MS) was very different, at 15.4 vs 8.3 months in favor of WBRT (reaching only borderline significance because of the small number of patients).[7]

These data allow one to posit the very reasonable hypothesis that a certain proportion of patients with brain metastases are destined to succumb to intracranial progression (and we do see such compartmental progression as a cause of death in other organs, such as the lungs, liver, etc), and that enhanced control of intracranial progression will lengthen their survival. A contemporary cohort (1998–2013) of 528 patients with brain metastases treated with SRS, either alone or in conjunction with resection, WBRT, or both, revealed that the MS for the single-metastasis cohort was 9 months for SRS alone and 19.1 months with the addition of WBRT. In fact, a multivariate analysis of the entire cohort revealed that the lowest MS was associated with the use of SRS alone.[8] Finally, a recent re-analysis of the randomized Japanese Radiation Oncology Study Group (JROSG) 99-1 trial, using the validated Graded Prognostic Assessment (GPA) stratification model to evaluate all non–small-cell lung cancer (NSCLC) patients in the trial, revealed an MS of 16.7 months vs 10.6 months in favor of WBRT + SRS (compared with SRS alone; P = .03) for the favorable-prognosis subgroup (GPA = 2.5–4), although an advantage for the inferior-prognosis group was not demonstrated. These data provided further support for the idea that intracranial control matters and that one accepts a lower rate of such control at the potential risk of reducing OS.[9]

So, what then about the cognitive “price” of WBRT? At least two recent prospective trials in the literature provide encouraging data supporting the development of strategies that could diminish WBRT-associated cognitive decline. The first trial utilized the N-methyl-D-aspartate (NMDA) receptor agonist memantine and demonstrated superior memory retention with this agent.[10] The second trial, developed on the basis of the recent recognition of perihippocampal stem cells and their specific role in the generation of memory-specific neurons, utilized a hippocampal-avoidance technique (HA-WBRT) that spared this compartment, thus allowing memory-specific neuronal regeneration; the investigators demonstrated superior memory function with HA-WBRT.[11-13] Both of these concepts are undergoing further randomized testing, holding out significant promise of “gentler” WBRT.

The emergence of targeted agents represents a major new frontier that holds considerable promise for the future. The substantial radiographic responses achieved anecdotally with such agents are certainly impressive. However, the initial hopes that such agents would produce dramatic intracranial responses and disease control have unfortunately been tempered by the mostly very low genuine response rates. (Several of the trials of these agents appear to show higher response rates, but these have actually been inflated by ratcheting down the threshold for conventional response definitions.) Further, although some reports demonstrate optimistic survival data, the only large prospective randomized trial performed using a combination of targeted agents with WBRT-the RTOG 0320 trial-actually demonstrated inferior survival with the combination, in a patient cohort not specifically selected for target expression.[14] Other combination trials in “enriched” patient populations, such as the RTOG 1119 trial, are currently underway. The effective control of micrometastatic disease with targeted agents (which would allow WBRT to be withheld), together with treatment of macroscopic disease via aggressive focal approaches such as SRS, is considered the “Holy Grail” of therapy for brain metastases. The LANDSCAPE trial, in human epidermal growth factor receptor 2 (HER2)-positive breast cancer patients with brain metastases, demonstrated a genuinely high response rate of 66% using the combination of lapatinib and capecitabine, prompting an in-house trial at our institution of the combination of these agents with SRS in patients with up to 10 brain metastases.[15] The advent of ado-trastuzumab emtansine and its early demonstration of efficacy in this setting also warrant prospective evaluation, as does the emergence of the new generation of anaplastic lymphoma kinase (ALK) inhibitors, such as ceritinib.[16,17]

The idea of SRS as a possible “radiogenic vaccine” also deserves prospective evaluation. The hypothesis underlying this use of SRS is that a single large fraction of radiation will induce robust cell death, unleashing a wave of antigens previously relatively “masked” in the so-called “immunoprivileged” environment of the brain, and that this “antigenic flood” will elicit an effective antitumor T-cell response. The avoidance of WBRT would protect these T cells from the lymphocidal effect of radiation, and in combination with an immune checkpoint inhibitor would negate the host- and tumor-mediated immune silencing associated with cytotoxic T-lymphocyte–associated antigen 4 (CTLA-4) and programmed death 1 (PD-1). Further, such a process would also lead to an abscopal, systemic effect, clearly a concept ripe for clinical testing and currently under development by NRG Oncology.[18] In fact, even more refined versions of this concept, including the hypothesis of “re-vaccination,” are undergoing preclinical testing (personal communication, Michael Chuong, University of Maryland).

Finally, one topic not addressed by the review authors is the critical need to develop predictive clinical models and/or molecularly directed tests that would predict and identify patients at considerable risk for developing brain metastases; there is also a need to develop prophylactic approaches for such patients. Although WBRT in the past has been rather successful in this latter regard, diminishing the likelihood of brain metastases developing in both small-cell lung cancer (SCLC) and NSCLC patients, a survival benefit has only been seen in SCLC patients. In fact, in NSCLC patients, cognitive decline with WBRT has been identified. Therefore, hippocampal-sparing WBRT approaches in this context are being pursued, as in the NRG CC003 trial. Systemic approaches, such as temozolomide, have unfortunately failed.[19] However, for appropriately selected patient subsets, blood-brain barrier–penetrating targeted agents might potentially be of value.

In summary, the review by Lin et al is indeed timely, and raises a variety of intriguing concepts that are deserving of further investigation. Undoubtedly, it is time to put aside the pessimism of the past when it comes to brain metastases and embrace the wide array of clinical investigational opportunities arising in this field.

Financial Disclosure: Dr. Mehta consults for Elekta, Novartis, and Novocure; receives grant funding from Novelos and Novocure; and serves on the Board of Directors of Pharmacyclis, with stock options.


1. Lin J, Jandial R, Nesbit A, et al. Current and emerging treatment approaches for brain metastases. Oncology (Williston Park). 2015;29:250-7.

2. Mehta M. The dandelion effect: treat the whole lawn or weed selectively? J Clin Oncol. 2011;29:121-4.

3. Aoyama H, Shirato H, Tago M, et al. Stereotactic radiosurgery plus whole-brain radiation therapy vs stereotactic radiosurgery alone for treatment of brain metastases: a randomized controlled trial. JAMA. 2006;295:2483-91.

4. Li J, Bentzen SM, Renschler M, Mehta MP. Regression after whole-brain radiation therapy for brain metastases correlates with survival and improved neurocognitive function. J Clin Oncol. 2007;25:1260-6.

5. Aoyama H, Tago M, Kato N, et al. Neurocognitive function of patients with brain metastasis who received either whole brain radiotherapy plus stereotactic radiosurgery or radiosurgery alone. Int J Radiat Oncol Biol Phys. 2007;68:1388-95.

6. Sahgal A, Aoyama H, Kocher M, et al. Phase 3 trials of stereotactic radiosurgery with or without whole-brain radiation therapy for 1 to 4 brain metastases: individual patient data meta-analysis. Int J Radiat Oncol Biol Phys. 2015;91:710-7.

7. Pirzkall A, Debus J, Lohr F, et al. Radiosurgery alone or in combination with whole-brain radiotherapy for brain metastases. J Clin Oncol. 1998;16:3563-9.

8. Wang TJ, Saad S, Qureshi YH, et al. Outcomes of gamma knife radiosurgery, bi-modality & tri-modality treatment regimens for patients with one or multiple brain metastases: the Columbia University Medical Center experience. J Neurooncol. 2015 Feb 17. [Epub ahead of print]

9. Aoyama H, Tago M, Kato N, et al. Neurocognitive function of patients with brain metastasis who received either whole brain radiotherapy plus stereotactic radiosurgery or radiosurgery alone. Int J Radiat Oncol Biol Phys. 2007:68:1388-95.

10. 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;15:1429-37.

11. Monje ML, Mizumatsu S, Fike JR, Palmer TD. Irradiation induces neural precursor-cell dysfunction. Nat Med. 2002;8:955-62.

12. Monje ML, Toda H, Palmer TD. Inflammatory blockade restores adult hippocampal neurogenesis. Science. 2003;302:1760-5.

13. 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;32:3810-6.

14. Sperduto PW, Wang M, Robins HI, et al. A phase 3 trial of whole brain radiation therapy and stereotactic radiosurgery alone versus WBRT and SRS with temozolomide or erlotinib for non-small cell lung cancer and 1 to 3 brain metastases: Radiation Therapy Oncology Group 0320. Int J Radiat Oncol Biol Phys. 2013;85:1312-8.

15. Bachelot T, Romieu G, Campone M, et al. Lapatinib plus capecitabine in patients with previously untreated brain metastases from HER2-positive metastatic breast cancer (LANDSCAPE): a single-group phase 2 study. Lancet Oncol. 2013;14:64-71.

16. Kalsi R, Feigenberg S, Kwok Y, et al. Brain metastasis and response to ado-trastuzumab emtansine: a case report and literature review. Clin Breast Cancer. 2014 Oct 19. [Epub ahead of print]

17. Shaw A, Mehra R, Tan DSW, et al. Ceritinib (LDK378) for treatment of patients with ALK-rearranged (ALK+) non-small cell lung cancer (NSCLC) and brain metastases (BM) in the ASCEND-1 trial. Neuro Oncol. 2014;16(suppl 5):v39.

18. Deng L, Liang H, Burnette B, et al. Irradiation and anti-PD-L1 treatment synergistically promote antitumor immunity in mice. J Clin Invest. 2014;124:687-95.

19. Boggs DH, Robins HI, Langer CJ, et al. Strategies to prevent brain metastasis in high-risk non-small-cell lung cancer: lessons learned from a randomized study of maintenance temozolomide versus observation. Clin Lung Cancer. 2014;15:433-40.