Brain mets in melanoma...a relatively irrelevant retrospective!

Malignant melanoma brain metastases:  Treatment results and prognostic factors - a single-center retrospective study. Ostheimer, Bormann, Fiedler, et al.  Int J Oncol.  April 20, 2015.

Brain is a frequent site of melanoma mets.  Study aimed to ID prognostic factors for overall survival (OS) and local tumor control (LC).  Patients were dx'd with brain mets from 1992 - 2011.  N=100.  53 patients has 1-2 brain mets, 47% had greater than 2, and 71% presented with additional extracranial mets.  Primary treatment included systemic therapy alone (temozolomide/fotemustine, 14%), local therapy (surg and/or SRS, 25%), whole brain radiation (WBR, 10%), combined WBRT and systemic therapy (18%), local therapy plus WBR (5%), and combo of local and systemic therapy (8%).  3% had local, WBR, and systemic therapy.  17% refused treatment.  Median f/u in surviving pts was 32 months.  Median OS in all pts = 3.9 months.  Local therapy, systemic therapy, # of brain mets, and primary therapy including local therapy were significantly associated with OS.  In the subgroup with multiple brain mets (n=35), a trend for improved OS after initial treatment with WBR plus systemic therapy was noted and use of these two modalities over the course of the disease was significantly associated with OS.  The best LC per single lesion (n=37) could be achieved by combo of local with systemic therapy.  Number of brain mets, extracranial mets and use of local therapy are independent prognostic factors in melanoma metastatic to the brain.

I don't really don't see much value in this report on patients with brain mets from 1992-2011.  Despite its recent publication it is dealing with a set of very old data...esp in melanoma world.  Ipi and the first BRAFi weren't FDA approved until 2011 and folks with brain mets weren't treated with those drugs initially.  It is very clear from more recent data that those drugs along with anti-PD1 products are far superior in eradicating melanoma tumors EVERYWHERE compared to the drugs used in these patients.  However, combo's still reigned supreme and folks with the most tumor burden (no matter if just multiple brain mets or brain mets along with mets elsewhere in the body) have the most difficulty.  For what it's worth.  We've come a long way baby!!!

Salvage whole brain radiotherapy or stereotactic radiosurgery after initial stereotactic radiosurgery for 1-4 brain metastases.  Liu, Alexander, Chen, Horvath, et al.  J Neurooncol.  Jun 25, 2015.

Patients with limited brain mets are often candidates for SRS or WBRT.  Among pts who receive SRS, the likelihood and timing of salvage WBRT or SRS remains unclear.  Study examined rates of salvage WBRT or SRS among 180 pts with 1-4 newly dx'd brain mets who received index SRS from 2008-2013.  Patients had NSCLC (53%), melanoma (23%), breast (10%), renal (6%), and other (8%) cancers.  Patients had SRS to 1 (60%), 2 (21%), 3 (13%), 4 (7%) brain mets.  Median survival after SRS was 9.7 months.  No further brain directed radiotherapy was delivered after index SRS in 55% pts.  27% of patients ever received salvage WBRT, and 30% ever received salvage SRS. 12% received both salvage WBRT and salvage SRS.  Median time to salvage WBRT and salvage SRS were 5.6 and 6.1 months respectively.  Age greater than 60 years and controlled/absent extracranial disease were associated with shorter time to salvage WBRT.  Isolated brain progression caused death in only 11% of decedents.  In summary, most patients with 1-4 brain mets receiving SRS never require salvage WBRT or SRS, and the remainder do not require salvage treatment for a median of 6 months.

Wow.  Guess I've sure out lived my shelf-life!  Again, these patients were not in receipt of radiation combined with more effective systemic therapies.  So, hopefully, a study looking back on us...say from 2010-2015...would paint a very different picture of duration of treatment effect.  I do find it strange that this study found that "controlled/absent extracranial disease were associated with a SHORTER time to WBRT."  You'd think that controlled or absent disease in the body would prolong the time before additional problems.   Hmmm....

Ipilimumab and stereotactic radiosurgery versus stereotactic radiosurgery alone for newly diagnosed melanoma brain metastases.  Patel, Shoukat, Oliver, et al.  Am J Clin Oncol.  May 16, 2015.

Compared safety and efficacy of ipi and SRS to SRS alone for newly dx'd brain mets.  Reviewed records from 2009-2013.  54 consecutive melanoma brain met pts were id'd with 20 receiving ipi within 4 months of SRS.  Ipi treated pts had similar baseline characteristics.  No difference between symptomatic radiation necrosis or hemorrhage was id'd between cohorts.  Compared with pts in the non-ipi group, 1 year local control 71.4% vs 92.3% and intracranial control 12.7% vs 29% were also statistically similar.  The ipi cohort also had no difference in 1 year OS (37% vs 38%).  Patients given ipi within 14 days of SRS had higher 1 year (42.9%) and 2 year OS (42.9%) relative to ipi delivered more than 14 days (33.8%, 16.9%) and SRS alone (38.5%, 25.7%) but these differences were not statistically significant.  

Again, a retrospective tally of patients from 2009-2013. The numbers (esp for those treated with ipi) are rather small.  I suspect that has something to do with the lack of statistical significance.  Looking at the numbers, I'd rather be in the ipi/SRS combo group!  Especially when the ipi is administered less than 14 days after SRS!!!  Take home message:  GET YOUR IPI SOONER RATHER THAN LATER AFTER SRS!!!!  Here's a post with more recent data:  Radiation for melanoma: better combined with immunotherapy!

Survival patterns following brain metastases for patients with melanoma in the MAP-kinase inhibitor era.  Wattson, Sulllivan. Neimierko, Flaherty, et al.  April 12, 2015.

Survival with BRAF-mutant metastatic melanoma is prolonged with MAP-kinase pathway inhibitors (MAPKi).  Among pts with brain mets, however, the clinical course of MAPKi-treated pts is not well described  We analyzed 106 pts who developed brain mets between 2007 and 2013.  Of these, 37 (35%) received de novo MAPKi for BRAF-mutant disease which preceded BM in 49%.  Immunotherapy was given to 54% of MAPKi-treated patients and 94% of those who did not receive MAPKi.  With a median f/u of 8 months after initial BM, MAPKi use was an independent predictor of prolonged survival after BM diagnosis (median 14.1 vs 7 months).  This survival advantage was driven by the 16.6 month median survival of pts who initiated MAPKi after BM were dx'd, vs 5.6 months if initiated prior to BM development.  Median survival from the onset of any systemic mets was 22 months regardless of the timing of MAPKi relative to BM appearance.  Time to in-brain progression was longer among patients whose MAPKi course was started after BM diagnosis, but MAPKi initiation prior to BM diagnosis was associated with longer time to intracranial involvement.  These findings are consistent with potential MAPKi activity in intracranial melanoma.

Before you get confused...MAP-kinase inhibitors = MEK inhibitors.  It is not clear which ones were used here or if they were combined with BRAFi as they almost always are today, thereby increasing effectiveness, while decreasing side effects and tumor work around. MEK inhibitors include:  trametinib, selumetinib, Binimetinib, PD325901, and cobimetinib.  So..another review of folks with brain mets from 2007-2013.  Use of MEKi prolonged survival in BRAF positive patients with brain mets from 7 months to 14 months.  However, if you took the MEKi before your brain met appeared median survival was only 5.6 months.  If you took it AFTER your brain met, median survival increased to 16.6 months.  Pts got 22 months on average before the appearance of mets elsewhere in the body, not matter when MEKi was started relative to brain mets.  So, yes, Virginia.  MEKi work in the brain.  

Don't feel that this was the most helpful bunch of gibberish I've ever plowed through.  But, I guess it is a pretty dismal synopsis of life with brain mets circa 1992 - 2013.  What a difference the past 5 years has made.  May we keep moving forward....QUICKLY!!!!  Best - c