Brain Mets - A mixture of recent reports

I've covered the data related to brain mets in melanoma for a long time - A few zillion relative reports  

Unfortunately, some older posts are at the top of that list, so scroll through for newer posts if you are interested.  Also unfortunately, not a lot has changed since many of those postings, but here are some reports published over the past year (my comments in red as ever) ~

Tumor Control Probability of Radiosurgery and Fractionated Stereotactic Radiosurgery for Brain Metastases.  Redmond, Gui, Benedict, et al.  Int J Radiat Oncol Biol Phys.  Dec 2020.

Purpose: As part of the American Association of Physicists in Medicine Working Group on Stereotactic Body Radiotherapy, tumor control probability (TCP) after stereotactic radiosurgery (SRS) and fractionated stereotactic radiosurgery (fSRS) for brain metastases was modeled based on pooled dosimetric and clinical data from published English-language literature.

Methods and materials: PubMed-indexed studies published between January 1995 and September 2017 were used to evaluate dosimetric and clinical predictors of TCP after SRS or fSRS for brain metastases. Eligible studies had greater than/= to10 patients and included detailed dose-fractionation data with corresponding greater than/= to 1-year local control (LC) data, typically evaluated as a greater than 20% increase in diameter of the targeted lesion using the pre-SRS diameter as a reference.

Results: Of 2951 potentially eligible manuscripts, 56 included sufficient dose-volume data for analyses. Accepting that necrosis and pseudoprogression can complicate the assessment of LC, for tumors less than/= to 20 mm, single-fraction doses of 18 and 24 Gy corresponded with greater than 85% and 95% 1-year LC rates, respectively. For tumors 21 to 30 mm, an 18 Gy single-fraction dose was associated with 75% LC. For tumors 31 to 40 mm, a 15 Gy single-fraction dose yielded ∼69% LC. For 3- to 5-fraction fSRS using doses in the range of 27 to 35 Gy, 80% 1-year LC has been achieved for tumors of 21 to 40 mm in diameter.

Conclusions: TCP for SRS and fSRS are presented. For small lesions less than/= to 20 mm, single doses of ≈18 Gy appear generally associated with excellent rates of LC; for melanoma, higher doses seem warranted. For larger lesions greater than 20 mm, local control rates appear to be ≈ 70% to 75% with usual doses of 15 to 18 Gy, and in this setting, fSRS regimens should be considered. Greater consistency in reporting of dosimetric and LC data is needed to facilitate future pooled analyses. As systemic and biologic therapies evolve, updated analyses will be needed to further assess the necessity, efficacy, and toxicity of SRS and fSRS.

Not stuff that we as melanoma patients have a lot of control of or say in - but there you go.

Long-term disease outcome and volume-based decision strategy in a large cohort of multiple brain metastases treated with a mono-isocentric linac-based Stereotactic Radiosurgery technique.  Alongi, Nicosia, Figlia, et al.  Clin Transl Oncol.  August 2021.

Purpose: Radiosurgery (SRS) is an effective treatment option for brain metastases (BMs). Long-term results of the first worldwide experience with a mono-isocentric, non-coplanar, linac-based stereotactic technique in the treatment of multiple BMs are reported.

Methods: Patients with multiple BMs, life expectancy greater than 3 months, and good performance status (less than/= to 2) were treated with simultaneous SRS with volumetric modulated arc technique. Data were retrospectively evaluated.

Results: 172 patients accounting for 1079 BMs were treated at our institution from 2017 to 2020. The median number of treated metastases was 4 (range 2-22). Primary tumor histology was: lung (44.8%), breast (32%), and melanoma (9.4%). The 2-year LPFS was 71.6%, respectively. A biological effective dose (BED) greater than/= to 51.3 Gy10 correlated with higher local control. Uncontrolled systemic disease and melanoma histology were independent prognostic factors correlated with decreased iPFS. Patients with greater than 10 BMs had a trend towards shorter iPFS. 31 patients received multiple SRS courses (2-7) in case of intracranial progression. The median iOS was 22.4 months. Brainstem metastases and total PTV greater than 7.1 cc correlated with shorter iOS. The 1- and 2-year WBRT-free survival was 83.2% and 61.1%, respectively.

Conclusion: Long-term results in a large patient population treated with a mono-isocentric, dedicated technique demonstrated its effectiveness and safety also in the case of multiple courses. The shortened treatment time and the possibility to safely spare healthy brain tissue allows the safe treatment of patients with a large number of metastases and to deliver multiple courses of SRS. In selected cases, the administration of WBRT can be delayed.

Not all melanoma patients here.  But good to know that multiple rounds of SRS were effective and well tolerated in some of these patients.

Time from stereotactic radiosurgery to immunotherapy in patients with melanoma brain metastases and impact on outcome.  Wegner, Abel, D’Amico, et al.  J Neurooncol.  Mar 2021.

Background: The role of immunotherapy for metastatic melanoma has expanded over the past decade triggering questions regarding the combination and timing of immunotherapy and radiation for brain metastases. We used the National Cancer Database (NCDB) to see if the time from radiation to immunotherapy in patients with melanoma brain metastases had an impact on survival.

Methods: We queried the NCDB from 2010 to 2015 for patients with melanoma brain metastases treated with immunotherapy and stereotactic radiosurgery (SRS). Receiver operator characteristic (ROC) curve analysis was done to determine a timepoint associated with outcome. Cox regression was used to identify predictors of survival. Propensity matching was done to account for indication bias.

Results: We identified 247 patients meeting the above criteria. The median patient age was 62 years (27-90) and the vast majority were Caucasian (99%). The median SRS dose was 22 Gy (18-24 Gy).The median time to SRS was 39 days (0-344) and the median time to immunotherapy was 56 days (6-454). The ROC analysis revealed 8 days from SRS to immunotherapy as associated with outcome. Fifty-six patients had immunotherapy prior to SRS, 30 patients had immunotherapy within 0-7 days of SRS, and the remaining 161 had immunotherapy greater than 7 days from SRS. Three year survival rates were 21%, 55%, and 35% for those timeframes, respectively. Propensity matching of the 0-7 day and greater than 7 day groups yielded 28 pairs and Kaplan Meier analysis showed 3 year overall survival of 55% and 35%, in favor of immunotherapy within 7 days of SRS. Multivariable Cox regression identified lack of extracranial disease, more recent year of treatment, and time from SRS to immunotherapy of 0-7 days as predictors of improved survival.

Conclusions: Immunotherapy within 7 days of SRS shows a possible association with improve outcomes in patients with brain metastases from melanoma.

Many other studies have already demonstrated this fact - outcomes are better when you DO NOT delay immunotherapy!!!!!!!!!!!!!!!!!!!!!!!!!!!!  Again = a zillion reports:  Radiation AND immunotherapy

Management of melanoma brain metastases: Evidence-based clinical practice guidelines by Cancer Council Australia.  Hong, Waldstein, Shivalingam, et al.  Eur J Cancer.  Jan 2021.

Introduction: The brain is a common site of metastatic disease for patients with advanced melanoma. Brain metastasis portends a poor prognosis, often causing deterioration in neurological function and quality of life, and leading to neurological death. Treatment approaches including surgery, radiotherapy and systemic therapy can lead to better control of this problem. Therefore, appropriate guidelines for the management of melanoma brain metastases need to be established, with regular updating when new treatment options become available.

Methods: A multidisciplinary working party established by Cancer Council Australia has produced up-to-date, evidence-based clinical practice guidelines for the management of melanoma. After selecting key clinical questions, a comprehensive literature search for relevant studies was conducted, followed by systematic review of those studies. Data were summarized and the evidence was assessed, leading to the development of recommendations.

Main recommendations: Symptomatic lesions are best treated with surgery, when possible; this provides safe and effective local control. For patients with single or a small number of asymptomatic brain metastases, stereotactic radiotherapy is recommended, but in asymptomatic patients who have not previously received systemic treatment, drug therapy can be considered as a first-line treatment option. Whole brain radiotherapy may provide palliative benefits in patients with multiple brain metastases. Whenever possible, melanoma patients with brain metastases should be managed by a multidisciplinary team of melanoma specialists that considers the optimal combination and sequencing of surgery, radiotherapy and systemic therapy.

All conclusions seem true based on current data.  There is even this confirming report from 2019 regarding immunotherapy as first line treatment (without radiation) for folks with melanoma brain mets - IPI/NIVO - results - in melanoma brain mets and long term follow-up in advanced melanoma  However, as I noted in that post - with the vast preponderance of evidence showing that responses are better when immunotherapy is COMBINED with radiation, you would have a hard time convincing me to roll with immunotherapy alone.  But, maybe that's just me!

Sustainable responses in metastatic melanoma patients with and without brain metastases after elective discontinuation of anti-PD1-based immunotherapy due to complete response.  Dimitriou, Zaremba, Allayous, et al. Eur J Cancer.  Jul 2021.

Background: Anti-PD1-based immunotherapy is currently used in most patients with advanced melanoma. Despite the remarkable data regarding overall survival, the optimal treatment duration is still unknown.

Methods: We evaluated the outcome of 125 patients with advanced melanoma with and without brain metastases (MBM), treated either with anti-PD1 monotherapy (N = 97) or combined with anti-CTLA4 (N = 28) after elective treatment discontinuation due to complete response (CR) (group A, N = 86), or treatment-limiting toxicity (N = 33) and investigator's decision (ID, N = 6) (group B) with subsequent CR.

Results: For group A, median duration of treatment (mDoT) was 22 months (range 5-49) and median time to CR 9 months (range 2-47). Accordingly, mDoT for group B was 3 months (range 0-36) and median time to CR 7 months (range 1-32). Seven patients from group A and three from group B experienced disease recurrence. Off-treatment survival was not reached. Median off-treatment response time (mOTRt) was 19 months (range 0-42) and 25 months (range 0-66), respectively. For MBM, mOTRt was 17 months (range 7-41) and 28 months (range 9-39), respectively. After a median follow-up of 38 months (range 9-70), seven (5.6%) patients had deceased, one (0.8%) due to melanoma.

Conclusions: Treatment discontinuation is feasible also in patients with MBM. Efficacy outcomes seemed to be similar in both groups of patients who achieved CR, regardless of reason for discontinuation. In patients who experienced disease relapse, treatment re-challenge with anti-PD1 resulted in subsequent renewed response.

Deciding when to stop therapy - esp when there has been no complete response, remains hard.

First line immunotherapy extends brain metastasis free survival, improves overall survival, and reduces the incidence of brain metastasis in patients with advanced melanoma.  Wang, Haaland, Hu-Lieskovan, et al.  Cancer Rep.  June 2021.

Background: Recent advances in targeted therapy and immunotherapy have improved the prognosis of melanoma patients but brain metastasis remains a major challenge. Currently, it is unclear how existing therapies can be best used to prevent or treat brain metastasis in melanoma patients.

Aims: We aimed to assess brain metastasis free survival (BMFS), overall survival (OS), incidence of brain metastases, and sequencing strategies of immunotherapy and targeted therapy in patients with BRAF-mutated advanced melanoma.

Methods and results: We retrospectively analyzed 683 patients with BRAF-mutated advanced melanoma treated with first line (1L) immunotherapy (N = 266) or targeted therapy (N = 417). The primary outcome was BMFS. Secondary outcomes included OS of all patients and incidence of brain metastases in patients without documented brain metastases prior to 1L therapy. The median BMFS was 13.7 months among all patients. The median BMFS for patients receiving 1L immunotherapy was 41.9 months and targeted therapy was 11.0 months. Median OS results were qualitatively similar to BMFS results. The cumulative incidence of brain metastases for patients receiving 1L targeted therapy was higher than for patients receiving 1L immunotherapy. Patients receiving 1L anti-CTLA4 plus anti-PD1 combination immunotherapy only or followed by second line (2L) targeted therapy had better BMFS, improved OS, and reduced incidence of brain metastases, than patients receiving 1L combination BRAF and MEK targeted therapy followed by 2L immunotherapy.

Conclusion: Patients with advanced BRAF mutant melanoma treated with 1L immunotherapy have significantly longer BMFS and OS, and reduced incidence of brain metastases, compared with those treated with 1L targeted therapy. Further studies evaluating the ability of immunotherapy and targeted therapy to improve OS and prevent brain metastases are warranted.

Interesting.

Melanoma brain metastasis presentation, treatment, and outcomes in the age of targeted and immunotherapies.  Bander, Yuan, Carnevale, et al.  Cancer.  June 2021.

Background: Historically, the prognosis for patients who have melanoma brain metastasis (MBM) has been dismal. However, breakthroughs in targeted and immunotherapies have improved long-term survival in those with advanced melanoma. Therefore, MBM presentation, prognosis, and the use of multimodality central nervous system (CNS)-directed treatment were reassessed.

Methods: In this retrospective study, the authors evaluated patients with MBM who received treatment at Memorial Sloan Kettering Cancer Center between 2010 and 2019. Kaplan-Meier methodology was used to describe overall survival (OS). Recursive partitioning analysis and time-dependent multivariable Cox modeling were used to assess prognostic variables and to associate CNS-directed treatments with OS.

Results: Four hundred twenty-five patients with 2488 brain metastases were included. The median OS after an MBM diagnosis was 8.9 months. Patients who were diagnosed with MBM between 2015 and 2019 experienced longer OS compared to those who were diagnosed between 2010 and 2014 (OS, 13.0 months vs 7.0 months). Prognostic multivariable modeling significantly associated shortened OS independently with leptomeningeal dissemination, increasing numbers of brain metastases at diagnosis, earlier MBM diagnosis year, higher serum levels of lactate dehydrogenase, receipt of immunotherapy before MBM diagnosis, and the presence of extracranial disease. The use of different CNS-directed treatment modalities was associated with presenting symptoms, diagnosis year, number and size of brain metastases, and the presence of extracranial disease. Multivariable analysis demonstrated improved survival for patients who underwent craniotomy.

Conclusions: The prognosis for patients with MBM has improved within the last 5 years, coinciding with the approval of PD-1 immune checkpoint blockade and combined BRAF/MEK targeting. Improving survival reflects and may influence the willingness to use aggressive multimodality treatment for MBM.

Lay summary: Historically, melanoma brain metastases (MBM) have carried a poor survival prognosis of 4 to 6 months; however, the introduction of immunotherapy and targeted precision medicines has altered the survival curve for advanced melanoma. In this large, single-institution, contemporary cohort, the authors demonstrate a significant increase in survival of patients with MBM to 13 months within the last 5 years of the study. A worse prognosis for patients with MBM was significantly associated with the number of metastases at diagnosis, previous exposure to immunotherapy, spread of disease to the leptomeningeal compartment, serum lactate dehydrogenase elevation, and the presence of extracranial disease. The current age of systemic treatments has also been accompanied by shifts in the use of central nervous system-directed therapies.

Yep.  Things are better.  But, not yet good enough.  Still, we know - if you have melanoma brain mets - hit 'em hard with everything you've got!  No waiting.  No pussy footing around!!!

Immune checkpoint inhibitor therapy may increase the incidence of treatment-related necrosis after stereotactic radiosurgery for brain metastases: a systematic review and meta-analysis.  Kim, Suh, Kim, et al.  Eur Radiol.  June 2021.

Objectives: To compare the incidence of treatment-related necrosis between combination SRS+ICI therapy and SRS therapy alone in patients with brain metastases from melanoma and non-small cell lung cancer (NSCLC).

Methods: A systematic literature search of Ovid-MEDLINE and EMBASE was performed up to August 10, 2020. The difference in the pooled incidence of treatment-related necrosis after SRS+ICI or SRS alone was evaluated. The cumulative incidence of treatment-related necrosis at the specific time point after the treatment was calculated and plotted. Subgroup and meta-regression analyses were additionally performed.

Results: Sixteen studies (14 on melanoma, 2 on NSCLC) were included. In NSCLC brain metastasis, the reported incidences of treatment-related necrosis in SRS+ICI and SRS alone ranged 2.9-3.4% and 0-2.9%, respectively. Meta-analysis was conducted including 14 studies on melanoma brain metastasis. The incidence of treatment-related necrosis was higher in SRS+ICI than SRS alone (16.0% vs. 6.5%). The incidence showed rapid increase until 12 months after the SRS when combined with ICI therapy (14%) and its pace of increase slowed thereafter. Histopathologic diagnosis as the reference standard for treatment-related necrosis and inclusion of only symptomatic cases were the source of heterogeneity in SRS+ICI.

Conclusions: Treatment-related necrosis tended to occur 2.4 times more frequently in the setting of combination SRS+ICI therapy compared with SRS alone in melanoma brain metastasis showing high cumulative incidence within the first year. Treatment-related necrosis should be considered when SRS+ICI combination therapy is used for melanoma brain metastasis, especially in the first year.

Key points: • Treatment-related necrosis occurred 2.4 times more frequently in the setting of combination SRS+ICI therapy compared with SRS alone in melanoma brain metastasis. • Treatment-related necrosis more frequently occurred in brain metastases from melanoma than NSCLC. • Reference standard for treatment-related necrosis and inclusion of only symptomatic treatment-related necrosis were a significant source of heterogeneity, indicating varying definitions of treatment-related necrosis in the literature need to be unified.

First of all, melanoma sucks.  Melanoma brain mets suck even more.  Yes, treatment necrosis is a real thing.  Yes, it seems to happen in melanoma brain mets more than in brain mets caused by other cancers.  BUT!  What 'cha gonna do?  Not treat and risk more mets and less survival?  Plus, this is a meta-analysis - NOT a real report with full intel on every rattie studied.  There are studies with real ratties that show this:  Immunotherapy with SRS does NOT increase risk of radiation necrosis in melanoma brain mets!!!

The combined use of steroids and immune checkpoint inhibitors in brain metastasis patients: a systematic review and meta-analysis.  Jessurun, Hulsbergen, Wit, et al.  Neuro Oncol.  August 2021.

Background: Immune checkpoint inhibitors (ICI) have been a breakthrough for selected cancer patients, including those with brain metastases (BMs). Likewise, steroids have been an integral component of symptomatic management of BM patients. However, clinical evidence on the interaction between ICI and steroids in BM patients is conflicting and has not adequately been summarized thus far. Hence, the aim of this study was to perform a systematic literature review and meta-analysis on the association between steroid use and overall survival (OS) in BM patients receiving ICI.

Methods: A systematic literature search was performed. Pooled effect estimates were calculated using random-effects models across included studies.

Results: After screening 1145 abstracts, 15 observational studies were included. Fourteen studies reported sufficient data for meta-analysis, comprising 1102 BM patients of which 32.1% received steroids. In the steroid group, median OS ranged from 2.9 to 10.2 months. In the nonsteroid group, median OS ranged from 4.9 to 25.1 months. Pooled results demonstrated significantly worse OS and systemic progression-free survival in the steroid group. Stratified analysis showed a consistent effect across the melanoma subgroup; not in the lung cancer subgroup. No significant association was shown between steroid use and intracranial PFS.

Conclusions: Administration of steroids was associated with significantly worse OS and PFS in BM patients receiving ICI. Further research on dose, timing, and duration of steroids is needed to elucidate the cause of this association and optimize outcomes in BM patients receiving ICI.

This article is proof that I share all the data that I find - even if it doesn't jive with most of the previous data.  To whit - steroids do NOT diminish response in melanoma patients - and are often in fact,  REQUIRED in order for melanoma patients to continue their life saving treatment!!!  While there may be some truth in the conclusion that folks who have to undergo steroids while on immunotherapy have a decreased response compared to those who do not - I think the REASON for that may not be the one first concluded - ie steroids themselves diminished the response.  RATHER, patients who must use steroids to tolerate immunotherapy often are unable to complete a sufficient quantity of immunotherapy to treat their disease effectively because they could not tolerate it.  The lack of knowledge about the specific patients in this review of 14 other studies demonstrates the severe limitations that this kind of compiled data in meta-analysis contains.  My opinions about the abstract of this study are much like those I discussed in a similar report from September of this year:  What to do about immunotherapy if you - take steroids or infliximab for side effects? Have a pre-existing autoimmune disease?????  If you are interested in the effects of steroids on immunotherapy, it is worth your time.  With repeated thanks to the Edster for help in analysis and provision of the complete article.

The studies in this post were all retrospective meta-analysis studies.  While reports like these can give a useful overview of the state of the science they are decidedly lacking in REASONS for outcomes.  For instance, there are absolutely NO elephants in Chattanooga, TN at this moment.  Further, I just clapped my hands three times.  Are those two things related?  Probably not!!!  Concurrent events and causative events are not the same.  Counting up a tally from some carefully chosen studies can be informative.  But, the results must be considered in the light of how they were attained and with recognition of the limited specifics known about the individual ratties in each of the studies, multiplied by how many studies and ratties there were.

See, Bentie?  All those crazy doctoral level statistic courses at UAB were worth the price of admission and tears of confusion, right????  BAHAHAHA!!!

Hang tough, ratties.  Melanoma isn't easy.  But there is hope. - c