The Impact of Timing of Immunotherapy with Cranial Irradiation on Early Distant Brain Progression and Overall Survival in Patients with Melanoma Brain Metastases

Background: The purpose of the study was to evaluate the impact of BRAF inhibitors on survival outcomes in patients receiving stereotactic radiosurgery (SRS) for melanoma brain metastases. Methods: We prospectively collected treatment outcomes for 80 patients with melanoma brain metastases who underwent SRS. Thirty-five patients harbored the BRAF mutation (BRAF-M) and 45 patients did not (BRAF-WT). Results: The median overall survival from first SRS procedure was 11.2 months if treated with a BRAF inhibitor and 4.5 months for BRAF-WT. Actuarial survival rates for BRAF-M patients on an inhibitor were 54% and 41% at 6 and 12 months after radiosurgery, in contrast to 28% and 19% for BRAF-WT. Overall survival was extended for patients on a BRAF inhibitor if initiated at or after the first SRS. The local control rate did not differ based on BRAF status and was over 90%. Patients with higher KPS, fewer treated metastases, controlled systemic disease, RPA class 1 and BRAF-M patients had extended overall survival. Conclusions: Patients with BRAF-M treated with both SRS and BRAF inhibitors, at or after SRS, have increased overall survival. As patients live longer due to more effective systemic and local therapies, close surveillance and early management of intracranial disease with SRS will become increasingly important.

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Ipilimumab and Stereotactic Radiosurgery with CyberKnife® System in Melanoma Brain Metastases: A Retrospective Monoinstitutional Experience

Cancers ◽

10.3390/cancers13081857 ◽

2021 ◽

Vol 13 (8) ◽

pp. 1857

Author(s):

Valentina Borzillo ◽

Rossella Di Franco ◽

Diana Giannarelli ◽

Fabrizio Cammarota ◽

Esmeralda Scipilliti ◽

...

Keyword(s):

Overall Survival ◽

Brain Metastases ◽

Local Control ◽

Immune Checkpoint Inhibitors ◽

Median Overall Survival ◽

Checkpoint Inhibitors ◽

Melanoma Brain Metastases ◽

One Year ◽

The Impact

The median overall survival (OS) and local control (LC) of patients with melanoma brain metastases (MBMs) are poor even with immune checkpoint inhibitors and/or radiotherapy (RT). The aims of the study were to evaluate the association and timing of stereotactic radiotherapy (SRT)/radiosurgery (SRS) performed with the CyberKnife® System and ipilimumab (IPI). A total of 63 MBMs patients were analyzed: 53 received RT+IPI and 10 RT alone. Therefore, the patients were divided into four groups: RT PRE-PI (>4 weeks before IPI) (18), RT CONC-IPI (4 weeks before/between first and last cycle/within 3 months of last cycle of IPI) (20), RT POST-IPI (>3 months after IPI) (15), and NO-IPI (10). A total of 127 lesions were treated: 75 with SRS (one fraction) and 24 with SRT (three to five fractions). The median follow-up was 10.6 months. The median OS was 10.6 months for all patients, 10.7 months for RT+IPI, and 3.3 months for NO-IPI (p = 0.96). One-year LC was 50% for all patients, 56% for RT+IPI, and 18% for NO-IPI (p = 0.08). The 1-year intracranial control was 45% for all patients, 44% for RT+IPI, and 51% for NO-IPI (p = 0.73). IPI with SRS/SRT in MBMs treatment could improve LC. However, the impact and timing of the two modalities on patients’ outcomes are still unclear.

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Melanoma Brain Metastases in the Era of Targeted Therapy and Checkpoint Inhibitor Therapy

Cancers ◽

10.3390/cancers13071489 ◽

2021 ◽

Vol 13 (7) ◽

pp. 1489

Author(s):

John M. Rieth ◽

Umang Swami ◽

Sarah L. Mott ◽

Mario Zanaty ◽

Michael D. Henry ◽

...

Keyword(s):

Overall Survival ◽

Brain Metastases ◽

Checkpoint Inhibitor ◽

Checkpoint Inhibitors ◽

Performance Status ◽

Multivariable Analysis ◽

Treatment Strategies ◽

Poor Performance Status ◽

Poor Overall Survival ◽

Melanoma Brain Metastases

Brain metastases commonly develop in melanoma and are associated with poor overall survival of about five to nine months. Fortunately, new therapies, including immune checkpoint inhibitors and BRAF/MEK inhibitors, have been developed. The aim of this study was to identify outcomes of different treatment strategies in patients with melanoma brain metastases in the era of checkpoint inhibitors. Patients with brain metastases secondary to melanoma were identified at a single institution. Univariate and multivariable analyses were performed to identify baseline and treatment factors, which correlated with progression-free and overall survival. A total of 209 patients with melanoma brain metastases were identified. The median overall survival of the cohort was 5.3 months. On multivariable analysis, the presence of non-cranial metastatic disease, poor performance status (ECOG 2–4), whole-brain radiation therapy, and older age at diagnosis of brain metastasis were associated with poorer overall survival. Craniotomy (HR 0.66, 95% CI 0.45–0.97) and treatment with a CTLA-4 checkpoint inhibitor (HR 0.55, 95% CI 0.32–0.94) were the only interventions associated with improved overall survival. Further studies with novel agents are needed to extend lifespan in patients with brain metastases in melanoma.

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The Impact of Prolonged Mechanical Ventilation on Overall Survival in Patients With Surgically Treated Brain Metastases

Frontiers in Oncology ◽

10.3389/fonc.2021.658949 ◽

2021 ◽

Vol 11 ◽

Author(s):

Patrick Schuss ◽

Niklas Schäfer ◽

Christian Bode ◽

Valeri Borger ◽

Lars Eichhorn ◽

...

Keyword(s):

Mechanical Ventilation ◽

Overall Survival ◽

Surgical Treatment ◽

Brain Metastases ◽

Prolonged Mechanical Ventilation ◽

Postoperative Phase ◽

Significant Prognostic Factor ◽

Cancer Disease ◽

Definition Of ◽

The Impact

ObjectiveSurgical resection represents a common treatment modality in patients with brain metastasis (BM). Postoperative prolonged mechanical ventilation (PMV) might have an enormous impact on the overall survival (OS) of these patients suffering from advanced cancer disease. We therefore have analyzed our institutional database with regard to a potential impact of PMV on OS of patients who had undergone surgery for brain metastases.Methods360 patients with surgically treated brain metastases were included. The definition of PMV consisted of postoperative mechanical ventilation lasting for more than 48 hours. Analysis of survival incorporating established prognostic factors such as age, location of BM, and preoperative physical status was performed.Results14 of 360 patients with BM (4%) suffered from postoperative PMV after surgical treatment of BM. Patients with PMV presented in a significantly more impaired neurological condition preoperatively than patients without (p<0.0001). Multivariate analysis determined PMV to be a significant prognostic factor for OS after surgical treatment in patients with BM, independent of other predictive factors (p<0.0001).ConclusionsThe present study demonstrates postoperative PMV as significantly related to poor OS in patients with surgically treated BM. Postoperative PMV is a so far underestimated prognostic predictor, but might be utilized for optimized patient management early in the postoperative phase. For this purpose, the results of the present study should encourage the initiation of further scientific efforts.

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Abstract 4847: Investigating the impact of astrocytes on targeted therapy of melanoma brain metastases

10.1158/1538-7445.am2019-4847 ◽

2019 ◽

Author(s):

Joshua Parris ◽

Subhasree Basu ◽

Thibaut Barnoud ◽

Yongkang Zhao ◽

Peter Somboonsong ◽

...

Keyword(s):

Targeted Therapy ◽

Brain Metastases ◽

Melanoma Brain Metastases ◽

The Impact

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New Era in the Management of Melanoma Brain Metastases

American Society of Clinical Oncology Educational Book ◽

10.1200/edbk_200819 ◽

2018 ◽

pp. 741-750 ◽

Cited By ~ 18

Author(s):

Hussein A. Tawbi ◽

Celine Boutros ◽

David Kok ◽

Caroline Robert ◽

Grant McArthur

Keyword(s):

Brain Metastases ◽

Systemic Therapy ◽

Single Agent ◽

Local Treatment ◽

New Era ◽

Therapeutic Modalities ◽

Melanoma Brain Metastases ◽

Extracranial Disease ◽

Induce Response ◽

The Impact

The remarkable advances in the systemic therapy of metastatic melanoma have now extended the 1-year overall survival rate from 25% to nearing 85%. Systemic treatment in the form of BRAF-targeted therapy and immunotherapy is slowly but surely proving its efficacy in the treatment of metatstatic brain metastases (MBM). Single-agent BRAF inhibitors provide an intracranial response rate of 25% to 40%, whereas the combination of BRAFi/MEKi leads to responses in up to 58%. However, the durability of responses induced by BRAFi/MEKi seems to be even shorter than in extracranial disease. On the other hand, single-agent ipilimumab provides comparable clinical benefit in MBMs as it does in extracranial metastases. Single-agent PD-1 anitbodies induce response rates of approximately 20%, and those responses appear durable. Similarly the combination of CTLA-4+ PD-1 antibodies induces durable responses at an impressive rate of 55% and is safe to administer. Although the local treatment approaches with radiation and surgery remain important and are critically needed in the management of MBM, systemic therapy offers a new dimension that can augment the impact of those therapies and come at a potentially lower cost of neurocognitive impairment. Considerations for combining those modalities are direly needed, in addition to considering novel systemic combinations that target mechanisms specific to MBM. In this report, we will discuss the underlying biology of melanoma brain metastases, the clinical outcomes from recent clinical trials of targeted and immunotherapy, and their impact on clinical practice in the context of existing local therapeutic modalities.

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The impact of targeted therapies and immunotherapy in melanoma brain metastases: A systematic review and meta‐analysis

Cancer ◽

10.1002/cncr.32375 ◽

2019 ◽

Vol 125 (21) ◽

pp. 3776-3789 ◽

Cited By ~ 10

Author(s):

Eliana Rulli ◽

Lorenzo Legramandi ◽

Lorenzo Salvati ◽

Mario Mandala

Keyword(s):

Systematic Review ◽

Brain Metastases ◽

Targeted Therapies ◽

Meta Analysis ◽

Melanoma Brain Metastases ◽

The Impact

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Early imaging radioresponsiveness of melanoma brain metastases as a predictor of patient prognosis

Journal of Neurosurgery ◽

10.3171/2017.1.jns162075 ◽

2018 ◽

Vol 129 (2) ◽

pp. 354-365 ◽

Cited By ~ 1

Author(s):

Irina Zubatkina ◽

Pavel Ivanov

Keyword(s):

Overall Survival ◽

Multivariate Analysis ◽

Brain Metastases ◽

Retrospective Analysis ◽

Systemic Disease ◽

Rapid Response ◽

Slow Response ◽

Melanoma Brain Metastases ◽

Radiological Response ◽

Patient Prognosis

OBJECTIVEThe aim of this study was to analyze the early radiological response of melanoma brain metastases to single high-dose irradiation and to reveal possible correlations between tumor radioresponsiveness and patient clinical outcomes.METHODSThe authors performed a retrospective analysis of the medical data for all patients with melanoma brain metastases who had undergone Gamma Knife radiosurgery (GKRS) and follow-up MRI examinations with standard protocols at regular 2- to 3-month intervals. Volumetric measurements of the metastases on pretreatment and initial posttreatment images were performed to assess the rate of early radiological response. Patients were divided into 2 groups according to the rate of response, and overall survival, local control, and the appearance of new metastases in the brain were compared in these groups using the long-rank test. Univariate and multivariate analyses were performed to identify predictors of clinical outcomes.RESULTSAfter retrospective analysis of 298 melanoma brain metastases in 78 patients, the authors determined that early radiological responses of these metastases to GKRS differ considerably and can be divided into 2 distinct groups. One group of tumors underwent rapid shrinkage after radiosurgery, whereas the other showed minor fluctuations in size (rapid- and slow-response groups, respectively). Median survival for patients with a slow response was 15.2 months compared with 6.3 months for those with a rapid response (p < 0.0001). In the multivariate analysis, improved overall survival was associated with a slow response to radiosurgery (p < 0.0001), stable systemic disease (p = 0.001), and a higher Karnofsky Performance Scale score (p = 0.001). Stratification by Recursive Partitioning Analysis, score index for radiosurgery, and diagnosis-specific Graded Prognostic Assessment classes further confirmed the difference in overall survival for patients with a slow versus rapid radiation response. Local recurrence was observed in 11% of patients with a rapid response and in 6% of patients with a slow response, at a median of more than 8 months after radiosurgery. New brain metastases were diagnosed in 67% of patients with a slow response at a median of 8.6 months after radiosurgery and in 82% of patients with a rapid response at a considerably earlier median time of 2.7 months. In the multivariate analysis, a longer time to the development of new brain metastases was associated with a slow response (p = 0.012), stable systemic disease (p = 0.034), and a single brain metastasis (p = 0.030).CONCLUSIONSMelanoma brain metastases show different early radioresponsiveness to radiosurgery. Rapid shrinkage of brain metastases is associated with poor patient prognosis, which may indicate more aggressive biological behavior of this tumor phenotype.

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Thoracic twice-daily radiotherapy and brain metastasis in patients with small cell lung cancer.

Journal of Clinical Oncology ◽

10.1200/jco.2019.37.15_suppl.8560 ◽

2019 ◽

Vol 37 (15_suppl) ◽

pp. 8560-8560

Author(s):

Haiyan Zeng ◽

Rui Li ◽

Chen Hu ◽

Guoqin Qiu ◽

Hong Ge ◽

...

Keyword(s):

Lung Cancer ◽

Overall Survival ◽

Brain Metastases ◽

Small Cell Lung Cancer ◽

Cell Lung Cancer ◽

Progression Free Survival ◽

Cranial Irradiation ◽

Prophylactic Cranial Irradiation ◽

Small Cell ◽

Small Cell Lung

8560 Background: Although thoracic twice-daily radiotherapy (TDRT) is one of standards of care for small cell lung cancer, its impact on brain metastases remains unknown. This study aimed to compare TDRT with once-daily radiotherapy (ODRT) for the brain metastases rate after prophylactic cranial irradiation in patients with small cell lung cancer. Methods: Consecutive patients received TDRT (45Gy/30f)/ODRT(50-66Gy/25-33f), chemotherapy and prophylactic cranial irradiation were retrieved from eight hospitals’ databases between 2003 and 2016. The endpoints included brain metastases, progression-free survival and overall survival. Brain metastases rate was evaluated using competing risk analysis. A 1:1 propensity score matching approach was used to control confounding between these two groups. Confounding covariates included eight demographic variables and eight treatment related covariates. Results: Of the 778 eligible patients with median age of 55-year (IQR, 48-61), 204 (26.2%) were female. At a median follow-up time of 23.6 months (IQR, 14.2- 38.2), 131 (16.8%) experienced brain metastases. The rates in TDRT were significantly higher than ODRT (3-year, 26.0% vs. 16.9%; HR = 1.55, 95%CI 1.06-2.26, P = 0.03). Of the 338 matched patients (169 in ODRT vs. 169 in TDRT), 60 (17.8%) experienced brain metastases with 3-year rate of 14.9% in ODRT vs 26.0% in TDRT (HR = 1.71, 95%CI 1.02-2.88, P = 0.04). Progression-free survival was similar in both the whole cohort and the matched one. Overall survival in ODRT tended to be significantly longer after matching (median, 47.2 months in ODRT vs. 32.8 months in TDRT; HR = 1.41, 95%CI 0.99-2.01, P = 0.06). When jointly evaluated biologically effective dose (BED), start of any therapy to the end of radiotherapy (SER) and TDRT/ODRT in the multivariable analysis, the impact of ODRT/TDRT on overall survival become more significant (HR = 1.69, 95%CI 1.05-2.71, P = 0.03). Conclusions: Patients with small cell lung cancer who were treated with thoracic TDRT appeared to have higher risk of brain metastases than those with ODRT, which strongly supports the need for further prospective randomized clinical trials, especially in China or other parts of Asia.

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