Control Of Brain Metastases Research Articles

Modern strategies for the treatment of patients with kidney cancer of brain metastases: literature review

According to the literature, metastatic brain damage in kidney cancer occurs in 6.5 % of patients. The introduction of new techniques associated with the use of targeted drugs, immune checkpoint inhibitors and innovative radiation therapy techniques can significantly increase patient survival. Effective drug therapy and local control of brain metastases are of paramount importance for predicting overall survival and quality of life for patients. This literature review summarizes the scientific literature data on the use of local and systemic methods of treatment in patients with metastases of kidney cancer to the brain.

P46.05 Durable Response to Double Dose Osimertinib 160mg in EGFR-Mutated Non-Small Cell Lung Cancer With Brain Metastases

In non-small cell lung cancer (NSCLC) patients, metastasis to the brain harbors a poor prognosis and it occurs more commonly in EGFR-mutated patients. Osimertinib has better CNS penetration compared to previous generations of EGFR-TKIs. However, progression of disease is commonly observed in a median of 10-14 months after the initiation of EGFR-TKI treatment. Although not endorsed by any guidelines, the use of double dose osimertinib has been reported anecdotally in clinical settings of CNS progression with limited durability. Herein, we present an EGFR-mutated NSCLC patient with brain metastases currently demonstrating exceptional durability in response to double dose osimertinib after CNS progression was observed with a standard dose. Case presentation A 47-year-old male was diagnosed with stage IV(cT2aN3M1) lung adenocarcinoma with multiple osseous and three subcentimeter brain metastases. Upon confirmation of EGFR exon 19 deletion mutation, the patient was started on afatinib. The patient demonstrated excellent overall response including a decrease of all three brain metastases until CNS progression occurred 12 months later. Subsequently, afatinib was discontinued and changed to standard dose osimertinib(80mg daily). The patient tolerated the treatment well with stable disease on MRI brain and CT chest until CNS progression of two lesions(right parietal lobe 6mm->10mm, left parietal lobe 1mm->3mm) was observed 9 months later. For better control of brain metastases, the dose of osimertinib was increased from 80mg to 160mg. The patient tolerated the double dose osimertinib(160mg daily) well with a decrease in size of the two largest, CNS progressive lesions(right parietal lobe 10mm->4mm, left parietal lobe 3mm->1mm) and resolution of smaller brain metastases. Thereafter, stable disease was observed on MRI brain and CT chest until CNS progression occurred 8 months later. Continuation of double dose osimertinib combined with stereotactic radiosurgery on the progressive lesions led to complete resolution of brain metastases. Recent follow-up imaging studies revealed no evidence of active metastases on MRI brain and stable disease on CT chest. The patient is demonstrating a durable response of over 24 months to double dose osimertinib and tolerating the treatment very well with grade 1-2 facial/scalp rash controlled with topical treatment. According to recent studies, the median PFS of double dose osimertinib after CNS progression from brain metastasis is less than 12 months. Our case demonstrated superior durability of double dose osimertinib for over 24 months. The case suggests that double dose osimertinib of 160mg can be well tolerated with minimal adverse events and demonstrate prolonged efficacy in treating EGFR-mutated NSCLC with brain metastasis after CNS progression from a standard dose of 80mg.

Metastatic Brain Tumors

Metastatic brain tumors are malignant lesions that spread to the brain from a primary neoplasm such as cancer or sarcoma located in other body organs. Brain metastases tend to cause deterioration of neurological function and negatively affect patients quality of life. Control of brain metastases is important, following improved outcomes that are being observed in patients with cancer. Recent advances in radiotherapy and drug therapy have led to a paradigm shift in the treatment of metastatic brain tumors. In this article, we review the clinical characterization of metastatic brain tumors that has reached a turning point in oncology.

Factors influencing disease control in metastatic lung cancer with intracranial metastasis post gamma-knife radiotherapy.

e21602 Background: Traditionally, disease control of brain metastases (BM) has dictated the prognosis of those with metastatic lung cancer. Immune check-point inhibitors (ICI) have shown intracranial response but data on the magnitude of such effect in combination with radiation is still evolving. We report the time to progression of intracranial and systemic disease post gamma-knife radiation (GK) and associations with the use of ICI in this cohort. Methods: Patients with metastatic lung cancer with BM treated with GK between 2015 and 2019 were retrospectively analysed in a single institution at the Princess Alexandra Hospital, Queensland. The primary endpoint was time from first GK to death. Results: 104 patients were eligible. Median age was 63 years. BM was seen in 46.7% at diagnosis (versus relapsed in brain). Solitary BM was seen in 37.1% patients. 7.7% had prior whole-brain radiation (WBRT) prior to GK. 45.7% received ICI either at the time of GK or as the next line of treatment immediately post GK. 56.2% received ICI at any time during the study period. Oncogenic driver mutations were seen in 13 cases [EGFR mutant (9.5%), ALK mutation (2.5%)]. 15.2% patients had a high-PDL1 (≥50%) level. Time from GK to death was: 14 (9.7-18.3) months for all patients. Incidence of progressive BM was 46.7%. Time to intracranial PD was 5 months. Systemic PD was seen post GK in 44.8% patients. Survival was improved in those patients with the presence of a driver mutation (p = 0.043) on univariate analysis. Factors which did not impact survival included: the number of BM (solitary vs multiple; p = 0.837), PD-L1 status (PD-L1 < 50% vs ≥50%; p = 0.186), use of ICI (used vs not used; p = 0.307) and previous WBRT (treated vs not treated; p = 0.251). Failure of BM requiring GK on ICI was not associated with a worse outcome (p = 0.707). Conclusions: The presence of driver mutations was associated with prolonged overall survival in select patients undergoing GK for BM. High PDL-1 expressivity and timing of ICI relative to GK do not appear to positively influence outcome in this retrospective study.

Management of Central Nervous System Metastases in Patients With Advanced Anaplastic Lymphoma Kinase-Rearranged Non–Small-Cell Lung Cancer During Crizotinib Treatment

BackgroundCentral nervous system (CNS) progression is a common manifestation of acquired resistance to crizotinib in anaplastic lymphoma kinase (ALK)-rearranged non–small-cell lung cancer (NSCLC). However, an optimal tailored treatment approach has not been established in patients with CNS failure during crizotinib treatment. Patients and MethodsPatients with ALK-rearranged NSCLC with CNS progression during crizotinib treatment between January 2013 and December 2016 were included for analysis. Clinical data for different treatments after CNS failure during crizotinib treatment were retrospectively collected. ResultsAmong the 44 patients who had CNS progression during crizotinib treatment, 19, 15, 8, and 2 patients received crizotinib treatment beyond progressive disease (CBPD), a second ALK tyrosine kinase inhibitor (TKI), chemotherapy, and best supportive care, respectively. Post progression survival offered by treatment with a second ALK TKI was significantly more favorable than that of chemotherapy (P < .001) or CBPD (P = .045). In addition, patients who received sequential treatment with a second ALK TKI had significantly longer intracranial time to progression (IC-TTP) compared with those treated with chemotherapy (P < .01) or CBPD after radiotherapy (P = .003). In the 7 patients who received brigatinib, the median IC-TTP was 21.8 months (95% confidence interval, 11.7-32.0). The additional use of CNS radiotherapy in patients treated with a second ALK TKI showed no significance in terms of IC-TTP (P = .54). ConclusionAlthough CBPD is an option in patients with isolated CNS progression during crizotinib treatment, sequential treatment with a second ALK TKI, particularly brigatinib, might be preferable. The newly approved TKI, brigatinib, showed promise in the control of brain metastases, even without radiotherapy.

Radiosurgery or hypofractionated stereotactic radiotherapy for brain metastases from radioresistant primaries (melanoma and renal cancer)

BackgroundUntil 50% of patients with renal cancer or melanoma, develop brain metastases during the course of their disease. Stereotactic radiotherapy has become a standard of care for patients with a limited number of brain metastases. Given the radioresistant nature of melanoma and renal cancer, optimization of the fractionation of stereotactic radiotherapy is needed. The purpose of this retrospective study was to elucidate if hypofractionated stereotactic radiotherapy (HFSRT) impacts local control of brain metastases from radioresistant tumors such as melanoma and renal cancer, in comparison with radiosurgery (SRS).MethodsBetween 2012 and 2016, 193 metastases, smaller than 3 cm, from patients suffering from radioresistant primaries (melanoma and renal cancer) were treated with HFSRT or SRS. The primary outcome was local progression free survival (LPFS) at 6, 12 and 18 months. Overall survival (OS) and cerebral progression free survival (CPFS) were secondary outcomes, and were evaluated per patient. Objective response rate and radionecrosis incidence were also reported. The statistical analysis included a supplementary propensity score analysis to deal with bias induced by non-randomized data.ResultsAfter a median follow-up of 7.4 months, LPFS rates at 6, 12 and 18 months for the whole population were 83, 74 and 70%, respectively. With respect to fractionation, LPFS rates at 6, 12 and 18 months were 89, 79 and 73% for the SRS group and 80, 72 and 68% for the HFSRT group. The fractionation schedule was not statistically associated with LPFS (HR = 1.39, CI95% [0.65–2.96], p = 0.38). Time from planning MRI to first irradiation session longer than 14 days was associated with a poorer local control rate. Over this time, LPFS at 12 months was reduced from 86 to 70% (p = 0.009). Radionecrosis occurred in 7.1% for HFSRT treated metastases to 9.6% to SRS treated metastases, without any difference according to fractionation (p = 0.55). The median OS was 9.6 months. Six, 12 and 18 months CPFS rates were 54, 24 and 17%, respectively.ConclusionFractionation does not decrease LPFS. Even for small radioresistant brain metastases (< 3 cm), HFSRT, with 3 or 6 fractions, leads to an excellent local control rate of 72% at 1 year with a rate of 7.1% of radionecrosis. HFSRT is a safe and efficient alternative treatment to SRS.

Prophylactic Cranial Irradiation for Extensive-Stage Small-Cell Lung Cancer: A Retrospective Analysis.

PurposeExtensive-stage small-cell lung cancer (esSCLC) is an incurable disease and represents a therapeutic challenge because of its poor prognosis. Studies in prophylactic cranial irradiation (PCI) in esSCLC have shown a decreased incidence of symptomatic brain metastases in patients who respond to systemic chemotherapy. However, its effect on overall survival is debatable. We evaluated the benefit of PCI in patients with esSCLC in terms of overall survival, progression-free survival, incidence of brain metastases, recurrence rate, and exposure to postrecurrence therapies.Materials and MethodsWe retrospectively reviewed electronic charts from patients diagnosed with esSCLC from 2008 to 2014 at our institution. All patients had negative baseline brain imaging before chemotherapy and PCI and received at least 4 cycles of platinum-based chemotherapy in the first-line setting without progressive disease on follow-up. PCI was performed at the discretion of the treating physician. Analyses were based on descriptive statistics. Survival curves were calculated by Kaplan-Meier method.ResultsAmong 46 eligible patients, 16 (35%) received PCI and 30 (65%) did not. Compared with no PCI, PCI led to improved progression-free survival (median, 10.32 v 7.66 months; hazard ratio, 0.4521; 95% CI, 0.2481 to 0.8237; P < .001) and overall survival (median, 20.94 v 11.05 months; hazard ratio, 0.2655; 95% CI, 0.1420 to 0.4964; P < .001) as well as lower incidence of brain metastases (19% v 53%; P = .0273) and higher exposure to second-line chemotherapy (87% v 57%; P = .0479).ConclusionCareful patient selection for PCI can improve not only brain metastases control and higher second-line chemotherapy exposure but also patient survival.

P16.23 Surgical resection of melanoma brain metastases, a highly effective modality for local control in the era of prolonged survival from stage IV melanoma

Abstract Introduction: Novel systemic therapies targeting the MAP kinase pathway (BRAF inhibitors) or immune checkpoints have significantly improved the overall survival of patients with metastatic melanoma, with a 2 year overall survival now above 50%. The importance of achieving durable local control of brain metastases is therefore reinforced. We sought to determine the local control rate after complete surgical resection of individual brain metastases in patients with stage IV melanoma. Secondary outcome measures were morbidity and mortality associated with these surgeries, frequency of distant recurrence of brain metastases, and overall survival. Additionally, we sought to define patterns of treatment in relation to radiation options and systemic therapies. METHODS: Clinicopathological data was retrospectively collected from 104 consecutive patients recorded in a prospective database who underwent surgical resection of 1 – 4 melanoma brain metastases between May 2008 and December 2014 at Melanoma Institute Australia and Royal Prince Alfred Hospital, Sydney Australia. Group 1 comprised all those treated between May 2008 and May 2011 (before the routine use of effective drug therapies). Group 2 comprised all those treated between June 2011 and December 2014. Given the marked heterogeneity between the treatment the two groups have received, we felt that statistical analyses for direct comparisons would be inappropriate. Results: Group 1 had 46 patients with a total of 78 cerebral melanoma metastatic lesions resected and Group 2 had 58 patients with a total of 106 lesions resected. The local control rate at 24 months was 91% in both Group 1 and Group 2. The median overall survival was higher in Group 2 than Group 1, as reflected by 13.5 months and 11.5 months respectively. The use of whole brain radiation therapy, systemic therapy, stereotactic ­radiosurgery (SRS) to cavity varied between the two groups, with 72%, 35%, 0% in Group 1 and 57%, 34%, 10% in Group 2, respectively. The rates of SRS failure varied between the two groups, with 4% in Group 1 and 34% in Group 2. Peri-operative complications rates and death rate of 4% and 1% respectively was detected in Group 1, and 6% and 2% respectively in Group 2. CONCLUSION: Surgical resection of melanoma brain metastases is a highly effective and safe means of local control for stage IV melanoma patients who now see prolonged survival when treated in a multimodal way by a cohesive multidisciplinary group.

Control of brain metastases with alectinib in anaplastic lymphoma kinase‐rearranged lung cancer

Brain metastasis from non‐small cell lung cancer remains a challenge to physicians. It occurs in 30% of patients with advanced stage adenocarcinoma of lung and is often regarded as the ominous sign of disease progression and death. Alectinib is likely to be a promising agent, even after the failure of crizotinib and ceritinib, for patients with anaplastic lymphoma kinase (ALK) ‐driven non‐small cell lung cancer with brain metastasis, resulting in a durable response for both intracranial and extra‐cranial diseases.

Efficacy of pemetrexed in a patient with brain metastases during crizotinib treatment.

ALK-positive patients with non-small-cell lung cancer (NSCLC) exhibit more aggressive clinical progression, a poorer response to chemotherapy, and less favorable survival outcomes in comparison with ALK-negative patients. Although crizotinib has proved effective in treating ALK-positive NSCLC, this agent penetrates the blood-brain barrier poorly and CNS progression is common. As pemetrexed, a multitargeted antifolate chemotherapeutic agent, has demonstrated benefit in the control of brain metastases in patients with NSCLC, treatment with pemetrexed was added to crizotinib in a young male patient with ALK-positive NSCLC who had developed brain metastases during crizotinib therapy. After four cycles of pemetrexed chemotherapy, the patient's brain lesions were significantly reduced in size and a chest CT scan showed that the lung lesions had stabilized.

Control of brain metastases from radioresistant tumors treated by stereotactic radiosurgery.

Renal cell carcinoma, sarcoma, and melanoma are considered to be "radioresistant" tumor histologies. Brain metastases (BM) from these tumors are considered unlikely to be controlled using the relatively low doses used in whole brain radiotherapy (WBRT). Our objective was to analyze the efficacy of stereotactic radiosurgery (SRS) on local control and overall survival of BM from radioresistant primary tumors. We reviewed all patients who received Gamma Knife Radiosurgery (GKRS) for BM at Columbia University Medical Center between January 2009 and April 2014. All patients were treated using the Gamma Knife Perfexion System. Dosimetric data was collected from treatment plans and metastases were categorized as radioresistant or not. Response was assessed by reviewing follow-up brain imaging studies and classified according to RECIST. Local control and median overall survival were calculated using the Kaplan-Meier method. In total, 373 tumors were analyzed from 126 patients. Of these tumors, 49 (13.1%) originated from radioresistant cancers. The overall local control rate in the radioresistant cohort was 89.8 and 90.1% in the non-radioresistant cohort. Univariate and multivariate analyses demonstrated that radioresistance status of the primary tumor had no statistically significant effect on local control with hazard ratios of 1.0 (p=1.0, 95% CI 0.388-2.576) and 0.954 (p=0.926, 95% CI 0.349-2.603) respectively. Median overall survival for both radioresistant and non-radioresistant cohorts was 20.0months, with a p value of 0.926. There was no significant difference in local control of BM from radioresistant and non-radioresistant primary tumors treated with GKRS. Both cohorts showed excellent response and local control, suggesting that SRS upfront or in addition to WBRT may be an appropriate strategy in the treatment of BM from radioresistant cancers. Median overall survival for both cohorts was equal, suggesting that improved local control may be associated with an improvement in long-term survival.

367TiP - Phase 1 Dose Escalation and Cohort Expansion Study of the Safety of Intrathecal Trastuzumab in Her2 Positive Parenchymal Brain Metastatic Breast Cancer: Trial Protocol

ABSTRACT Background: The brain is described frequently as the first site of relapse in women with HER2 positive breast cancer treated with trastuzumab. Strategies for better control of brain metastases and outcome improvement are lacking. Intrathecal trastuzumab (IT) was safely performed in cynomolgus monkeys and is being investigated in early trials for meningeal carcinomatosis. Case reports showed clinical benefit and radiological response in HER2 positive parenchymal brain metastatic breast cancer (bMBC) patients. The primary objectives of this study are to determine safety and tolerability of IT. The secondary objectives are to establish IT pharmacokinetic (PK) profile and to measure its preliminary anti-tumor activity. Trial design: Open label single-arm interventional study, non-randomized, phase 1 study, using a “3 + 3” design followed by expansion cohorts. Patients will be treated in cohorts of 3-6 based on standard phase I dose escalation parameters requiring 0/3 or 1/6 patients per cohort to have a DLT before dose escalation. Dosing is as follows: cohort 50 mg IT, cohort 100 mg IT, cohort 150 mg IT. An Ommaya reservoir for IT will be placed surgically. Patients will be treated every 3 weeks concurrently with standard systemic therapy, after local treatment: surgery/stereostatic surgery and/or WBRT. Expansion cohorts will be stratified for each modality of previous local treatment. Safety will be assessed by incidence of DLT, establishment of the MTD, RP2D and schedule. Tolerability will be assessed by incidence of Adverse Events according to the CTCAE v4.0. Trastuzumab PK profile will be determined in CSF and plasma during dose escalation and expansion cohort. Preliminary IT anti-tumor activity will be determined by radiological response assessed by brain MRI using RECIST 1.1 criteria; biological response, accessed by CSF cytology; time to neurological progression, assessed with EORTC QOL QLCQ- 30 and time to progression via Kaplan-Meier curves. This study will be the first to determine the recommended dose for IT in HER2 positive parenchymal bMBC and may support development of future phase II/III clinical trials. Disclosure: All authors have declared no conflicts of interest.

A phase II study of whole brain radiotherapy with simultaneous integrated boost using volumetric modulated arc therapy for 1 to 10 brain metastases.

2078 Background: Local control of brain metastases reduces risk of death from intracranial progression and improves survival in selected patients. Volumetric modulated arc therapy can deliver a fra...

EP-1834: Correlation between BED and local control of brain metastases post stereotactic radiotherapy

EP-1834: Correlation between BED and local control of brain metastases post stereotactic radiotherapy

Linac-Based SRS Dose–Volume Relationship for Optimal Local Control of Brain Metastases

Linac-Based SRS Dose–Volume Relationship for Optimal Local Control of Brain Metastases

Efficacy of erlotinib plus concurrent whole-brain radiation therapy for patients with brain metastases from non-small cell lung cancer.

Treatment and control of brain metastases are important in patients with non-small cell lung cancer (NSCLC). Whole brain radiation therapy (WBRT) has a major role in the management of brain metastasis. Recently, efficacy erlotinib plus concurrent WBRT for patients with brain metastases from NSCLC was reported. Herein, we discussed the results and commented the clinical matters in future.

Incidence of brain metastases in HER2+ gastric or esogastric junction adenocarcinoma.

126 Background: HER2 overexpression is associated with a high risk for brain metastases in breast cancer. We aimed to study if the same correlation exists in gastric or oesogastric junction (OGJ) adenocarcinoma, where brain metastases are uncommon. Methods: We retrospectively reviewed data of patients treated at our institution for metastatic gastric or OGJ adenocarcinoma. We compared incidences with a Fisher’s exact test. Survival was analyzed by the Kaplan-Meier method. Results: Between 2007 and 2011, 74 patients were treated at our institution, 63 patients were analyzed for HER2 status. Median age was 62 (range: 22-81). There were 52 men (82.5%) and 11 women (17.5%). 36 patients (57.1%) had gastric cancer, 27 (42.9%) OGJ adenocarcinoma. After a median follow-up of 9.4 months, 52 patients progressed and 38 patients died. Median progression-free survival was 5.3 months and median overall survival was 15.9 months. 38 patients (60.3%) had hepatic metastases, 32 (50.8%) lymph node metastases, 20 (31.7%) peritoneal carcinomatosis, 12 (19.0%) lung metastases and 3 (4.8%) brain metastases. HER2 was overexpressed in 11 (17.5%) patients (confirmed by IHC in 58 patients, by FISH in 5 patients). Two HER2+ patients did not received trastuzumab. Three HER2+ patients (27.3%) had brain metastases, as compared with 0 (0%) HER2- patients (p=0.004). Control of brain metastases was obtained in all 3 patients with multimodal treatment (surgery for 1 patient, radiotherapy for 3 patients and trastuzumab-containing chemotherapy in 3 patients). Progression-Free Survival (PFS) was significantly higher in HER2+ patients treated with trastuzumab than in HER2- patients: median 9.4 months vs 5.0 months (p=0.049). There was no apparent difference in PFS or overall survival between patients with or without brain metastases, but the numbers are too small to conclude. Conclusions: In this retrospective single-center series, we showed an increased incidence of brain metastases in patients with HER2+ gastric or OGJ adenocarcinoma. Patients with brain metastases benefited from multimodal treatment. Prognosis of HER2+ patients treated with trastuzumab seems better than HER2- patients. These results need confirmation in a multicenter study.

Radiosurgery alone can achieve local control of brain metastases

Radiosurgery alone can achieve local control of brain metastases

Neurocognitive function impairment after whole brain radiotherapy for brain metastases: actual assessment

Whole brain radiation therapy (WBRT) is an effective treatment in brain metastases and, when combined with local treatments such as surgery and stereotactic radiosurgery, gives the best brain control. Nonetheless, WBRT is often omitted after local treatment due to its potential late neurocognitive effects. Publications on radiation-induced neurotoxicity have used different assessment methods, time to assessment, and definition of impairment, thus making it difficult to accurately assess the rate and magnitude of the neurocognitive decline that can be expected. In this context, and to help therapeutic decision making, we have conducted this literature review, with the aim of providing an average incidence, magnitude and time to occurrence of radio-induced neurocognitive decline. We reviewed all English language published articles on neurocognitive effects of WBRT for newly diagnosed brain metastases or with a preventive goal in adult patients, with any methodology (MMSE, battery of neurcognitive tests) with which baseline status was provided. We concluded that neurocognitive decline is predominant at 4 months, strongly dependant on brain metastases control, partially solved at later time, graded 1 on a SOMA-LENT scale (only 8% of grade 2 and more), insufficiently assessed in long-term survivors, thus justifying all efforts to reduce it through irradiation modulation.

Do patients with a limited number of brain metastases need whole-brain radiotherapy in addition to radiosurgery?

About 40% of patients with brain metastases have a very limited number of lesions and may be candidates for radiosurgery. Radiosurgery alone is superior to whole-brain radiotherapy (WBRT) alone for control of treated and new brain metastases. In patients with a good performance status, radiosurgery also resulted in better survival. However, the question is whether the results of radiosurgery alone can be further improved with additional WBRT. Information for this review was compiled by searching the PubMed and MEDLINE databases. Very important published meeting abstracts were also considered. Based on both retrospective and prospective studies, the addition of WBRT to radiosurgery improved control of treated and new brain metastases but not survival. However, because a recurrence within the brain has a negative impact on neurocognitive function, it is important to achieve long-term control of brain metastases. The addition of WBRT provides significant benefits. Further randomized studies including adequate assessment of neurocognitive function and a follow-up period of at least 2years are needed to help customize the treatment for individual patients.