Diagnosis Of Intracranial Metastases Research Articles

P16.07.B PROSPECTIVE DOUBLE ARM PHASE 2 RANDOMIZED TRIAL FOR PATIENTS WITH MULTIPLE BRAIN METASTASIS AND/OR LEPTOMENINGEAL CARCINOMATOSIS: COMPARISON OF WHOLE BRAIN RADIATION THERAPY (WBRT) ALONE AND WBRT PLUS SILIBININ

Abstract BACKGROUND Occurrence of brain metastases (BMs) is increasing given availability of Magnetic Resonance Imaging (MRI) able to detect also small brain lesions, and most effective systemic therapy able to better control extra-cranial disease. Estimated 20% of patients with cancer will develop BMs. In case of limited brain metastases, radiosurgery or hypofractionated radiosurgery is treatment of choice. A subgroup of patients characterized by extensive brain disease and/or leptomeningeal carcinomatosis can require whole brain radiotherapy (WBRT). Since the 1950s, WBRT has been the most treatment used for patients with multiple BMs, given its effectiveness in palliation, widespread availability, and ease to deliver. However, the median overall survival (OS) recorded is restricted to 3 months, on the average. A better understanding of molecular and cellular mechanisms underlying brain metastasis might be expected to lead of improvements in overall survival. Recent studies demonstrated that active signal transducer and activator of transcription 3 (STAT3) in reactive astrocytes correlates with reduced survival from diagnosis of intracranial metastases. Blocking STAT3 signaling in reactive astrocytes reduces experimental brain metastasis, even at advanced stages of colonization. Silibinin is a natural polyphenolic flavonoid isolated from seed extracts of herb milk thistle. It has been shown to impair STAT3 activation, and in preclinical studies, show an anticancer effects in vitro and in vivo. Based on this background, we designed a double arm phase 2 randomized trial evaluating the benefit of Silibinin associated to WBRT respect to WBRT alone. Primary endpoint is OS, secondary endpoints are toxicity in term of corticosteroid therapy use, brain failure (BF) and progression free survival (PFS). MATERIAL AND METHODS Forty-four patients will be enrolled in two years. Patients with histological or cytological confirmation of solid tumor malignancy, clinical indication for WBRT and Karnofsky performance status (KPS) ≥60 will be enrolled. In arm A experimental, WBRT is concomitant to Silibinin, in arm B control, WBRT alone will be administered. In both arms, total dose of radiotherapy is 30 Gy in 10 fractions. Quality of life and use of corticosteroids will be evaluated first, last day of RT, and during follow-up. Outcome will be evaluated by MRI or CT at 2 months after RT, and every 3 months thereafter. RESULTS From March 2023, 6 patients were enrolled, 2 patients in Arm A and 4 in arm B. Primary histology was breast cancer in 3 patients and non small cell lung cancer in 3. In arm A, 1 patients dismissed RT for worsening of general conditions related to rapid lung progression. CONCLUSION WBRT with or without Silibinin was well tolerated, no acute toxicities or increase of corticosteroids were observed.

Survival outcomes and predicting intracranial metastasis in stage III non-small cell lung cancer treated with definitive chemoradiation: Real-world data from a tertiary cancer center

Purpose/ObjectiveAround 30% of patients with non-small cell lung cancers (NSCLC) are diagnosed with stage III disease at presentation, of which about 50% are treated with definitive chemoradiation (CRT). Around 65–80% of patients will eventually develop intracranial metastases (IM), though associated risk factors are not clearly described. We report survival outcomes and risk factors for development of IM in a cohort of patients with stage III NSCLC treated with CRT at a tertiary cancer center. Materials/MethodsWe identified 195 patients with stage III NSCLC treated with CRT from January 2010 to May 2021. Multivariable logistic regression was used to generate odds ratios for covariates associated with development of IM. Kaplan-Meier analysis with the Log Rank test was used for unadjusted time-to-event analyses. P-value for statistical significance was set at < 0.05 with a two-sided test. ResultsOut of 195 patients, 108 (55.4%) had stage IIIA disease and 103 (52.8%) had adenocarcinoma histology. The median age and follow-up (in months) was 67 (IQR 60–74) and 21 (IQR 12–43), respectively. The dose of radiation was 60 Gy in 30 fractions for148 patients (75.9%). Of the 77 patients who received treatment since immunotherapy was available and standard at our cancer center, 45 (58.4%) received at least one cycle. During follow-up, 84 patients (43.1%) developed any metastasis, and 33 (16.9%) developed IM (either alone or with extracranial metastasis). 150 patients (76.9%) experienced a treatment delay (interval between diagnosis and treatment > 4 weeks). Factors associated with developing any metastasis included higher overall stage at diagnosis (p = 0.013) and higher prescribed dose (p = 0.022). Factors associated with developing IM included higher ratio of involved over sampled lymph nodes (p = 0.001) and receipt of pre-CRT systemic or radiotherapy for any reason (p = 0.034). On multivariate logistical regression, treatment delay (OR 3.9, p = 0.036) and overall stage at diagnosis (IIIA vs. IIIB/IIIC) (OR 2.8, p = 0.02) predicted development of IM. These findings were sustained on sensitivity analysis using different delay intervals. Median OS was not reached for the overall cohort, and was 43.1 months for patients with IM and 40.3 months in those with extracranial-only metastasis (p = 0.968). In patients with any metastasis, median OS was longer (p = 0.003) for those who experienced a treatment delay (48.4 months) compared to those that did not (12.2 months), likely due to expedited diagnosis and treatment in patients with a higher symptom burden secondary to more advanced disease. ConclusionsIn patients with stage III NSCLC treated with definitive CRT, the risk of IM appears to increase with overall stage at diagnosis and, importantly, may be associated with experiencing a treatment delay (> 4 weeks). Metastatic disease of any kind remains the primary life-limiting prognostic factor in these patients with advanced lung cancer. In patients with metastatic disease, treatment delay was associated with better survival. Patients who experience a treatment delay and those initially diagnosed at a more advanced overall stage may warrant more frequent surveillance for early diagnosis and treatment of IM. Healthcare system stakeholders should strive to mitigate treatment delay in patients with locally NSCLC to reduce the risk of IM. Further research is needed to better understand factors associated with survival, treatment delay, and the development of IM after CRT in the immunotherapy era.

Cranial Radiotherapy for Prostate Cancer Patients With Brain Metastases Inaccessible to Stereotactic Radiotherapy.

To evaluate patients and treatment characteristics as well as clinical outcome in patients with intracranial metastases from prostate cancer (PCA) treated with palliative radiotherapy. Fifteen patients treated for intracranial metastases of PCA were identified. The median age of patients was 69 years. 80% of patients received whole brain radiotherapy and 20% received partial brain radiotherapy. Clinical outcome was assessed. Univariate analysis was performed to analyze the impact of patient specific parameters on survival. There was no >G2 acute or any late toxicity. Median time from the first diagnosis of PCA to first diagnosis of intracranial metastases was 62 months (range=15-160 months). Median survival from first diagnosis of intracranial metastases was 14 weeks (range=0-126 weeks) and 6 weeks (range=0-47 weeks) from the start of radiotherapy. In univariate analysis, survival was significantly better for patients with an Eastern Cooperative Oncology Group (ECOG) performance status 1 compared to ECOG 2-3 [18 weeks (range=5-47 weeks) vs. 3 weeks (range=0-21 weeks), p=0.030] and Recursive Partitioning Analysis (RPA) class 2 compared to RPA class 3 [18 weeks (range=5-47 weeks) vs. 6 weeks (range=0-21 weeks), p=0.045]. Overall survival of the patients with wide-spread intracranial metastases from PCA was poor. The decision for a radiotherapy should be done on individual patient basis.

Intracranial Metastases Tend to Be Overt and Predict Poor Prognosis in Children With Neuroblastoma.

Background: Neuroblastoma (NB) is the most common pediatric extracranial solid neoplasm after leukemia. Intracranial metastases (IM) rarely occur in patients with NB. The present study aimed to review the clinical characteristics of NB patients from a single center presenting with IM.Methods: Two hundred children (aged 3–91 months) with NB admitted to the Fourth Affiliated Hospital of China Medical University between January 2009 and December 2015 were enrolled, and their clinical characteristics were recorded. The patients were divided into two groups based on the presence of IM. Their clinical characteristics, including demographics, clinical features, and laboratory and imaging studies, were retrospectively analyzed.Results: IM occurred in 22 of 200 (11%) neuroblastoma patients, with a median age of 42.5 months (range, 3–91 months), with a male-to-female ratio of 1.4:1. Seven patients had IM at the initial diagnosis. Among the 15 children who did not have IM at initial presentation, the median interval from presentation to the diagnosis of IM was 17.3 months (range, 1–55 months). Compared with the control group, NB patients with IM tended to be asymptomatic at the time of NB diagnosis, which was made incidentally during routine physical examination (5 of 22, 22.7%, p < 0.05). In addition, this group had more primary intra-abdominal sites (18 of 22, 81.8%, p < 0.001) and worse prognosis (5 of 22, 22.7%, p < 0.05).Conclusions: NB patients with IM have insidious onset in the early stage and a lower survival rate, especially patients with primary intra-abdominal lesions. Regular neurological monitoring could improve the rate of early diagnosis and prognosis of NB children with IM. Familiarity with the characteristic findings of NB with IM is necessary to avoid misdiagnosis and initiate necessary interventions.

Combined Immunotherapy and Stereotactic Radiotherapy Improves Neurologic Outcomes in Patients with Non–small-cell Lung Cancer Brain Metastases

BackgroundThe purpose of this study was to compare the outcomes of patients with non-small cell lung cancer (NSCLC) brain metastases treated with stereotactic radiotherapy (SRT) alone versus SRT and immune checkpoint inhibitors (ICIs). Patients and MethodsPatients treated for their first diagnosis of intracranial metastases with SRT or SRT plus ICI were retrospectively identified. Overall survival (OS), local control (LC), distant brain failure (DBF), neurologic death, and rates of radiation necrosis were calculated. Univariate (UVA) and multivariable (MVA) analyses with competing risk analysis were performed. ResultsSeventy-seven patients with 132 lesions were analyzed, including 44 patients with 68 lesions in the SRT group and 33 patients with 64 lesions in the SRT plus ICI group. There were no differences in baseline factors between groups. Use of ICI predicted for decreased DBF (hazard ratio [HR], 0.45; 95% confidence interval [CI], 0.24-0.84; P = .01), decreased rates of neurologic death (HR, 0.29; 95% CI, 0.10-0.85; P = .02), and better OS (HR, 0.46; 95% CI, 0.23-0.91; P = .03). Two-year LC was 97% for the SRT + ICI group, and 86% for the SRT-alone group (P = .046). Actuarial 2-year DBF was 39% for the SRT + ICI group and 66% for the SRT alone group (P = .016). On MVA, ICI use persisted in predicting lower incidence of neurologic death (HR, 0.25; 95% CI, 0.09-0.72; P = .01) and DBF (HR, 0.47; 95% CI, 0.25-0.85; P = .01) when adjusted for competing risk of death. ConclusionIn this cohort of patients with NSCLC brain metastases, ICI use combined with SRT predicted for improved LC and OS and decreased DBF and risk of neurologic death.

STAT3 labels a subpopulation of reactive astrocytes required for brain metastasis

The brain microenvironment imposes a particularly intense selective pressure on metastasis-initiating cells, but successful metastases bypass this control through mechanisms that are poorly understood. Reactive astrocytes are key components of this microenvironment that confine brain metastasis without infiltrating the lesion. Here, we describe that brain metastatic cells induce and maintain the co-option of a pro-metastatic program driven by signal transducer and activator of transcription 3 (STAT3) in a subpopulation of reactive astrocytes surrounding metastatic lesions. These reactive astrocytes benefit metastatic cells by their modulatory effect on the innate and acquired immune system. In patients, active STAT3 in reactive astrocytes correlates with reduced survival from diagnosis of intracranial metastases. Blocking STAT3 signaling in reactive astrocytes reduces experimental brain metastasis from different primary tumor sources, even at advanced stages of colonization. We also show that a safe and orally bioavailable treatment that inhibits STAT3 exhibits significant antitumor effects in patients with advanced systemic disease that included brain metastasis. Responses to this therapy were notable in the central nervous system, where several complete responses were achieved. Given that brain metastasis causes substantial morbidity and mortality, our results identify a novel treatment for increasing survival in patients with secondary brain tumors.

Chapter 5 - Metastatic diseases of the central nervous system – neuropathologic aspects

A large percentage of patients with cancer will develop brain metastases, and many of them will die within a few months following diagnosis of intracranial metastasis. Although the majority of the central nervous system metastases are derived from a well-known primary neoplasm, about 5-10% of brain metastases are from an unknown source, making the tissue diagnosis a first step in the search for a primary malignancy. The pathologist utilizes several immunohistochemical and molecular diagnostic tools for such investigation, helping the clinical oncologist to narrow down the clinical and radiologic exploration. Recently, analysis of actionable biomarkers for target therapy in brain metastasis has become significant due to reports of discrepancy of potential biomarkers between primary tumors and metastatic brain deposits.

Clinical characteristics and follow-up of intracranial metastases from thyroid cancer.

Intracranial metastasis from thyroid cancer is extremely rare. However, less is known about the risk factors for intracranial metastasis and its treatment from few retrospective studies. The aim of this study was to contribute to the understanding of this disease by analyzing patients with intracranial metastases from thyroid cancer. Between 2001 and 2014, the database of the National Cancer Center of Korea was searched for thyroid cancer patients. The clinical characteristics and site of distant metastasis according to the histological type were evaluated in the thyroid cancer cohort. Among the patients with intracranial metastases, the characteristics, histological type of primary cancer and metastatic brain tumor, additional synchronous or previous distant metastasis, treatment modalities, locations and characteristics on radiologic findings, time interval between the first diagnosis of the primary thyroid cancer and brain metastasis, thyroglobulin level at the first detection of intracranial metastasis and survival were reviewed. A total of 10 (0.032 %) out of 3,090 thyroid cancer patients in the National Cancer Center database were identified as having intracranial metastases. The histological types of the primary thyroid cancers were papillary for six patients, follicular for three, and poorly differentiated carcinoma for one. Six of these ten patients underwent surgical resection for intracranial lesions. Whole-brain radiotherapy or tyrosine kinase inhibitors were applied to the patients as postoperative adjuvant treatment, and stereotactic radiosurgery was considered for recurrent or surgically inoperable lesions. The overall median survival time was 33 months (range, 0.5-78 months) after diagnosis of intracranial metastasis. Surgical resection and adjuvant treatments in the contemporary era seem to result in improved survival after intracranial metastases compared with what has been reported in past studies. Considering the grave course of intracranial metastasis, the early detection and aggressive treatment of patients with a good performance status are crucial.

Impact of Triple-Negative Phenotype on Prognosis of Patients With Breast Cancer Brain Metastases

To elucidate survival times and identify potential prognostic factors in patients with triple-negative (TN) phenotype who harbored brain metastases arising from breast cancer and who underwent stereotactic radiosurgery (SRS). A total of 103 breast cancer patients with brain metastases were treated with SRS and then studied retrospectively. Twenty-four patients (23.3%) were TN. Survival times were estimated using the Kaplan-Meier method, with a log-rank test computing the survival time difference between groups. Univariate and multivariate analyses to predict potential prognostic factors were performed using a Cox proportional hazard regression model. The presence of TN phenotype was associated with worse survival times, including overall survival after the diagnosis of primary breast cancer (43 months vs. 82 months), neurologic survival after the diagnosis of intracranial metastases, and radiosurgical survival after SRS, with median survival times being 13 months vs. 25 months and 6 months vs. 16 months, respectively (p < 0.002 in all three comparisons). On multivariate analysis, radiosurgical survival benefit was associated with non-TN status and lower recursive partitioning analysis class at the initial SRS. The TN phenotype represents a significant adverse prognostic factor with respect to overall survival, neurologic survival, and radiosurgical survival in breast cancer patients with intracranial metastasis. Recursive partitioning analysis class also served as an important and independent prognostic factor.

Gamma Knife Radiosurgery as a Therapeutic Strategy for Intracranial Sarcomatous Metastases

To determine the indication and outcomes for Gamma Knife stereotactic radiosurgery (GKSRS) in the care of patients with intracranial sarcomatous metastases. Data from 21 patients who underwent radiosurgery for 60 sarcomatous intracranial metastases (54 parenchymal and 6 dural-based) were studied. Nine patients had radiosurgery for solitary tumors and 12 for multiple tumors. The primary pathology was metastatic leiomyosarcoma (4 patients), osteosarcoma (3 patients), soft-tissue sarcoma (5 patients), chondrosarcoma (2 patients), alveolar soft part sarcoma (2 patients), and rhabdomyosarcoma, Ewing's sarcoma, liposarcoma, neurofibrosarcoma, and synovial sarcoma (1 patient each). Twenty patients received multimodality management for their primary tumor, and 1 patient had no evidence of systemic disease. The mean tumor volume was 6.2 cm(3) (range, 0.07-40.9 cm(3)), and a median margin dose of 16 Gy was administered. Three patients had progressive intracranial disease despite fractionated whole-brain radiotherapy before SRS. A local tumor control rate of 88% was achieved (including patients receiving boost, up-front, and salvage SRS). New remote brain metastases developed in 7 patients (33%). The median survival after diagnosis of intracranial metastasis was 16 months, and the 1-year survival rate was 61%. Gamma Knife radiosurgery was a well-tolerated and initially effective therapy in the management of patients with sarcomatous intracranial metastases. However, many patients, including those who also received fractionated whole-brain radiotherapy, developed progressive new brain disease.

Prognostic evaluation of intracranial metastasis in malignant melanoma.

Malignant melanoma (MM) is often reported as the third most common cause of intracranial metastasis (IM) after carcinoma of the breast and lung. Most patients with advanced MM will have widespread extracranial disease, but the majority will die from intracerebral spread. A retrospective review of 117 patients with documented IM from MM over the past 25 years was undertaken. Various factors (including age, race, sex distribution, primary lesions with Clark's level, Breslow's thickness, primary sites and staging at initial presentation, diagnosis of IM and its various treatment methods, survival data, and autopsy findings) were analyzed. Prognostic indicators were clarified from this analysis as a predictor of central nervous system (CNS) metastasis. An ideal treatment plan was also analyzed in order to predict a better survival. Fifty-eight percent of patients were male; 42% were female. Seventy-one percent of the primary lesions were of Clark's level IV and V, with mean Breslow's thickness of 3.5 mm. Median time interval between the initial diagnosis and development of IM was 3.5 years. Complete surgical resection of the intracranial lesion in the brain resulted in the longest mean survival of 10.3 months, whereas mean survival for the group with no treatment was only 3 weeks. Patients with primary lesions of the head and neck had the lowest mean survival of 3.3 months, whereas those whose primary sites were unknown had the longest mean survival of 7.5 months. One- and 2-year survival were 9% and 3%, respectively. All but one of the 30 patients at autopsy were found to have visceral metastasis, namely of the lung, liver, and bone. An aggressive search for metastasis should be undertaken in patients at high risk of developing CNS metastasis, e.g., male, head and neck primary, Clark's level IV and V, Breslow's thickness of > 3 mm, and presence of visceral metastases, mainly lung. A complete surgical resection should be attempted whenever possible, with adjunctive use of whole-brain irradiation, along with systemic chemotherapy for further control of recurrence and to prolong survival.