Occult Brain Metastases Research Articles

Botensilimab plus balstilimab in microsatellite stable metastatic colorectal cancer: Assessing efficacy in non-liver metastatic sites.

3556 Background: Botensilimab (BOT) is an Fc-enhanced, multifunctional anti-CTLA-4 antibody with unique mechanisms of action. In microsatellite stable colorectal cancer (MSS CRC), previous I-O combinations have shown poorer responses in metastatic sites of disease outside of the lungs and lymph nodes, even in non-liver metastases (NLM) populations. Here we present updated efficacy data with longer follow-up from an expanded phase 1b study (NCT03860272) in patients with NLM MSS CRC treated with BOT and balstilimab (BAL; anti-PD-1). Methods: As of Nov 29, 2023, 77 patients with NLM MSS CRC (median follow-up 13.0 months [range 0.6–42.6]) with ≥6 months follow-up were included (intention to treat [ITT]; all treated); of these, 70 had ≥1 post-baseline scan (efficacy evaluable [EE]). Patients received BOT 1 or 2 mg/kg every 6 weeks (Q6W) and BAL 3 mg/kg every 2 weeks. Endpoints included RECIST 1.1 confirmed objective response rate (ORR), disease control rate (DCR), duration of response (DOR), and overall survival (OS). Results: Median age was 56 years (range 36–82), 48% male, and median prior lines of therapy was 4 (range 1–10). ORR was 22% (17/77) and DCR was 73% (56/77), with the median DOR not reached (NR; 95% CI 5.7–NR). An additional response confirmed after the data cutoff (18/77; ORR 23%), with 11/18 responses ongoing. Subgroup analyses revealed that BOT and BAL showed comparable activity (ORR 18–33%) across metastatic sites outside of the lungs, including the peritoneum, soft tissue, pleura, and the brain (Table). One responder with an occult brain metastasis experienced pseudoprogression, followed by a complete systemic response to treatment in target lung lesions. No new safety signals were observed and updated safety and translational data will be presented. Conclusions: In summary, for MSS CRC, BOT and BAL is differentiated from previous I-O combinations by producing deep and durable responses even in difficult-to-treat metastatic sites. In NLM patients, responses were observed in 18–33% of sites of disease including the peritoneum, soft tissue, pleura, and the brain. These compelling results support further investigation in the fully enrolled, randomized, global phase 2 trial in MSS CRC (NCT05608044) and a planned global phase 3 trial. Clinical trial information: NCT03860272 . [Table: see text]

A Need for More Molecular Profiling in Brain Metastases.

As local disease control improves, the public health impact of brain metastases (BrM) continues to grow. Molecular features are frequently different between primary and metastatic tumors as a result of clonal evolution during neoplasm migration, selective pressures imposed by systemic treatments, and differences in the local microenvironment. However, biomarker information in BrM is not routinely obtained despite emerging evidence of its clinical value. We review evidence of discordance in clinically actionable biomarkers between primary tumors, extracranial metastases, and BrM. Although BrM biopsy/resection imposes clinical risks, these risks must be weighed against the potential benefits of assessing biomarkers in BrM. First, new treatment targets unique to a patient’s BrM may be identified. Second, as BrM may occur late in a patient’s disease course, resistance to initial targeted therapies and/or loss of previously identified biomarkers can occur by the time of occult BrM, rendering initial and other targeted therapies ineffective. Thus, current biomarker data can inform real-time treatment options. Third, biomarker information in BrM may provide useful prognostic information for patients. Appreciating the importance of biomarker analyses in BrM tissue, including how it may identify specific drivers of BrM, is critical for the development of more effective treatment strategies to improve outcomes for this growing patient population.

Prognosis of Incidental Brain Metastases in Patients With Advanced Renal Cell Carcinoma.

Metastatic renal cell carcinoma (mRCC) management guidelines recommend brain imaging if clinically indicated and the rate of occult central nervous system (CNS) metastasis is not well-defined. Early detection could have major therapeutic implications, because timely interventions may limit morbidity and mortality. A retrospective review was performed to characterize patients with mRCC incidentally diagnosed with asymptomatic brain metastases during screening for clinical trial participation at Gustave Roussy and Memorial Sloan Kettering Cancer Center. Descriptive statistics and time-to-event methods were used to evaluate the cohort. Across 68 clinical trials conducted between 2001 and 2019 with a median 14.1-month follow-up, 72 of 1,689 patients (4.3%) with mRCC harbored occult brain metastases. The International Metastatic RCC Database Consortium (IMDC) risk status was favorable (26%), intermediate (61%), and poor (13%), and 86% of patients had ≥2 extracranial sites of disease, including lung metastases in 92% of patients. CNS involvement was multifocal in 38.5% of patients, and the largest brain metastasis was >1 cm in diameter in 40% of the cohort. Localized brain-directed therapy was pursued in 93% of patients, predominantly radiotherapy. Median overall survival was 10.3 months (range, 7.0-17.9 months), and the 1-year overall survival probability was 48% (95% CI, 37%-62%). IMDC risk and number or size of lesions did not correlate with survival (log-rank, P=.3, P=.25, and P=.067, respectively). This large multi-institutional mRCC cohort study identified occult brain metastasis in a notable proportion of patients (4.3%) and highlights that the risk of asymptomatic CNS involvement extends to those with favorable risk features per IMDC risk assessment. These data provide rationale for brain screening in patients with advanced RCC.

Overuse of Diagnostic Brain Imaging Among Patients With Stage IA Non-Small Cell Lung Cancer.

Among patients diagnosed with stage IA non-small cell lung cancer (NSCLC), the incidence of occult brain metastasis is low, and several professional societies recommend against brain imaging for staging purposes. The goal of this study was to characterize the use of brain imaging among Medicare patients diagnosed with stage IA NSCLC. Using data from linked SEER-Medicare claims, we identified patients diagnosed with AJCC 8th edition stage IA NSCLC in 2004 through 2013. Patients were classified as having received brain imaging if they underwent head CT or brain MRI from 1 month before to 3 months after diagnosis. We identified factors associated with receipt of brain imaging using multivariable logistic regression. Among 13,809 patients with stage IA NSCLC, 3,417 (25%) underwent brain imaging at time of diagnosis. The rate of brain imaging increased over time, from 23.5% in 2004 to 28.7% in 2013 (P=.0006). There was significant variation in the use of brain imaging across hospital service areas, with rates ranging from 0% to 64.0%. Factors associated with a greater likelihood of brain imaging included older age (odds ratios [ORs] of 1.16 for 70-74 years, 1.13 for 75-79 years, 1.31 for 80-84 years, and 1.46 for ≥85 years compared with 65-69 years; all P<.05), female sex (OR, 1.09; P<.05), black race (OR 1.23; P<.05), larger tumor size (ORs of 1.23 for 11-20 mm and 1.28 for 21-30 mm tumors vs 1-10 mm tumors; all P<.05), and higher modified Charlson-Deyo comorbidity score (OR, 1.28 for score >1 vs score of 0; P<.05). Roughly 1 in 4 patients with stage IA NSCLC received brain imaging at the time of diagnosis despite national recommendations against the practice. Although several patient factors are associated with receipt of brain imaging, there is significant geographic variation across the United States. Closer adherence to clinical guidelines is likely to result in more cost-effective care.

1826 74-Year-Old Man With Esophageal Adenocarcinoma and Right Sided Weakness: Is Brain Involved?

INTRODUCTION: Esophageal cancer with an incidence of 4.3 per 100,000 per year and a death rate of 4.0 per 100,000 per year accounts for about 1% of all cancers diagnosed in the US. Within the past four decades, while the incidence of esophageal cancer has remained stable in the US, an increasing trend for the adenocarcinoma form has been observed in men mainly due to increased obesity and gastroesophageal reflux disorders. Remarkably, Hispanic-Americans have a lower rate of esophageal cancer. Brain metastasis from esophageal cancer is an extremely rare condition with an incidence of 0.6-1.5%. Here we report a Hispanic-American white patient with brain metastasis from esophageal adenocarcinoma. CASE DESCRIPTION/METHODS: 74-year-old Hispanic man with history of esophageal adenocarcinoma status post chemo-radiation with resection and gastric pull-through was referred to our hospital 4 years after surgery due to progressive left upper and lower extremity weakness, left facial droop and slurred speech for almost a month. He denied any prior history of headache, trauma, weakness or falls. Brain MRI showed a 61.6 x 47.3 x 45.0 mm heterogeneous/enhancing/intra-axial tumor projected at the level of the right supramarginal gyrus, and another smaller 9 mm intra-axial enhancing lesion in the medial aspect of the right superior temporal gyrus associated with perilesional vasogenic edema and 12 mm right to left midline shift (Figure 1). CT thorax, abdomen and pelvis did not reveal any mass or lymphadenopathy. The patient underwent a right-sided temporal craniotomy for resection of the temporal hemorrhagic tumor with a moderately hard capsule and significant fibrous adhesions invading the M2 branch of the middle cerebral artery with a small rim of tumor left along the back of the middle cerebral artery. He was scheduled for Whole Brain Radiation Therapy (WBRT) showing an improvement in his muscular strength. Pathology report demonstrated metastatic brain adenocarcinoma from the esophagus (Figure 1). DISCUSSION: Brain metastasis is a rare condition which should be suspected in patients with esophageal cancer and neurological manifestations. Routine preoperative neuroimaging is not recommended for identification of occult brain metastasis in esophageal cancer rather than in those with a primary esophageal tumor of &gt;8 cm in diameter. Prognosis of this condition is overall poor and treatment should be personalized based on the patient’ general condition. When brain mass is resectable, surgery followed by WBRT is recommended.

Rates of occult brain metastases in patients (pts) with advanced renal cell carcinoma (RCC): A cohort study from patients treated across 22 clinical trials.

673 Background: National guidelines for RCC management only recommend brain imaging ‘if clinically indicated’; the rate of occult brain metastases is not defined. Early detection of CNS disease has major implications as it typically triggers early intervention with the aim to limit morbidity, including major complications of local progression. In an effort to define the utility of brain screening, we investigated the rate of occult brain metastasis in a large cohort of metastatic RCC pts. Methods: We performed a retrospective review of completed and actively accruing metastatic RCC clinical trials conducted at Memorial Sloan Kettering Cancer Center. Individual charts of pts screening for those studies with mandatory brain imaging at baseline were reviewed to identify subjects harboring occult brain metastases. We collected patient demographics, International Metastatic Database Consortium (IMDC) risk status, sites of metastatic disease, and tumor histology. Patients with neurologic symptoms were excluded. Descriptive statistics were applied to analyze findings across the cohort. Results: A total of 22 clinical trials for metastatic RCC conducted from 2004-2017 required brain imaging at baseline, and a total of 535 pts were screened in this context. A total of 25/535 pts were found to have occult brain metastasis (4.67%), which was multi-focal in 10/25 (40%) and sub-cm in 15/25 (60%). For these 25 pts, the mean age at diagnosis was 56 years (38-77), and IMDC risk score at enrollment was: 1/24 favorable (4%), 21/24 intermediate (88%), and 2/24 poor-risk (8%) patients. 18/25 patients presented with de novo metastatic disease; 13/25 had received prior therapies; and 24/25 patients (96%) had &gt; 2 additional non-CNS sites of metastatic disease at time of screening. 21/23 pts and 2/23 pts were then treated with radiation and surgical resection, respectively. Conclusions: This retrospective cohort study shows a 5% rate of occult CNS disease in asymptomatic patients with advanced RCC. These findings can inform current screening guidelines for full disease assessment in metastatic RCC patients.

Abstract P6-03-06: Assessing occult brain metastasis with CT scan or MRI in HER2-positive breast cancer patients at initial diagnosis

Abstract Patients (pts) with HER2-positive breast cancer (BC) have a high risk of developing brain metastases (BM) that might be due to longer survival, low diffusion of Trastuzumab (T) in the CNS or an unknown incidence of occult BM at diagnosis. In a series of metastatic BC, occult metastasis was found in 15 % of the patients and Her2 over expression was an independent risk factor 1.In a series of early BC treated with T the cumulative incidence of BM at 12 and 24 months was 0.6 and 2 % respectively 2. Time to BM was 13.7 months in retrospective study 3 . Systematic cranial magnetic resonance imaging (MRI) in the staging of HER2-positive BC pts detected BM in 22 % of asymptomatic, metastatic pts versus 3.6 % in asymptomatic, non-metastatic pts 4. Early detection of BM decreases the cerebral death rate, but do not prolong survival in metastatic pts 4 . Therefore brain imaging is not recommended at diagnosis. However, retrospective trials assessing the incidence of BM in HER2-positive BC were mainly performed during follow up and not at the initial diagnosis. Pts treated for HER2-positive locally BC with adjuvant sequential chemotherapy including anthracycline and taxane associated with T, classified according to classical prognosis factor as histological subtype, TNM, SBR and hormonal receptor (HR), were systematically assessed for occult BM at initial diagnosis with CT scan or MRI. Retrospectively analyzed for the occurrence of BM was performed. Disease free metastatic survival (DFMS) and overall survival (OS) was estimated by Kaplan Meier estimation. Between March 2006 and July 2013 84 pts were included. The median follow up is 4.7 years. The characteristics pts were median age 57 years [30-86], ductal carcinoma 67 pts (93 %), lobular carcinoma 5 pts (7%), pT1 to 4 respectively 38 (48 %), 28 (36 %), 3 (4%), 9 pts (12%), pN 0 to 3 respectively 44 (54%), 27 (33%), 5 (6%), 5 pts (6%), SBR 1 to 3 respectively 1 (1%), 35 (43%), 43 pts (54%), RO positive 47 pts (59 %), RP positive 27 pts (63%). Thirty eight pts (45 %) had brain imaging at diagnosis or within 5 months of diagnosis. Only one pt with a pT4, pN2, ductal carcinoma, RO+, RP-, SBR 2 presented with BM (2.6 %) at initial diagnosis, with simultaneous lung, liver, bone and nodes metastasis. Four pts (4.8 %) presented BM during follow up, among those two symptomatic pts (2.4 %) as the only site of recurrence at 21 and 28 months. Median DFMS was 8.5 years and median OS was 16.7 years. This is the first report of systemic imaging at initial diagnosis of HER2 positive locally BC pts. The results did not support initial brain imaging in this subset of pts. Only pts with symptoms seems to benefit from brain imaging. Further prospective study should be launched to confirm this observation. Citation Format: Delbaldo C, Sarrade T, Brieau B, Billemont B, Denis J, Cojean-Zelek I, Bornier C, Vincens E. Assessing occult brain metastasis with CT scan or MRI in HER2-positive breast cancer patients at initial diagnosis [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr P6-03-06.

Phase I Pharmacokinetic and Pharmacodynamic Study of Pazopanib in Children With Soft Tissue Sarcoma and Other Refractory Solid Tumors: A Children's Oncology Group Phase I Consortium Report

Pazopanib, an oral multikinase angiogenesis inhibitor, prolongs progression-free survival in adults with soft tissue sarcoma (STS). A phase I pharmacokinetic and pharmacodynamic study of two formulations of pazopanib was performed in children with STS or other refractory solid tumors. Pazopanib (tablet formulation) was administered once daily in 28-day cycles at four dose levels (275 to 600 mg/m(2)) using the rolling-six design. Dose determination for a powder suspension was initiated at 50% of the maximum-tolerated dose (MTD) for the intact tablet. Ten patients with STS underwent dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) scanning at baseline and 15 ± 2 days after initiation of pazopanib at the tablet MTD. Fifty-three patients were enrolled; 51 were eligible (26 males; median age, 12.9 years; range, 3.8 to 23.9 years). Hematologic and nonhematologic toxicities were generally mild, with dose-limiting lipase, amylase, and ALT elevation, proteinuria, and hypertension. One patient with occult brain metastasis had grade 4 intracranial hemorrhage. The MTD was 450 mg/m(2) for tablet and 160 mg/m(2) for suspension. Steady-state trough concentrations were reached by day 15 and did not seem to be dose dependent. One patient each with hepatoblastoma or desmoplastic small round cell tumor achieved a partial response; eight patients had stable disease for ≥ six cycles, seven of whom had sarcoma. All patients with evaluable DCE-MRI (n = 8) experienced decreases in tumor blood volume and permeability (P < .01). Placental growth factor increased, whereas endoglin and soluble vascular endothelial growth factor receptor-2 decreased (P < .01; n = 41). Pazopanib is well tolerated in children, with evidence of antiangiogenic effect and potential clinical benefit in pediatric sarcoma.

Cranial Magnetic Resonance Imaging in the Staging of HER2-positive Breast Cancer Patients

Aim: The aim of the current study was to evaluate whether early detection of brain metastases (BMs) could improve survival outcomes in human epidermal growth factor receptor 2 (HER2)-positive breast cancer patients. Material and Methods: HER2-positive breast cancer patients without BMs who had no neurological symptoms within 12 months from diagnosis or relapse time of the disease were included in the study. The patients were distributed into 2 groups: Group 1 comprised patients without metastases; group 2 comprised patients with metastases. The symptomatic historic control group with BMs was defined retrospectively for survival comparisons. Results: 55 (57.3%) and 41 (42.7%) patients were in groups 1 and 2, respectively. 11 of the 96 patients (11.5%) had occult BMs, and 9 of them were in group 2 whereas only 2 patients were in group 1 (22% vs. 3.6%, respectively; p = 0.008). While the median survival times from the first metastasis (28.7 vs. 22.5 months, respectively; p = 0.561) and BM (6.8 vs. 6.1 months, respectively; p = 0.511) were similar, cerebral death was numerically different (16.7% vs. 46.3%; p = 0.221) between asymptomatic (n = 9) and symptomatic patients (n = 53). Conclusions: BMs were detected very rarely in asymptomatic, non-metastatic HER2-positive breast cancer patients compared with asymptomatic, metastatic patients. Furthermore, although early detection of BMs decreases the cerebral death rate, it does not prolong the survival rate in metastatic patients.

Screening for brain metastases in patients with stage III non-small cell lung cancer: Is there additive value of magnetic resonance imaging above a contrast-enhanced computed tomography of the brain?

IntroductionStage III NSCLC patients are candidates for treatment with curative intent. Current guidelines advise post contrast magnetic resonance imaging (MRI) or contrast enhanced computed tomography (CE-CT) of the brain in these patients to exclude brain metastases (BM). In previous small studies MRI was reported to be superior to CE-CT. However, CT and MR technology have evolved and 18F-deoxyglucose-positron-emission-tomography (18FDG-PET) has been implemented in staging of NSCLC. If CE-CT, performed together with 18FDG-PET-CT shows the same yield of BM detection as an additionally performed MRI, substantial gain in time and resources is expected. MethodsAll NSCLC patients who underwent a staging 18FDG-PET-CT between January 2008 and September 2011 were reviewed. Neurological asymptomatic patients with stage III NSCLC who were eligible for treatment with curative intent were selected, without taking into account the results of brain MRI. CT was compared to MRI to investigate whether additional BM were detected on MRI. Development of BM within a year after negative MRI was recorded. Results97/429 NSCLC patients who underwent a PET-CT had stage III disease. Three otherwise stage III patients already had occult BM on CE-CT. 77/97 (79%) patients underwent MRI, 45/77 (58%) CE-CT and 32/77 (42%) LD-CT. In none of the CE-CT, but in 5/32 (16%) LD-CT patients BM were detected on MRI. 9/72 patients (13%) without BM on MRI at diagnosis developed BM within a year. ConclusionsThis retrospective study suggests that there is no additive value of MRI to 18FDG-PET-CT with CE-CT in screening for BM in neurological asymptomatic patients with stage III NSCLC.

387 - Cranial Magnetic Resonance Imaging (MRI) in the Staging of HER2-Positive Breast Cancer Patients

ABSTRACT Purpose The aim of the current study was to evaluate whether early detection of brain metastases could improve survival outcomes in HER2-positive breast cancer patients. Patients and methods HER2-positive breast cancer patients without neurological symptoms within 12 months from current stage of diagnosis were included in the study. The factors affecting the development of brain metastasis in the entire group and the metastatic patients were investigated, respectively. Survival durations after first metastasis and brain metastasis were compared between the asymptomatic and symptomatic patients Results Eleven of the 96 patients (11.5%) had occult brain metastasis. Of whom 9 patients were in the metastatic group, only 2 patients were in the non-metastatic group, (22% vs 3.6%, respectively, p = 0.008). Although median survival durations from first metastasis (27.4 vs 20.2 months, respectively, p = 0.858) and brain metastasis (5.2 vs 4.4 months, respectively, p = 0.710) similar, cerebral death was numerically different (22% vs 46%, p = 0.271) in the asymptomatic and symptomatic patients. Conclusion Present study suggests that routine cranial imaging do not bring any benefit to the non-metastatic HER2-positive breast cancer patients. Furthermore, although early detection of brain metastasis provides reduction in cerebral deaths, it does not prolong survival in metastatic patients. Disclosure All authors have declared no conflicts of interest.

Neuropsychiatric side effects of high-dose IL-2 on patient with advanced melanoma or renal cell carcinoma.

e19030 Background: Treatment of patients with end stage renal cell carcinoma (RCC) or melanoma remains difficult. Immunotherapy with high-dose bolus interleukin (IL-2) is the first biological product clinically approved for the treatment of these cancers. Although effective in 15-20% of patients, high-dose IL-2 treatment has significant neuropsychiatric side effects that mandate treatment cessation. Currently, there is little information available on patients who are prone to these neuro-psychiatric side effects. The main objective was to investigate whether occult brain metastases predispose the patient to developing neuro-psychiatric side effects. Methods: We performed retrospective medical chart reviews of patients who had either RCC or malignant melanoma. Variables considered include patient demographics, cancer type, IL-2 treatment, response to treatment, location of metastasis, prior surgery, prior psychiatric history, and substance abuse. We conducted multivariable log-binomial regression analyses to examine the association between risk factors and neuro-psychiatric side effects. Results: Our study population included 261 cancer patients, among them 54% had melanoma (N=141) and 31% had post neuro-psychiatric disorders (N=81). We found that nicotine abstinence in past smokers (remission) was significantly associated with increased neuro psychiatric side-effects (RR=1.88, P=.015) among melanoma patients, but not RCC patients. The multivariable regression analysis showed that having pre-existing psychiatric disorders was the only factor significantly associated with neuropsychiatric effects (aRR=1.92, P&lt;0.0001), after adjusting for potential confounders. Having brain metastasis, however, was not significantly associated with neuropsychiatric effects (aRR=1.10, P=0.627). Conclusions: Contrary to our original hypothesis, prior psychiatric history was the only significant factor predisposing patients to develop neuro-psychiatric side effects during IL-2 treatment and not occult brain metastases. Future studies with larger patient numbers and longitudinal design will help to refine the findings from this research.

P4-17-03: Incidence Rate of Asymptomatic Brain Metastases in Patients with HER2+ Metastatic Breast Cancer Screened for EGF111438/CEREBEL Study.

Abstract BACKGROUND Brain metastases constitute a major clinical concern occurring in 28–43% of women treated for HER2+ metastatic breast cancer (MBC). The initial diagnosis of Central Nervous System (CNS) lesion is commonly based upon development of neurological symptoms. Data to address incidence of CNS lesions in asymptomatic patients are rare and not generally reported. EGF111438/CEREBEL study requires systematic screening for brain metastases by brain MRI and the ineligible patients due to detection of asymptomatic brain metastases are reported here. METHODS The patients screened for CEREBEL have consented to a multi-centre, open-label Phase III study in subjects with HER2+ metastatic breast cancer who received prior treatment with anthracyclines or taxanes and trastuzumab in the adjuvant or metastatic setting. Eligible subjects must not have any history of CNS metastases (including leptomeningeal involvement) or have evidence of benign or malignant brain tumours and/or clinical evidence of spinal cord metastases at baseline. In order to confirm this, subjects must have negative brain MRI at baseline as confirmed by independent review (IR). All MRI scans of the brain had to be acquired with gadolinium contrast agent (T1 only) and 3mm slice thickness without gaps. The primary endpoint of CEREBEL is the incidence of CNS lesions as first site of relapse. A total of 650 subjects (325 per group) are expected to be randomized between capecitabine + trastuzumab versus capecitabine + lapatinib. RESULTS The study is currently recruiting with 322 patients enrolled as of 15.06.2011. At this date, the total number of patients screened were 492 and 170 of these patients were screen failures. There are 15 patients in screening. The percentage of screen failures due to asymptomatic brain metastases assessed by investigators was 13.5% (23/170). The overall incidence of clinically asymptomatic brain metastases assessed by investigators for this study is 4.7% (23/492). CONCLUSIONS Around 5% of all screened patients (14% of screen failures) in this study who were clinically thought to be free of brain lesions actually had brain metastases verified by brain MRI. We therefore conclude that screening for occult brain metastases by MRI is important for trials with defined CNS endpoints. Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P4-17-03.

Bevacizumab Safety in Patients with Central Nervous System Metastases

Patients with central nervous system (CNS) metastases were excluded from bevacizumab trials following a case of fatal cerebral hemorrhage in a patient with hepatocellular carcinoma in 1997. Safety information for bevacizumab-treated patients with CNS metastases was reviewed to determine whether general exclusion of these patients from bevacizumab treatment is still justified. A retrospective exploratory analysis was conducted using datasets from 13 randomized controlled phase II/III trials (dataset A), two open-label single-arm safety trials (dataset B), and two prospective studies including patients with treated CNS metastases (dataset C). In datasets A and B, known CNS metastasis was an exclusion criterion; patients with CNS metastasis had unrecognized CNS metastases at study entry or developed them during the trial. All reported cerebral hemorrhage grades in patients with CNS metastases were quantified. In dataset A, occult brain metastases were identified in 187 of 8,443 patients (91 in bevacizumab arms and 96 in non-bevacizumab arms). Three bevacizumab-treated patients (3.3%) developed grade 4 cerebral hemorrhage, whereas one control-arm patient (1.0%) developed grade 5 cerebral hemorrhage. In dataset B, 321 of 4,382 patients had initially occult CNS metastases, in whom two grade 1 and one grade 3 cerebral hemorrhage (0.9%) were reported. In 131 patients with treated CNS metastases in dataset C, one bevacizumab-treated patient (0.8%) developed grade 2 cerebral hemorrhage. In this selected population, patients with CNS metastases are at similar risk of developing cerebral hemorrhage, independent of bevacizumab therapy. Consequently, such patients with CNS metastases from advanced/metastatic breast cancer, non-small cell lung carcinoma, and renal and colorectal cancer should not be generally excluded from bevacizumab therapy or clinical trials.

The Effect of Early Detection of Occult Brain Metastases in HER2-Positive Breast Cancer Patients on Survival and Cause of Death

The aim of the study is to evaluate disease-free survival, survival from the detection of brain metastases, overall survival, and cause of death in patients with occult brain metastases (Group I) vs. patients with symptomatic brain metastases (Group II). In 80 HER2-positive breast cancer patients, treated with trastuzumab and cytostatic agents for metastatic disease, magnetic resonance imaging screening of the brain was performed, and in 29 patients (36%) occult brain metastasis was detected (Group I). Whole-brain radiotherapy was delivered to Group I. This first group was compared with 52 patients who had symptomatic brain metastases (Group II) and was treated the same way, at the same clinic, during the same time period. Median disease-free survival was 17 months in Group I and 19.9 months in Group II (p = 0.58). The median time interval between the dissemination of the disease and the detection of occult or symptomatic brain metastases was 9 and 15 months, respectively (p = 0.11). When the brain metastases were detected, the median survival was 9 and 8.78 months, respectively (p = 0.80). The median overall survival was 53 and 51 months, respectively (p = 0.94). In the group with occult brain metastases (Group I) 16% of patients died because of progression within the brain. In the group with symptomatic brain metastases (Group II) the rate of cerebral death was 48% (p = 0.009). Whole-brain radiotherapy of occult brain metastases in HER2-positive breast cancer patients with visceral dissemination produces a three-fold decrease in cerebral deaths but does not prolong survival.

Detection of Occult Brain Metastasis with High Resolution MRI using Double vs. Single Dose Gadolinium

Detection of Occult Brain Metastasis with High Resolution MRI using Double vs. Single Dose Gadolinium

Effect of early detection of occult brain metastases in HER2-positive breast cancer patients on survival

1015 Aim: The aim of the study was to compare disease free survivals (DFS), survivals from the detection of brain metastases, overall survivals (OS) and the causes of death between two patient groups: group I with disseminated HER2-positive breast cancer and occult brain metastases and group II with symptomatic brain metastases. Material and Methods: MRI screening of the brain was performed in 80 HER2-positive breast cancer pts treated with trastuzumab and cytostatics for visceral metastases. In 29 pts (34%) in whom occult brain metastases were detected, whole brain radiotherapy (WBR) to the brain (30 Gy in 10 fractions) was performed (Group I). They were compared with 48 pts with symptomatic brain metastases treated at the same clinic during the same time period (Group II). Both groups were comparable regarding the site of distant metastases and the type of treatment. All pts in both groups had distant metastases to the lung and/or liver. Results: Median DFS in group I was 17 months and in Group II- 19.9 months (p=0.61). Median survival from dissemination of the disease (visceral metastases) to the detection of occult and symptomatic brain metastases was 9 and 15 months, respectively (p=0.21). Median survival calculated from the detection of brain metastases was 9 and 9.3 months, respectively (p=0.76). Median OS of pts with occult and symptomatic brain metastases was 53.8 and 52 months, respectively (p=0.79). In the group with occult brain metastases 15% of pts died because of progression in the brain and in the group of symptomatic brain metastases the rate of cerebral death was 48%. Conclusions: WBR performed during the asymptomatic period decreased the rate of cerebral deaths, but did not prolong overall survival. Screened MRI of the brain during the asymptomatic period did not improve the outcome of pts with HER2-positive breast cancer and with visceral metastases. No significant financial relationships to disclose.

Identification of occult brain metastases amenable to stereotactic radiosurgery by motexafin gadolinium (MGd) based treatment planning MRI: Results of a phase II trial of MGd and whole brain radiotherapy (WBRT) with stereotactic radiosurgery (SRS)

2037 Background: Motexafin gadolinium (MGd) is a novel anti-cancer agent that selectively localizes in tumors and is detectable by MRI. Previous studies of patients (pts) with brain metastases (BM) demonstrated the detection of occult lesions after MGd administration not visible with gadolinium MRI contrast. The purpose of this study was to evaluate if MRI scanning after MGd improves SRS treatment-planning and treatment outcome by identifying and better defining lesions that can be treated with the SRS boost. Methods: Pts with 1–4 BM (&lt; 4 cm diameter, or, if multiple, &lt; 3cm) received WBRT (37.5 Gy) and MGd, 5 mg/kg/day during weeks 2–3 of WBRT, plus MGd, 5 mg/kg prior to treatment planning MRI and prior to SRS (21 Gy for lesions = 2 cm, 18 Gy for lesions 2.1–3.0 cm, and 15 Gy for lesions 3.1–4.0 cm). MRI was obtained within 4 weeks prior to enrollment with standard contrast, and after WBRT for SRS treatment planning with MGd and standard contrast. Patients were followed for neurologic progression and survival. Results: 45 patients with either lung cancer (76%), breast cancer (11%), melanoma (7%), or other cancers (7%), a median age of 58 years (range 42–74), and a median of 2 BM (range 1–4) were evaluable. In 9 of 42 patients (21%) with MRI data available, the MGd-based treatment planning MRI demonstrated at least one occult lesion not visualized on the screening MRI. The MGd-based treatment planning MRI detected 1 occult lesion in 6 pts, 2 occult lesions in 1 patient, and 3 occult lesions in 2 patients. Median survival for evaluable pts is 10 months; median time to neurologic progression or radiologic progresssion is not reached at 15 months. Grade 3+ neurotoxicity was limited to 1 pt with tumor necrosis and 1 pt with motor weakness. Most common Grade 3+ adverse events were pneumonia (9%) and DVT (9%). Conclusions: MGd-based treatment planning MRI for SRS identified occult BM that are amenable to SRS and are undetected with standard gadolinium contrast agents in 21% of the pts enrolled in this phase II trial. Treatment with MGd, WBRT and SRS to all lesions visualized resulted in improved survival and local control compared with historical results. [Table: see text]

Occult brain metastases in her-2-positive breast cancer patients

Development of targeted therapeutic agents in colorectal cancer (CRC) is impeded by the lack of a noninvasive surrogate of drug effect. This pilot study evaluated the ability of immunomagnetic separation to isolate circulating tumor cells (CTCs) and of the fluorescent microscope system and flow cytometry to enumerate and characterize CTCs from patients with metastatic CRC.Fifty patients with metastatic CRC contributed 50 mL of blood at treatment initiation and disease evaluation timepoints. Fresh tumor specimens were obtained from 17 patients for comparison of circulating and in situ tumor cell characteristics. Epithelial cells were magnetically isolated from whole blood targeting the antiepithelial cell adhesion molecule (EpCAM). Circulating tumor cells were defined as EpCAM isolated, cytokeratin positive, nuclear stain positive, and CD45 negative. Total RNA was isolated from EpCAMenriched CTCs and multigene reverse-transcriptase polymerase chain reaction analyses were performed.The median number of CTCs detected by flow cytometry was 2/7.5 mL blood. Mean change in cell count was significantly different for patients with tumor progression versus nonprogression (+6.7 vs. +0.2/7.5 mL; P = 0.001). A correlation was noted between mean fluorescence intensity (flow cytometry) of cytokeratin in CTC and matched tumor specimens (r = 0.79, P = 0.06). Nearly 80% (15 of 19) of samples with ≥ 2 CTCs expressed ≥ 1 epithelial marker gene (CK19, CK20, carcinoembryonic antigen, or epidermal growth factor receptor).Isolating and characterizing CTCs from patients with metastatic CRC is feasible. Change in the CTC number might reflect clinical status, and flow cytometric and gene expression data suggest similarity of circulating and in situ tumor cells. Further evaluation of CTCs for pharmacodynamic and clinical monitoring in patients with CRC is warranted.

Primary Clear Cell Adenocarcinoma of the Fallopian Tube with Brain Metastasis: A Case Report

The first reported case of cerebellar metastasis from primary clear cell adenocarcinoma of the fallopian tube is presented. Initially diagnosed as stage Ia, the patient underwent total abdominal hysterectomy, bilateral salpingo-oophorectomy and omentectomy, followed by cisplatin-based chemotherapy and whole pelvic irradiation. Thirty six months later multiple pulmonary metastases were detected that did not respond to chemotherapy. Later the patient presented with cerebellar metastasis. She received whole brain radiotherapy and steroids. The brain lesion partially responded and the patient's neurologic symptoms improved. Throughout there was no evidence of local recurrence. This case suggests that with the prolonged survival achieved by aggressive treatment occult brain metastases might become apparent.