Brain Metastases Of Solid Tumors Research Articles

Risk factors, prognostic factors, and nomograms for synchronous brain metastases of solid tumors: a population-based study.

In previous literatures, we found that similar studies on the short-term prognosis of synchronous brain metastases (S-BM) from other systems are rare. Our aim was to evaluate the early mortality rate of patients with S-BM from the Surveillance, Epidemiology, and End Result (SEER) database and explore the risk factors for early mortality (≤ 1 year). We used Kaplan-Meier (KM) curves to evaluate early mortality in patients with S-BM from the SEER database. Logistic regression analyses were used to identify significant independent prognostic factors in patients with a follow-up time > 12 months. And the meaningful factors were used to construct a nomogram of overall early death. The receiver operating characteristic (ROC) curve was used to test the predictive ability of the model, while the decision curve analysis (DCA) curve was used to validate the clinical application ability of the model. A total of 47,284 patients were used for univariate and multivariate logistic regression analysis to screen variables to constructing a nomogram. In the all-cause early mortality specific model, the area under the ROC (AUC) curve of the training set was 0.764 (95% confidence interval (CI): 0.758-0.769), and the AUC of the validation set was 0.761 (95% CI: 0.752-0.770). The DCA calibration curves of the training set and validation set indicate that the 1-year early mortality rate predicted by this model is consistent with the actual situation. We found that the 1-year early mortality rate was 76.4%. We constructed a validated nomogram using these covariates to effectively predict 1-year early mortality in patients with S-BM. This nomogram can help clinical workers screen high-risk patients to develop more reasonable treatment plans.

A Phase II Trial of Bevacizumab in Patients with Recurrent/Progressive Solid Tumor Brain Metastases That Have Progressed Following Whole-Brain Radiation Therapy.

Patients with solid tumor brain metastases that progress after whole-brain radiation have limited options. This prospective trial investigated the efficacy, safety, and tolerability of bevacizumab as salvage therapy in this population. Eligible patients received bevacizumab 10 mg/kg intravenously every 2 weeks until progression. The primary endpoint was radiologic response using Response Assessment in Neuro-Oncology (RANO) criteria. The secondary endpoints were progression-free survival (PFS), overall survival (OS), duration of response, and safety. Quality of life (QOL) was studied using the Functional Assessment of Cancer Therapy-Brain (FACT-Br) scale. Twenty-seven patients were enrolled, with twenty-four having evaluable data for response. The majority of histologies (n = 21, 78%) were breast cancer. The remaining histologies were non-small-cell lung cancer (n = 4, 15%), neuroendocrine cancer (n = 1, 3%), and papillary fallopian serous adenocarcinoma (n = 1, 3%). Eighteen patients had radiologic response, with two patients demonstrating partial response (8.33%) and sixteen patients demonstrating stable disease (66.7%). The median duration of response was 203 days. PFS at 6 months was 46%, median PFS was 5.3 m, and median OS was 9.5 m. Treatment was well tolerated, with six patients experiencing grade 3 lymphopenia and hypertension. There was one grade 3 thromboembolism. QOL was not negatively impacted. Bevacizumab is a safe and feasible salvage treatment with durable response and favorable overall survival for patients with progressive brain metastases after whole-brain radiation.

NEIM-05 PURSUE: RESULTS FROM A PROSPECTIVE, PHASE 2B TRIAL TO DEFINE IMAGE INTERPRETATION CRITERIA FOR18F-FLUCICLOVINE-PET FOR DETECTION OF RECURRENT BRAIN METASTASES AFTER RADIATION THERAPY

Abstract BACKGROUND After radiation therapy (RT) for brain metastases (BM), differentiating radiation necrosis from tumor recurrence remains challenging. PURSUE (NCT04410367) evaluated various measures of lesion 18F-fluciclovine uptake to establish image interpretation criteria (IIC) for 18F-fluciclovine-PET to accurately diagnose recurrent BM. METHODS Patients with solid tumor BM and a previously irradiated ‘reference’ lesion equivocal for recurrence on MRI who were scheduled for craniotomy underwent 18F-fluciclovine-PET (185 MBq) <42 days post-MRI and 1-21 days pre-craniotomy. Lesion 18F-fluciclovine uptake was qualitatively rated as ‘mild’ (up to blood pool), ‘moderate’ (above blood pool to parotid gland), or ‘marked’ (above parotid gland) by three independent blinded readers. The primary endpoint was diagnostic performance of different uptake thresholds on qualitative reads vs central histopathology. Secondary endpoints included diagnostic performance, based on different thresholds, of quantitative (e.g., lesion standardized uptake value [SUV]) and dynamic measures. IIC were determined by committee and subsequently used to assess the diagnostic performance of 18F-fluciclovine. RESULTS All 23 reference lesions from 23 enrolled patients underwent histopathological analysis; 10 (43%) were pathologically-confirmed BM recurrence. The highest performing qualitative measure was ‘marked’, rendering 92-100% sensitivity and 40-80% specificity across readers. SUVmax was a reader-independent, high-performing quantitative metric (AUC 0.87, SUVmax threshold 4.8, 80% sensitivity, 85% specificity). Dynamic measures did not add diagnostic value. Thus, IIC was established as: “Lesions with 18F-fluciclovine uptake of SUVmax equal to or greater than 4.8, or visually greater than the parotid gland, should be considered suspicious for recurrence. Otherwise, recurrence should be considered unlikely.” Application of the IIC resulted in 80% sensitivity, 77-85% specificity, 73-80% PPV, and 83-85% NPV across the readers. CONCLUSIONS PURSUE is the first prospective, multicenter trial to establish IIC for 18F-fluciclovine-PET for suspected recurrent BM after RT, verified by histopathology. Finalized IIC demonstrated excellent diagnostic performance for 18F-fluciclovine and will help evaluate 18F-fluciclovine-PET in future studies.

Evaluating the diagnostic performance of 18F-fluciclovine for detection of recurrent brain metastases after radiation therapy: Results from a prospective phase 2 trial.

2001 Background: Differentiating radiation necrosis from tumor progression remains one of the most commonly encountered and clinically challenging scenarios after radiation therapy (RT) for brain metastases (BM). PURSUE (NCT04410367) evaluated the diagnostic performance of 18F-fluciclovine, an amino acid PET radiopharmaceutical, based on various lesion metrics, to establish image interpretation criteria (IIC) for suspected recurrent BM after RT. Methods: Patients with solid tumor BM were enrolled across 7 US sites if they had a previously irradiated ‘reference’ lesion equivocal on MRI for recurrence and were planned for craniotomy. 18F-Fluciclovine PET (185 MBq) took place <42 days post-MRI and 1-21 days pre-craniotomy. The primary endpoint was the diagnostic performance (sensitivity, specificity, positive-, and negative-predictive value [PPV/NPV]) of different thresholds of lesion 18F-fluciclovine uptake on qualitative, visual reads vs central histopathological analysis. Lesion 18F-fluciclovine uptake was assessed qualitatively by 3 independent blinded readers who visually rated the uptake as ‘mild’ (up to blood pool), ‘moderate’ (above blood pool to parotid), or ‘marked’ (above parotid). Secondary endpoints included the diagnostic performance based on different thresholds of quantitative (e.g., lesion SUV) and dynamic measures of uptake. A committee, including 2 expert imaging physicians independent to PURSUE, reviewed all data in round-table meetings to establish the IIC, which were subsequently used to assess diagnostic performance. Results: All 23 reference lesions in 23 subjects underwent histopathological analysis, with 10 (43%) confirmed as recurrent tumor. The highest performing qualitative measure was ‘marked’, rendering a sensitivity of 92-100%, with variable specificity of 40-80% across readers. SUVmax was a reader-independent, high-performing quantitative metric on ROC analysis (AUC 0.87, SUVmax threshold 4.8 conferring a sensitivity of 80% and specificity of 85%). Dynamic measures did not provide added diagnostic value. After analyzing these metrics, the committee established IIC as: Lesions with 18F-fluciclovine uptake of a SUVmax equal to or greater than 4.8, or visually greater than the parotid gland, should be considered suspicious for recurrence. Otherwise, recurrence should be considered unlikely. Application of the IIC resulted in a sensitivity of 80%, specificity of 77-85%, PPV of 73-80%, and NPV of 83-85% across the readers. Conclusions: This is the first prospective multicenter trial to evaluate PET characteristics of suspected recurrent BM after RT, verified by histopathology. Qualitative and quantitative IIC show 18F-fluciclovine to be a high-performing diagnostic tool. These IIC will help evaluate the diagnostic performance of 18F-fluciclovine PET in future trials. Clinical trial information: NCT04410367 .

S396 Higher Rates of Dysphagia Incidence Among Patients With Malignant Primary Brain Tumors Compared to Brain Metastases: A National Study of Medicare Beneficiaries

Introduction: Dysphagia occurs frequently with central nervous system (CNS) diseases. Additionally, rates of dysphagia increase with age. However, there are no population-based estimates of dysphagia among older patients with malignant primary brain tumors (PBTs) or brain metastases. Therefore, we aimed to describe the incidence of new-onset dysphagia among Medicare beneficiaries with CNS malignancies and compare rates of dysphagia between those with malignant PBTs and solid tumor brain metastases. Methods: Using the 2013-2018 Medicare 5% Data sample and ICD-9/10 codes, we identified beneficiaries at least 65 years of age with malignant PBTs as well as the five most common solid tumors metastasizing to the brain (lung, breast, melanoma, renal, and colorectal). Those with coexisting disorders predisposing to symptomatic dysphagia such as head and neck cancer, achalasia, or relevant neurological conditions, were excluded. We estimated rates of new onset dysphagia, defined as occurring within one year from the time of cancer diagnosis, among those with continuous Medicare enrollment for at least six months of follow-up time. Comparisons were made between 1) beneficiaries with malignant PBTs and those with brain metastases and 2) beneficiaries with brain metastases and their counterparts without CNS metastases. A Chi-squared test was used to assess differences between groups. Results: Of the 80,187 beneficiaries identified, the median age of all patients was 72 and most patients (64.9%) were female, primarily due to the large number of breast cancer patients in the cohort. There were 3,018 (3.8%) beneficiaries with malignant PBTs and 805 (1.0%) had brain metastases (Table). Dysphagia occurred in 3,396 (4.2%) of the overall population. Patients with malignant PBTs were significantly more likely to have dysphagia than those with brain metastases (9.7% vs 6.5%, p< 0.01). Patients with brain metastases were more likely to have dysphagia than those without CNS involvement (6.5% vs 4.0%, p< 0.01) (Figure). Conclusion: The incidence of dysphagia is high among older patients with CNS malignancies, with significantly higher rates among those with PBTs compared to brain metastases. The presence of CNS metastases among commonly occurring solid tumors is also associated with the development of dysphagia. These results warrant further investigation to identify predictors of dysphagia among this population as well as to describe its impact on clinical outcomes and overall health care utilization.Figure 1.: Rates of new onset dysphagia within one year of cancer diagnosis among Medicare beneficiaries by disease subgroups: primary brain tumors, solid tumors (lung, breast, melanoma, renal, and colorectal cancer) with brain metastases, and solid tumors without brain metastases. Table 1. - Clinical and demographic data among Medicare beneficiaries studied. #Primary tumor type by brain metastases are not reported to meet CMS censoring reporting requirements. Primary Brain Tumors (N=3,018) Solid tumors with brain metastases (N=805) Solid tumors without brain metastases (N=76,364) Age, median (Q1, Q3) 73 (68, 78) 71 (67, 76) 72 (67, 79) Female 1,672 (55.4%) 478 (59.4%) 49,866 (65.3%) RaceWhiteBlackOther 2,520 (83.5%)248 (8.2%)250 (8.3%) 671 (83.4%)9 (8.6%)65 (8.1%) 66,284 (86.8%)5,727 (7.5%)4,353 (5.6%) Primary tumor typeBreastColorectalLungMelanomaRenal -- --# 29,739 (38.9%)14,378 (18.8%)13,464 (17.6%)12,225 (16.0%)6,558 (8.6%) New onset dysphagia(within 1 year of cancer diagnosis) 293 (9.7%) 52 (6.5%) 3,055 (4.0%)

P15.10.B A multicenter phase 3 trial in progress: diagnostic performance of18F-fluciclovine PET for the detection of recurrent brain metastases after radiation therapy (REVELATE)

Abstract Background Following treatment of brain metastases, which can affect up to 40% of patients with cancer, patients will typically be closely monitored with serial brain magnetic resonance imaging (MRI) owing to the high likelihood of recurrence. The recommended follow-up modalities (CE-T1-weighted and FLAIR/T2-weighted MRI) have poor specificity, meaning that differentiation of true disease from treatment-related changes such as radiation necrosis can be difficult. Recent pilot studies have reported amino acid PET radiopharmaceutical, 18F-fluciclovine, to be potentially useful in discriminating brain tumor recurrence from treatment-related changes. This may potentially help physicians to make confident diagnoses and inform subsequent treatment plans. Material and Methods REVELATE (NCT04410133) will evaluate the diagnostic performance of 18F-fluciclovine PET (read with conventional MRI for anatomical reference) for the detection of recurrent brain metastases in patients for whom MRI is equivocal. This multicenter, phase 3, prospective, open-label trial aims to enroll approximately 150 subjects from across 19 US sites with solid tumor brain metastases who have undergone radiation therapy, if they have a lesion considered equivocal on MRI that requires further confirmatory diagnostic procedures (either biopsy/neurosurgical intervention or clinical follow-up). Patients will undergo 18F-fluciclovine PET &amp;lt;42 days after the equivocal MRI and 1-21 days pre-biopsy/neurosurgical intervention. Clinical follow-up will occur for 6m post-18F-fluciclovine PET. Results The primary endpoint of REVELATE is the subject-level 18F-fluciclovine negative and positive percent agreement (equivalent to specificity and sensitivity, respectively) for detection of recurrent brain metastases. Further objectives include evaluation of the lesion-level diagnostic performance, inter-reader and intra-reader agreement, and safety evaluations. Conclusion This ongoing phase 3 study will provide efficacy and safety data for the use of 18F-fluciclovine for the detection of recurrent brain metastases. Enrolment began in October 2020 and the trial is active but not recruiting at the time of submission.

NEIM-03 A MULTICENTER PHASE 3 TRIAL IN PROGRESS: DIAGNOSTIC PERFORMANCE OF18F-FLUCICLOVINE PET FOR THE DETECTION OF RECURRENT BRAIN METASTASES AFTER RADIATION THERAPY (REVELATE)

INTRODUCTIONFollowing treatment of brain metastases, which can affect up to 40% of patients with cancer, patients will typically be closely monitored with serial brain magnetic resonance imaging (MRI) owing to the high likelihood of recurrence. The recommended follow-up modalities (CE-T1-weighted and FLAIR/T2-weighted MRI) have poor specificity, meaning that differentiation of true disease from treatment-related changes such as radiation necrosis can be difficult. Recent pilot studies have reported amino acid PET radiopharmaceutical, 18F-fluciclovine, to be potentially useful in discriminating tumor recurrence from treatment-related changes. This may potentially aid physicians in making confident diagnoses and inform subsequent treatment plans. METHODSREVELATE (NCT04410133) will evaluate the diagnostic performance of 18F-fluciclovine PET (read with conventional MRI for anatomical reference) for the detection of recurrent brain metastases in patients for whom MRI is equivocal. This multicenter, phase 3, prospective, open-label trial aims to enroll approximately 150 subjects from across 19 US sites with solid tumor brain metastases who have undergone radiation therapy, if they have a lesion considered equivocal on MRI that requires further confirmatory diagnostic procedures (either biopsy/neurosurgical intervention or clinical follow-up). Patients will undergo 18F-fluciclovine PET <42 days after the equivocal MRI and 1–21 days pre-biopsy/neurosurgical intervention. Clinical follow-up will occur for 6m post-18F-fluciclovine PET. Secondary objectives include evaluation of subject- and lesion-level 18F-fluciclovine negative and positive percent agreement (equivalent to specificity and sensitivity, respectively) for recurrent brain metastases, inter-reader and intra-reader agreement, and safety evaluations. Enrolment began in October 2020 and the trial is active but not recruiting at the time of submission.

MMAP-05 PHASE I STUDY OF CONCURRENT PAXALISIB AND RADIATION THERAPY IN PATIENTS WITH SOLID TUMOR BRAIN METASTASES OR LEPTOMENINGEAL METASTASES HARBORING PI3K PATHWAY MUTATIONS: RESULTS FROM THE DOSE-ESCALATION COHORT

INTRODUCTIONRadiation therapy (RT) is an effective treatment for patients with central nervous system metastases, but disease control is poor in patients with tumors that harbor PI3K pathway alterations. We hypothesized that combining RT with paxalisib, a CNS-penetrant small molecule PI3K/mTOR inhibitor, could abrogate this effect via downregulation of prosurvival pathways. METHODSThis is a single institution, open-label, phase I trial of concurrent paxalisib and RT (NCT04192981) for patients with brain metastases, leptomeningeal metastases, or both with PI3K pathway mutations. Part A comprised a standard 3 + 3 dose escalation of paxalisib at 45mg, 60mg, or 75mg daily for two weeks with concomitant RT. The primary objective was to establish the maximum tolerated dose (MTD) of paxalisib when combined with cranial RT. RESULTSBetween 3/2020-1/2022, 12 patients were enrolled to Part A, of which 9 were evaluable (3 did not complete protocol therapy). Median followup was 4.5 months (0.9-14.9 months). All patients received paxalisib with whole brain RT (30Gy in 10 fractions)- 10 patients for brain metastases, and 2 for leptomeningeal metastases. The most common histology was breast cancer (4 [33%]), and the most common PI3K pathway alterations were PIK3CA mutation (7 [58%]). No patient experienced dose-limiting toxicity (DLT) at 45mg paxalisib daily with concurrent RT, and 2 experienced DLT at 60mg paxalisib: 1 with grade 3 nausea and vomiting and 1 with grade 4 enterocolitis and neutropenia. When combined with cranial RT, the paxalisib MTD was established at 45mg/day. We also observed robust response with all evaluable patients experiencing partial or complete response per RANO-BM within 3 months of protocol therapy. CONCLUSIONA MTD of 45mg/day has been established for paxalisib with concurrent cranial RT in patients with solid tumor brain metastases and leptomeningeal metastases harboring PI3K pathway mutations. Additional patients are being recruited to an expansion cohort at this dose (Part B) to confirm safety and preliminary evidence of activity.

Brain Metastasis and Radiotherapy Due to Childhood Clear Cell Sarcomas of the Kidney: A Case Report and Brief Review

Brain metastases of solid tumors in childhood are rare events. Clear cell sarcomas of the kidney, which are among the causes of brain metastasis observed in this age group, constitute only 2-3% of kidney tumors. Even though clear cell sarcoma of the kidney and their metastases are rarely seen, they have a poor prognosis. In this case report and a brief review of the relevant literature, we aimed to summarize the diagnosis, follow-up, and treatment processes of pediatric cases with brain metastasis due to clear cell sarcoma. Changing of clear cell sarcoma treatment planning in recent years and the possibility of difference in relapsing pattern because of this change are also mentioned in this review.

Прогноз перебігу та системна терапія хворих із метастазами солідних пухлин у головний мозок (огляд літератури)

Огляд присвячено системній терапії хворих із метастазами в головний мозок (МГМ) з урахуванням прогнозу перебігу онкологічного захворювання. З огляду на той факт, що наявність МГМ значно погіршує прогноз перебігу, в цій статті представлено огляд шкал оцінки прогнозу виживаності хворих із МГМ, їх характеристику з урахуванням застосування як у рутинній клінічній практиці, так і в клінічних дослідженнях. МГМ зустрічаються в 10 разів частіше, ніж первинні пухлини центральної нервової системи, та діагностуються у 10–20 % онкологічних хворих. Зважаючи на значну поширеність і відсутність загальноприйнятих клінічних рекомендацій щодо лікування хворих із МГМ, у роботі наведено огляд існуючих прогностичних факторів, що визначають тактику лікування, представлено дані про роль гематоенцефалічного бар’єра в патогенезі та ефективності лікування МГМ, розглянуто можливі механізми розвитку резистентності до системної протипухлинної терапії (СППТ), шляхи їх подолання, а також відображено результати досліджень з вивчення ефективності застосування СППТ у хворих із МГМ солідних пухлин. Огляд літератури вказує на важливість застосування мультидисциплінарного підходу до визначення тактики лікування хворих із використанням шкал оцінки прогнозу перебігу, що сприяє більш обґрунтованому призначенню променевої терапії, хірургічного лікування, системної протипухлинної і симптоматичної терапії з метою збереження неврологічної і нейрокогнітивної функцій, а також якості життя хворих.

CLRM-02. TRIAL IN PROGRESS: A PROSPECTIVE, MULTICENTER PHASE 2B STUDY TO ESTABLISH IMAGE INTERPRETATION CRITERIA FOR 18F-FLUCICLOVINE PET IN DETECTING RECURRENT BRAIN METASTASES AFTER RADIATION THERAPY (PURSUE)

BACKGROUNDBrain metastases represent the most common intracranial tumor in adults, occurring in 10-40% of cancer patients. Most patients undergo multimodal treatment approaches and post-treatment follow-up with conventional MRI (CE-T1-weighted and FLAIR/T2-weighted) of the brain is performed to monitor for disease recurrence. However, owing to the similar appearance of treatment-related changes like radiation necrosis with that of true recurrence, conventional MRI alone suffers from low specificity. Given the high mortality of patients with brain metastases and the considerable treatment-associated morbidity, a need remains for an imaging modality that accurately differentiates recurrence from treatment-related changes. Accurate imaging is key to preventing unnecessary surgery or changes in effective therapy in patients mistaken for disease progression as well as prevent continuation of ineffective therapy if radiation necrosis is incorrectly diagnosed. To this end, 18F-fluciclovine is a synthetic amino acid-based PET imaging agent that has potential to evaluate primary and metastatic brain cancers owing to its low normal background uptake in the brain and increased uptake in brain tumors.METHODSNCT04410367 is a prospective, open-label, single-arm, single-dose (185 MBq ± 20%) study with a primary objective to establish visual image interpretation criteria for 18F-fluciclovine PET studies of recurrent brain metastases. Forty subjects with solid tumor brain metastases who have undergone radiation therapy will be enrolled across ~8 US sites if they have a reference lesion considered equivocal on MRI for recurrent disease and are planned for craniotomy. Subjects will undergo 18F-fluciclovine PET <42 days after the MRI and 1–21 days before planned craniotomy. Outcome measures comprise the diagnostic performance of 18F-fluciclovine PET at different thresholds of 18F-fluciclovine uptake compared with histopathology, subject- and lesion-level diagnostic performance based on established image interpretation criteria, and safety evaluations. Enrolment began in August 2020 and the trial is open at the time of submission.

NEIM-02. TRIAL IN PROGRESS: A MULTICENTER PHASE 3 STUDY TO ESTABLISH THE DIAGNOSTIC PERFORMANCE OF 18F-FLUCICLOVINE PET IN DETECTING RECURRENT BRAIN METASTASES AFTER RADIATION THERAPY (REVELATE)

Abstract BACKGROUND Brain metastases occur in up to 40% of patients with cancer and are associated with poor prognosis and considerable levels of recurrence. Consequently, close follow-up with serial brain MRI is performed post-treatment to monitor for recurrent disease. Although conventional MRI (CE-T1-weighted and FLAIR/T2-weighted) is the recommended follow-up modality, it has poor specificity with limited ability to differentiate between true disease recurrence and treatment-related changes such as radiation necrosis. Therefore, alternative imaging options are sought in order to help physicians confidently diagnose treatment-related changes and thus reliably stratify the risk of continuation of a therapeutic regimen, especially given the morbidity associated with current treatments. Amino acid PET imaging agent, 18F-fluciclovine, has increased uptake in brain tumors relative to normal tissue and may be useful for detecting recurrent brain metastases. METHODS NCT04410133 is a prospective, open-label, single-arm, single-dose (185 MBq ±20%) study with a primary objective to confirm the diagnostic performance of 18F-fluciclovine PET (read with conventional MRI for anatomical reference) for detection of recurrent brain metastases where MRI is equivocal. Approximately 150 subjects with solid tumor brain metastases who have undergone radiation therapy will be enrolled in this multicenter trial (~18 US sites) if they have a lesion considered equivocal on MRI that requires further confirmatory diagnostic procedures such as biopsy/neurosurgical intervention or clinical follow-up. Subjects will undergo 18F-fluciclovine PET &amp;lt;42 days after the equivocal MRI and 1–21 days pre-biopsy/neurosurgical intervention. Clinical follow-up will occur for 6m post-18F-fluciclovine PET. Secondary objectives include evaluation of subject- and lesion-level 18F-fluciclovine negative and positive percent agreement (equivalent to specificity and sensitivity, respectively) for recurrent brain metastases, inter-reader and intra-reader agreement, and safety evaluations. Enrolment began in October 2020 and the trial is open at the time of submission.

TRLS-02. Trial in Progress: A Multicenter Phase 3 Study to Establish the Diagnostic Performance of 18F-Fluciclovine PET in Detecting Recurrent Brain Metastases after Radiation Therapy (REVELATE)

BackgroundBrain metastases occur in up to 40% of patients with cancer and are associated with poor prognosis and considerable levels of recurrence. Consequently, close follow-up with serial brain MRI is performed post-treatment to monitor for recurrent disease. Although conventional MRI (CE-T1-weighted and FLAIR/T2-weighted) is the recommended follow-up modality, it has poor specificity with limited ability to differentiate between true disease recurrence and treatment-related changes such as radiation necrosis. Therefore, alternative imaging options are sought in order to help physicians confidently diagnose treatment-related changes and thus reliably stratify the risk of continuation of a therapeutic regimen, especially given the morbidity associated with current treatments. Amino acid PET imaging agent, 18F-fluciclovine, has increased uptake in brain tumors relative to normal tissue and may be useful for detecting recurrent brain metastases.MethodsNCT04410133 is a prospective, open-label, single-arm, single-dose (185 MBq ±20%) study with a primary objective to confirm the diagnostic performance of 18F-fluciclovine PET (read with conventional MRI for anatomical reference) for detection of recurrent brain metastases where MRI is equivocal.Approximately 150 subjects with solid tumor brain metastases who have undergone radiation therapy will be enrolled in this multicenter trial (~18 US sites) if they have a lesion considered equivocal on MRI that requires further confirmatory diagnostic procedures such as biopsy/neurosurgical intervention or clinical follow-up. Subjects will undergo 18F-fluciclovine PET <28 days after the equivocal MRI and 2–21 days pre-biopsy/neurosurgical intervention. Clinical follow-up will occur for 6m post-18F-fluciclovine PET. Secondary objectives include evaluation of subject- and lesion-level 18F-fluciclovine negative and positive percent agreement (equivalent to specificity and sensitivity respectively) for recurrent brain metastases, inter-reader and intra-reader agreement, and safety evaluations. Enrolment began in October 2020 and the trial is open at the time of submission.

TRLS-01. Trial in Progress: A Prospective, Multicenter Phase 2b Study to Establish Image Interpretation Criteria for 18F-Fluciclovine PET in Detecting Recurrent Brain Metastases after Radiation Therapy (PURSUE)

BackgroundBrain metastases are the most common intracranial tumor in adults, occurring in 10–40% of patients with cancer. Despite multimodal treatment approaches, the prognosis remains poor and post-treatment follow-up with conventional MRI (CE-T1-weighted and FLAIR/T2-weighted) of the brain is recommended to monitor for disease recurrence. However, owing to the similar appearance of treatment-related changes like radiation necrosis with that of true recurrence, conventional MRI has low specificity.Given the high mortality of patients with brain metastases and the considerable treatment-associated morbidity, a need remains for an imaging modality that accurately differentiates recurrence from treatment-related changes. Accurate imaging could help physicians identify patients for whom non-effective or unneeded treatments can be ceased in order to minimize treatment-associated morbidity, and to avoid erroneous premature cessation of potentially effective therapy.18F-Fluciclovine is a synthetic amino acid-based PET imaging agent that has potential to evaluate primary and metastatic brain cancers owing to its low normal background uptake in the brain and increased uptake in brain tumors.MethodsNCT04410367 is a prospective, open-label, single-arm, single-dose (185 MBq ± 20%) study with a primary objective to establish visual image interpretation criteria for 18F-fluciclovine PET studies of recurrent brain metastases. Forty subjects with solid tumor brain metastases who have undergone radiation therapy will be enrolled across 8 US sites if they have a reference lesion considered equivocal on MRI for recurrent brain metastasis and are planned for craniotomy. Subjects will undergo 18F-fluciclovine PET <28 days after the equivocal MRI and 2–21 days before planned craniotomy. Outcome measures comprise diagnostic performance of 18F-fluciclovine PET at different thresholds of 18F-fluciclovine uptake compared with histopathology, subject- and lesion-level diagnostic performance based on application of the established image interpretation criteria, and safety evaluations. Enrolment began in August 2020 and the trial is open at the time of submission.

Systemic chemotherapeutic treatment of patients with breast cancer brain metastases.

Brain metastases of solid tumors are the most common intracranial neoplasms in adults. We provide a short overview of the role of the blood-brain barrier ​​in the pathogenesis of breast cancer brain metastases, and the effectiveness of systemic anticancer therapy in the treatment of such patients.

Abstract CT252: A dose escalation phase I study of concurrent GDC-0084 with radiation therapy for patients with solid tumor brain metastases or leptomeningeal metastases harboring PI3K pathway mutations

Abstract Patients with metastatic solid tumors frequently develop central nervous system (CNS) metastases as part of their disease course. Radiation therapy (RT) is an effective treatment for disease control and symptom management of CNS metastases. Genomic predictors of poor CNS disease control include patients whose tumors harbor PI3K pathway alterations. Hyperactivation of the phosphatidylinositol-3-kinase/protein kinase b (PI3K-Akt) pathway has been associated with radioresistance. GDC-0084 (paxalisib) is a potent, oral, selective, CNS-penetrant small molecule inhibitor of phosphoinositide 3-kinase and of mammalian target of rapamycin (PI3K/mTOR) that has been specifically designed for treatment of CNS tumors. It is active against all four isoforms of PI3K (α, β, γ, and δ) and has moderate activity against mTOR. While PI3K inhibitors usually elicit cytostatic activity, they are thought to enhance radiation-induced DNA damage, G2/M arrest and apoptosis when combined with radiation. The synergistic effect is due to the abrogation of RT-induced phosphorylation of Akt with PI3K-Akt inhibition and therefore downregulation of the prosurvival pathways. In addition, PI3K inhibitors have been found to cause significant decrease in glycolysis at the step catalyzed by aldolase, and the inhibition of aldolase leads to the reduction of its product, Ga3P, which is the source for nucleotide synthesis. This has significant implication in a cell's ability to undergo efficient DNA repair and causes DNA damage through nucleoside depletion. This is a single institution, open label, prospective phase I clinical trial for patients with metastatic solid tumors harboring PI3K pathway mutations with parenchymal brain metastases or leptomeningeal metastases. Our primary aim is to assess the toxicity and safety of concurrent GDC-0084 administration with RT (30Gy in 10 fractions) to the brain (NCT04192981). Efficacy (local control per Response Assessment in Neuro-Oncology, intracranial progression-free survival, overall survival) will be evaluated as a secondary objectives. Pre- and post-treatment cerebrospinal fluid (CSF) biomarkers including circulating tumor cells, mutated allelic burden in cell-free DNA, cytokines, RNA and protein analysis of the cellular component will also be investigated as exploratory objectives. The starting dose of GDC-0084 is 45mg daily and a maximum of 24 patients will be required to establish the maximum-tolerated dose (MTD). Once the MTD is determined, an expansion cohort of 12 patients will be treated. Citation Format: T. Jonathan Yang, Zhigang Zhang, Robert Young, James S. Garner, Jeremy Simpson, Adrienne Boire, Michael Offin, Eli Diamond. A dose escalation phase I study of concurrent GDC-0084 with radiation therapy for patients with solid tumor brain metastases or leptomeningeal metastases harboring PI3K pathway mutations [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr CT252.

Whole-brain irradiation with hippocampal sparing and dose escalation on metastases: neurocognitive testing and biological imaging (HIPPORAD) \u2013 a phase II prospective randomized multicenter trial (NOA-14, ARO 2015\u20133, DKTK-ROG)

BackgroundWhole brain radiation therapy (WBRT) is the standard therapy for multiple brain metastases. However, WBRT has a poor local tumor control and is associated with a decline in neurocognitive function (NCF). Aim of this trial is to assess the efficacy and safety of a new treatment method, the WBRT with hippocampus avoidance (HA) combined with the simultaneous integrated boost (SIB) on metastases/resection cavities (HA-WBRT+SIB).MethodsThis is a prospective, randomized, two-arm phase II multicenter trial comparing the impact of HA on NCF after HA-WBRT+SIB versus WBRT+SIB in patients with multiple brain metastases. The study design is double-blinded. One hundred thirty two patients are to be randomized with a 1:1 allocation ratio. Patients between 18 and 80 years old are recruited, with at least 4 brain metastases of solid tumors and at least one, but not exceeding 10 metastases ≥5 mm. Patients must be in good physical condition and have no metastases/resection cavities in or within 7 mm of the hippocampus. Patients with dementia, meningeal disease, cerebral lymphomas, germ cell tumors, or small cell carcinomas are excluded. Previous irradiation and resection of metastases, as well as the number and size of metastases to be boosted have to comply with certain restrictions. Patients are randomized between the two treatment arms: HA-WBRT+SIB and WBRT+SIB. WBRT is to be performed with 30 Gy in 12 daily fractions and the SIB with 51 Gy/42 Gy in 12 daily fractions on 95% of volume for metastases/resection cavities. In the experimental arm, the dose to the hippocampi is restricted to 9 Gy in 98% of the volume and 17Gy in 2% of the volume. NCF testing is scheduled before WBRT, after 3 (primary endpoint), 9, 18 months and yearly thereafter. Clinical and imaging follow-ups are performed 6 and 12 weeks after WBRT, after 3, 9, 18 months and yearly thereafter.DiscussionThis is a protocol of a randomized phase II trial designed to test a new strategy of WBRT for preventing cognitive decline and increasing tumor control in patients with multiple brain metastases.Trial registrationThe HIPPORAD trial is registered with the German Clinical Trials Registry (DRKS00004598, registered 2 June 2016).

GDC-0084 With Radiation Therapy for People With PIK3CA-Mutated Solid Tumor Brain Metastases or Leptomeningeal Metastases

GDC-0084 With Radiation Therapy for People With PIK3CA-Mutated Solid Tumor Brain Metastases or Leptomeningeal Metastases

The Promise of Immunotherapy for Breast Cancer Brain Metastases

The goal of our review is to describe the rationale for immunotherapy in the treatment of breast cancer brain metastases (BCBM), the current landscape of clinical trials for this disease process, and possible future directions based on anticipated results. Immune checkpoint inhibition has shown efficacy in the treatment of several solid tumor brain metastases (i.e., melanoma and non-small cell lung cancer), but data specific to BCBM is relatively sparse. Preclinical studies in BCBM have illustrated a lower immune content in the brain microenvironment measured by tumor-infiltrating lymphocytes (TILs) in brain metastases compared to primary tumors. Yet, improved outcomes are associated with higher TIL content in the BCBM, and strategies to understand and alter the complex brain immune microenvironment are needed. Based on observations in the non-breast cancer setting and early results in advanced breast cancer, it is likely that novel, strategic combination immunotherapy strategies will be needed to yield meaningful outcomes for BCBM patients. Some exciting concepts underway include novel immunotherapy combinations, concurrent stereotactic radiosurgery, bi-specific antibody armed activated T cells, and HER2-chimeric antigen receptor T cells for leptomeningeal disease.

Impact of solid tumor brain metastases on end-of-life healthcare utilization.

e18373 Background: Patients with brain metastases (BMets) represent a subset of cancer patients who may experience high costs and frequent healthcare utilization. This study aims to assess whether patients with BMets have higher likelihood of low-value healthcare utilization at the end of life compared to other patients with metastatic cancer. Methods: Using the Cancer Information and Population Health Resource, linking North Carolina Medicare and Medicaid and cancer registry data, we conducted an observational cohort study of decedents with metastatic cancer with or without BMets. The cohorts included adults with melanoma, renal cell carcinoma, breast cancer, or lung cancer, diagnosed 2003 to 2014. Multivariate logistic regression, adjusting for demographics, cancer type, systemic treatment, comorbidity, frailty, and hospice use, was used to examine the impact of BMets on emergency department (ED) use, hospitalization, and intensive care (ICU) in the 30 days prior to death. Results: Relative to patients without BMets, patients with BMets were more likely to experience a hospitalization (12.9% vs 9%, p &lt; 0.001), but experience no difference in ED or ICU use. In adjusted analyses, BMets patients receiving systemic treatment were particularly high risk for hospitalization (OR 1.823, CI 1.504, 2.209). Black race; receipt of systemic therapy near the end of life; and Charlson comorbidity score of 3+ confers increased risk of ED use, hospitalization, and ICU use (Table). Utilization did not vary by cancer type. Conclusions: Patients with BMets are high risk for hospitalization at the end of life. Further study is needed to determine if targeted health system interventions can decrease hospitalizations in this patient group. [Table: see text]