Treatment of unmethylated MGMT-promoter recurrent glioblastoma with cancer stem cell assay-guided chemotherapy and the impact on patients' healthcare costs.

Background: Glioblastoma (GBM) is a lethal disease. At least in part, the recurrence of GBM is caused by cancer stem cells (CSCs), which are resistant to chemotherapy. Personalized anticancer therapy against CSCs can improve treatment outcomes. We present a prospective cohort study of 40 real-world unmethylated Methyl-guanine-methyl-transferase-promoter GBM patients treated utilizing a CSC chemotherapeutics assay-guided report (ChemoID). Methods: Eligible patients who underwent surgical resection for recurrent GBM were included in the study. Most effective chemotherapy treatments were chosen based on the ChemoID assay report from a panel of FDA-approved chemotherapies. A retrospective chart review was conducted to determine OS, progression-free survival, and the cost of healthcare costs. The median age of our patient cohort was 53 years (24-76). Results: Patients treated prospectively with high-response ChemoID-directed therapy, had a median overall survival (OS) of 22.4 months (12.0-38.4) with a log-rank P = .011, compared to patients who could be treated with low-response drugs who had instead an OS of 12.5 months (3.0-27.4 months). Patients with recurrent poor-prognosis GBM treated with high-response therapy had a 63% probability to survive at 12 months, compared to 27% of patients who were treated with low-response CSC drugs. We also found that patients treated with high-response drugs on average had an incremental cost-effectiveness ratio (ICER) of $48,893 per life-year saved compared to $53,109 of patients who were treated with low-response CSC drugs. Conclusions: The results presented here suggest that the ChemoID Assay can be used to individualize chemotherapy choices to improve poor-prognosis recurrent GBM patient survival and to decrease the healthcare cost that impacts these patients.

Cancer stem cell assay-guided chemotherapy improves survival of patients with recurrent glioblastoma in a randomized trial.

Therapy-resistant cancer stem cells (CSCs) contribute to the poor clinical outcomes of patients with recurrent glioblastoma (rGBM) who fail standard of care (SOC) therapy. ChemoID is a clinically validated assay for identifying CSC-targeted cytotoxic therapies in solid tumors. In a randomized clinical trial (NCT03632135), the ChemoID assay, a personalized approach for selecting the most effective treatment from FDA-approved chemotherapies, improves the survival of patients with rGBM (2016 WHO classification) over physician-chosen chemotherapy. In the ChemoID assay-guided group, median survival is 12.5 months (95% confidence interval [CI], 10.2-14.7) compared with 9 months (95% CI, 4.2-13.8) in the physician-choice group (p = 0.010) as per interim efficacy analysis. The ChemoID assay-guided group has a significantly lower risk of death (hazard ratio [HR] = 0.44; 95% CI, 0.24-0.81; p = 0.008). Results of this study offer a promising way to provide more affordable treatment for patients with rGBM in lower socioeconomic groups in the US and around the world.

Laser interstitial thermal therapy (LITT) for intracranial lesions: a single-institutional series, outcomes, and review of the literature.

INTRODUCTION: Laser interstitial thermal therapy (LITT) is a minimally invasive treatment method in managing primary brain neoplasms, brain metastases, radiation necrosis, and epileptogenic lesions, many of which are located in operative corridors that would be difficult to address. Although the use of lasers is not a new concept in neurosurgery, advances in technology have enabled surgeons to perform laser treatment with the aid of real-time MRI thermography as a guide. In this report, we present our institutional series and outcomes of patients treated with LITT. METHODS: We retrospectively evaluated 19 patients (age range, 28-77 years) who underwent LITT at one or more targets from 2015 to 2019. Primary endpoint observed was mean progression free survival (PFS) and overall survival (OS). RESULTS: Seven patients with glial neoplasms and 12 patients with metastatic disease were reviewed. Average hospitalization was 2.4 days. Median PFS was 7 and 4 months in the metastatic group and primary glial neoplasm group, respectively (p = 0.01). Median OS from time of diagnosis was 41 and 32 months (p = 0.02) and median OS after LITT therapy was 25 and 24 months (p = 0.02) for the metastatic and primary glial neoplasm groups, respectively. One patient experienced immediate post-procedural morbidity secondary to increased intracerebral edema peri-lesionally while one patient experienced post-operative mortality and expired secondary to hemorrhage 1-month post-procedure. Median follow-up was 10 months. CONCLUSION: Laser interstitial thermal therapy (LITT) is a safe, minimally invasive treatment method that provides surgeons with cytoreductive techniques to treat neurosurgical conditions. Both PFS and OS appear to be more favorable after LITT in patients with metastatic disease. In properly selected patients, this modality offers improved survival outcomes in conjunction with other salvage therapies.

Cancer Stem Cell Chemotherapeutics Assay for Prospective Treatment of Recurrent Glioblastoma and Progressive Anaplastic Glioma: A Single-Institution Case Series.

BACKGROUND: Chemotherapy-resistant cancer stem cells (CSC) may lead to tumor recurrence in glioblastoma (GBM). The poor prognosis of this disease emphasizes the critical need for developing a treatment stratification system to improve outcomes through personalized medicine. METHODS: We present a case series of 12 GBM and 2 progressive anaplastic glioma cases from a single Institution prospectively treated utilizing a CSC chemotherapeutics assay (ChemoID) guided report. All patients were eligible to receive a stereotactic biopsy and thus undergo ChemoID testing. We selected one of the most effective treatments based on the ChemoID assay report from a panel of FDA approved chemotherapy as monotherapy or their combinations for our patients. Patients were evaluated by MRI scans and response was assessed according to RANO 1.1 criteria. RESULTS: Of the 14 cases reviewed, the median age of our patient cohort was 49 years (21-63). We observed 6 complete responses (CR) 43%, 6 partial responses (PR) 43%, and 2 progressive diseases (PD) 14%. Patients treated with ChemoID assay-directed therapy, in combination with other modality of treatment (RT, LITT), had a longer median overall survival (OS) of 13.3 months (5.4-NA), compared to the historical median OS of 9.0 months (8.0-10.8 months) previously reported. Notably, patients with recurrent GBM or progressive high-grade glioma treated with assay-guided therapy had a 57% probability to survive at 12 months, compared to the 27% historical probability of survival observed in previous studies. CONCLUSIONS: The results presented here suggest that the ChemoID Assay has the potential to stratify individualized chemotherapy choices to improve recurrent and progressive high-grade glioma patient survival. IMPORTANCE OF THE STUDY: Glioblastoma (GBM) and progressive anaplastic glioma are the most aggressive brain tumor in adults and their prognosis is very poor even if treated with the standard of care chemoradiation Stupp's protocol. Recent knowledge pointed out that current treatments often fail to successfully target cancer stem cells (CSCs) that are responsible for therapy resistance and recurrence of these malignant tumors. ChemoID is the first and only CLIA (clinical laboratory improvements amendment) -certified and CAP (College of American Pathologists) -accredited chemotherapeutic assay currently available in oncology clinics that examines patient's derived CSCs susceptibility to conventional FDA (Food and Drugs Administration) -approved drugs. In this study we observed that although the majority of our patients (71.5%) presented with unfavorable prognostic predictors (wild type IDH-1/2 and unmethylated MGMT promoter), patients treated with ChemoID assay-directed therapy had an overall response rate of 86% and increased median OS of 13.3 months compared to the historical median OS of 9.1 months (8.1-10.1 months) previously reported [1] suggesting that the ChemoID assay may be beneficial in personalizing treatment strategies.

National trends in radiation dose escalation for glioblastoma.

PURPOSE: Glioblastoma (GBM) carries a high propensity for in-field failure despite trimodality management. Past studies have failed to show outcome improvements with dose-escalation. Herein, we examined trends and outcomes associated with dose-escalation for GBM. MATERIALS AND METHODS: The National Cancer Database was queried for GBM patients who underwent surgical resection and external-beam radiation with chemotherapy. Patients were excluded if doses were less than 59.4 Gy; dose-escalation referred to doses ≥66 Gy. Odds ratios identified predictors of dose-escalation. Univariable and multivariable Cox regressions determined potential predictors of overall survival (OS). Propensity-adjusted multivariable analysis better accounted for indication biases. RESULTS: Of 33,991 patients, 1,223 patients received dose-escalation. Median dose in the escalation group was 70 Gy (range, 66 to 89.4 Gy). The use of dose-escalation decreased from 8% in 2004 to 2% in 2014. Predictors of escalated dose were African American race, lower comorbidity score, treatment at community centers, decreased income, and more remote treatment year. Median OS was 16.2 months and 15.8 months for the standard and dose-escalated cohorts, respectively (p = 0.35). On multivariable analysis, age >60 years, higher comorbidity score, treatment at community centers, decreased education, lower income, government insurance, Caucasian race, male gender, and more remote year of treatment predicted for worse OS. On propensity-adjusted multivariable analysis, age >60 years, distance from center >12 miles, decreased education, government insurance, and male gender predicted for worse outcome. CONCLUSION: Dose-escalated radiotherapy for GBM has decreased over time across the United States, in concordance with guidelines and the available evidence. Similarly, this large study did not discern survival improvements with dose-escalation.

Re-Irradiation with Stereotactic Radiosurgery/Radiotherapy for Recurrent High-Grade Gliomas: Improved Survival in the Modern Era.

OBJECTIVE: The aim of this study was to evaluate the efficacy of stereotactic radiosurgery (SRS) and fractionated stereotactic radiotherapy (fSRT) as salvage therapy for recurrent high-grade glioma and to look at the overall efficacy of treatment with linear accelerator (LINAC)-based radiosurgery and fractionated radiotherapy. METHODS: From 2010 to 2017, a total of 25 patients aged 23-74 years were re-irradiated with LINAC-based SRS and fSRT. Patients were treated to a median dose of 25 Gy in 5 fractions. RESULTS: The median overall survival (OS) after (initial) diagnosis was 39 months with an actuarial 1-, 3-, and 5-year OS rate of 88, 56, and 30%, respectively. After treatment with SRS or fSRT, the median OS was 9 months with an actuarial 1-year OS rate of 29%. Local control, assessed for 28 tumors, after 6 months was 57%, while local control after 1 year was 39%. Three patients experienced local failure. There was no evidence of toxicity noted after SRS or fSRT throughout the follow-up period. CONCLUSION: SRS and fSRT remain a safe, reasonable, effective treatment option for re-irradiation following recurrent glioblastoma. Additionally, treatment volume may predict local control in the salvage setting.

Central nervous system lymphoma in immunocompetent patients: the North Shore-Long Island Jewish Health System experience.

Of the 74 immunocompetent patients diagnosed between July 2004 and June 2011 at the North Shore University Hospital and Long Island Jewish Medical Center with primary central nervous system lymphoma, 71 (95.9%) had diffuse large B-cell lymphomas (DLBCL). The median patient age was 68 years (range: 19-87 years) with a slight male preponderance (1.1:1). The overall median survival time was 21 months. For patients older than 70 years, the median survival time was 8 months while for those 70 years or younger, the median survival time was 27 months (p<0.01). Female patients had a worse prognosis than male patients (p<0.05, median survival time, 17 months compared to 23 months). We had enough data from 52 of these 71 patients to define the lymphomas as either germinal center B-cell-like (GCB) or activated B-cell-like (ABC) DLBCL. Of these 52 patients, 42 (80.8%) had ABC DLBCL while only 10 (19.2%) had GCB DLBCL. The patients in the GCB subgroup seemed to survive longer than the patients in the ABC subgroup, although the difference did not reach statistical significance. No statistically significant difference in overall survival was seen between patients with BCL-6 positive or negative DLBCL; or between patients with BCL-2 positive or negative DLBCL.

Glioblastoma with PNET-like components has a higher frequency of isocitrate dehydrogenase 1 (IDH1) mutation and likely a better prognosis than primary glioblastoma.

Glioblastoma with primitive neuroectodermal tumor-like components (GBM-PNET), a rare variant of glioblastoma, poses both diagnostic and therapeutic challenges. Ten patients with GBM-PNET were investigated with a median age of 51.5 years and the male to female ratio of 4:1. The majority of patients (7 out of 10) showed ring-enhancing lesions on magnetic resonance imaging (MRI), which is classic for GBMs. Restricted diffusion was noted in 7 cases where diffusion weighted imaging (DWI) was performed, which correlates with the presence of PNET-like components. CD56 and vimentin immunostaining made the diagnosis of GBM-PNET much easier. Vimentin strongly and diffusely highlighted the astrocytic components and was negative in PNET-like components, while CD56 was strongly and diffusely positive in both astrocytic and PNET-like components. Seven out of 9 cases were positive for p53 in both astrocytic and PNET-like components. Two out of 8 cases harbored isocitrate dehydrogenase 1 (IDH1) R132H mutation, while IDH2 R172 mutations were not identified. Three out of 10 patients had a median survival time of 17 months while the two patients, whose tumor carried IDH1 mutation, were still alive after 15 and 31 months of follow-up. Compared to primary GBMs, GBM-PNETs might have a better prognosis. Further large scale studies are necessary to confirm this observation.

Current management of metastatic brain disease.

Brain metastases are the most common intracranial tumor in adults. The incidence of metastases is thought to be rising due to better detection and treatment of systemic malignancy. More widespread use and improved quality of MRI may lead to early detection of brain metastases. Available evidence suggests that survival is longer and quality of life improved if brain metastases are treated aggressively. This article reviews current therapeutic management used for brain metastases. To select the appropriate therapy, the physician must consider the extent of the systemic disease, primary histology, and patient age and performance status, as well as the number, size, and location of the brain metastases. Available treatment options include whole-brain radiotherapy (WBRT), stereotactic radiosurgery (SRS), surgery, and chemotherapy. Multidisciplinary approaches such as the combination of WBRT with SRS or surgery have shown superior results in terms of survival time, neurocognitive function, and quality of life. The utility and optimal use of chemotherapy and radiosensitizing agents is less clear. It is hoped that further advances and multidisciplinary approaches currently under study will result in improved patient outcomes.