Denise Damek

Intravenous methotrexate as initial treatment for primary central nervous system lymphoma: response to therapy and quality of life of patients.

In anticipation of a consortium study of methotrexate (MTX) therapy provided to patients with primary central nervous system lymphoma (PCNSL) we have provided intravenous MTX without irradiation therapy to 31 non-immunosuppressed individuals. Twenty (65%) achieved complete response and 11 (35%) partial response to therapy. For the 31 patients the median survival was 30.43 months with an actuarial median follow up time of 30.69 months. The 2+ year survival was 63% for all patients and 90% for complete responders. Of 375 drug cycles, grade 3 leukopenia was identified in 3 cycles, mucositis in 6 cycles and delayed drug clearance in 47 cycles. Recurrences included brain (9/20) and/or spinal fluid (2/20). The median Karnofsky scale improved from 40 (10–80) prior to therapy to 90 after treatment. Eleven patients, in complete response for a median of 22+ months after diagnosis were evaluated using 4 instruments that assess Quality of Life Functional Assessment of Cancer Therapy – Brain (FACT-BR) modified, Symptom Questionnaire, Social Adjustment Scale-Self-Report and Problem Solving Inventory. Their psychosocial adjustment, well-being and stress coping abilities were comparable to the normative groups. Further there was no evidence of any MTX-induced, Magnetic Resonance Imaging (MRI)-detected encephalopathy in these individuals and there was preservation of clinical cognition and memory. We conclude that therapy with MTX, without radiation can be used in PCNSL patients without limitations of age or pretreatment Karnofsky scores. Further rates of response and median survival approach those of therapies using multiple drugs and radiation, but with a less likely risk of dementia.

Epstein Barr virus-associated primary CNS lymphomas in elderly patients on immunosuppressive medications.

Unlike primary central nervous system lymphomas (PCNSLs) in patients with AIDS or organ transplants, PCNSLs in the elderly are usually not considered to be mediated by Epstein Barr virus (EBV); hence, diagnostic studies for EBV are not routinely performed. We encountered 4 patients, 65 years or older, who developed EBV-associated PCNSLs and who had been treated with a variety of immunosuppressive drugs for different autoimmune/collagen vascular disorders, including autoimmune polyneuropathy (mycophenolate mofetil for 5 years), polymyositis (prednisone for 16 years with intermittent methotrexate, azathioprine, and cyclophosphamide), myasthenia gravis (azathioprine >10 years), and rheumatoid arthritis (methotrexate >10 years). All patients had multifocal, necrotic brain lesions typical of EBV-positive PCNSLs on neuroimaging. Withdrawing immunosuppressives lead to PCNSL regression in some patients. The patient who had received mycophenolate mofetil was treated successfully for his EBV-associated PCNSL with rituximab and methotrexate, but later developed fatal systemic malignant melanoma, which was likely immunosuppression related. The striking feature of these cases is the variety of underlying diseases-and hence accompanying medications-that can be associated with EBV-associated PCNSLs. They serve as a diagnostic alert for neuropathologists and suggest that increased testing of PCNSLs for EBV by immunohistochemistry or in situ hybridization may be warranted in any patient on any immunosuppressive medication, but particularly the elderly.

Phase I Trial of Hypofractionated Intensity-Modulated Radiotherapy With Temozolomide Chemotherapy for Patients With Newly Diagnosed Glioblastoma Multiforme

PURPOSE To determine the maximal tolerated biologic dose intensification of radiotherapy using fractional dose escalation with temozolomide (TMZ) chemotherapy in patients with newly diagnosed glioblastoma multiforme. METHODS AND MATERIALS Patients with newly diagnosed glioblastoma multiforme after biopsy or resection and with adequate performance status, bone marrow, and organ function were eligible. The patients underwent postoperative intensity-modulated radiotherapy (IMRT) with concurrent and adjuvant TMZ. All patients received a total dose of 60 Gy to the surgical cavity and residual tumor, with a 5-mm margin. IMRT biologic dose intensification was achieved by escalating from 3 Gy/fraction (Level 1) to 6 Gy/fraction (Level 4) in 1-Gy increments. Concurrent TMZ was given at 75 mg/m(2)/d for 28 consecutive days. Adjuvant TMZ was given at 150-200 mg/m(2)/d for 5 days every 28 days. Dose-limiting toxicity was defined as any Common Terminology Criteria for Adverse Events, version 3, Grade 3-4 nonhematologic toxicity, excluding Grade 3 fatigue, nausea, and vomiting. A standard 3+3 Phase I design was used. RESULTS A total of 16 patients were accrued (12 men and 4 women, median age, 69 years; range, 34-84. The median Karnofsky performance status was 80 (range, 60-90). Of the 16 patients, 3 each were treated at Levels 1 and 2, 4 at Level 3, and 6 at Level 4. All patients received IMRT and concurrent TMZ according to the protocol, except for 1 patient, who received 14 days of concurrent TMZ. The median number of adjuvant TMZ cycles was 7.5 (range, 0-12). The median survival was 16.2 months (range, 3-33). One patient experienced vision loss in the left eye 7 months after IMRT. Four patients underwent repeat surgery for suspected tumor recurrence 6-12 months after IMRT; 3 had radionecrosis. CONCLUSIONS The maximal tolerated IMRT fraction size was not reached in our study. Our results have shown that 60 Gy IMRT delivered in 6-Gy fractions within 2 weeks with concurrent and adjuvant TMZ is tolerable in selected patients with a T(1)-weighted enhancing tumor <6 cm.

Phase I Dose Escalation Trial of Vandetanib With Fractionated Radiosurgery in Patients With Recurrent Malignant Gliomas

PURPOSE To determine the maximum tolerated dose (MTD) of vandetanib with fractionated stereotactic radiosurgery (SRS) in patients with recurrent malignant gliomas. METHODS AND MATERIALS Patients with a recurrent malignant glioma and T1-enhancing recurrent tumor ≤ 6 cm were eligible. Vandetanib was given orally, once per day, 7 days a week, starting at least 7 days before SRS and continued until a dose-limiting toxicity (DLT) or disease progression. The planned vandetanib daily dose was 100 mg, 200 mg, and 300 mg for the cohorts 1, 2, and 3, respectively, and was escalated using a standard 3+3 design. A total SRS dose of 36 Gy, 12 Gy per fraction, was delivered over 3 consecutive days. The MTD was defined as the dose of vandetanib at which less than 33% of patients developed DLTs, defined by the Common Terminology Criteria for Adverse Events (CTCAE) version 3 as any Grade 3 or greater nonhematologic toxicity and Grade 4 or greater hematologic toxicity. RESULTS Ten patients were treated, 6 on cohort 1 and 4 on cohort 2. Treatment characteristics were: 7 men, 3 women; median age, 40 years (range, 22-72); 7 GBM, 3 anaplastic astrocytoma (AA); median initial radiation (RT) dose, 60 Gy (range, 59.4-70); median interval since initial RT, 14.5 months (range, 7-123); All patients received SRS per protocol. The median follow-up time was 4 months (range, 1-10 months). Median time on vandetanib was 3 months (range 1-11). One of 6 patients in the first cohort developed a DLT of Grade 3 hemothorax while on anticoagulation. The MTD was reached when 2 of the 4 patients enrolled in the second cohort developed DLTs. Six patients had radiographic response, 2 with stable disease. CONCLUSION The MTD of vandetanib, with SRS in recurrent malignant glioma, is 100 mg daily. Further evaluation of safety and efficacy is warranted.

Favorable prognosis in patients with high-grade glioma with radiation necrosis: the University of Colorado reoperation series.

PURPOSE To analyze the pathology, outcomes, and prognostic factors in patients with high-grade glioma undergoing reoperation after radiotherapy (RT). METHODS AND MATERIALS Fifty-one patients with World Health Organization Grade 3-4 glioma underwent reoperation after prior RT. The median dose of prior RT was 60 Gy, and 84% received chemotherapy as part of their initial treatment. Estimation of the percentage of necrosis and recurrent tumor in each reoperation specimen was performed. Pathology was classified as RT necrosis if ≥80% of the specimen was necrotic and as tumor recurrence if ≥20% was tumor. Predictors of survival were analyzed using log-rank comparisons and Cox proportional hazards regression. RESULTS The median interval between the completion of RT and reoperation was 6.7 months (range, 1-59 months). Pathologic analysis showed RT necrosis in 27% and recurrence in 73% of cases. Thirteen patients required a reoperation for uncontrolled symptoms. Among them, 1 patient (8%) had pathology showing RT necrosis, and 12 (92%) had tumor recurrence. Median survival after reoperation was longer for patients with RT necrosis (21.8 months vs. 7.0 months, p=0.047). In 7 patients with Grade 4 tumors treated with temozolomide-based chemoradiation with RT necrosis, median survival from diagnosis and reoperation were 30.2 months and 21.8 months, respectively. CONCLUSIONS Patients with RT necrosis at reoperation have improved survival compared with patients with tumor recurrence. Future efforts to intensify local therapy and increase local tumor control in patients with high-grade glioma seem warranted.

Cerebral Edema, Altered Mental Status, Seizures, Acute Stroke, Leptomeningeal Metastases, and Paraneoplastic Syndrome

Neurologic symptoms commonly occur in oncology patients, and in some cases they may be the presenting symptom of malignancy. Cancer-related neurologic syndromes are rarely pathognomonic and must be differentiated from other benign or serious conditions. This article reviews common neuro-oncologic syndromes that may lead to urgent evaluation in the emergency department, including cerebral edema, altered mental status, seizures, acute stroke, leptomeningeal metastases, and paraneoplastic neurologic syndromes.

The Impact of Adjuvant Radiation Therapy for High-Grade Gliomas by Histology in the United States Population

PURPOSE To compare the survival impact of adjuvant external beam radiation therapy (RT) for malignant gliomas of glioblastoma (GBM), anaplastic astrocytoma (AA), anaplastic oligodendroglioma (AO), and mixed anaplastic oligoastrocytoma (AOA) histology. METHODS AND MATERIALS The Surveillance, Epidemiology, and End Results (SEER) database was queried from 1998 to 2007 for patients aged ≥18 years with high-grade gliomas managed with upfront surgical resection, treated with and without adjuvant RT. RESULTS The primary analysis totaled 14,461 patients, with 12,115 cases of GBM (83.8%), 1312 AA (9.1%), 718 AO (4.9%), and 316 AOA (2.2%). On univariate analyses, adjuvant RT was associated with significantly improved overall survival (OS) for GBMs (2-year OS, 17% vs 7%, p<.001), AAs (5-year OS, 38% vs 24%, p<.001), and AOAs (5-year OS, 55% vs 44%, p=.026). No significant differences in OS were observed for AOs (5-year OS, with RT 50% vs 56% without RT, p=.277). In multivariate Cox proportional hazards models accounting for extent of resection, age, sex, race, year, marital status, and tumor registry, RT was associated with significantly improved OS for both GBMs (HR, 0.52; 95% CI, 0.50-0.55; P<.001) and AAs (HR, 0.57; 95% CI, 0.48-0.68; P<.001) but only a trend toward improved OS for AOAs (HR, 0.70; 95% CI, 0.45-1.09; P=.110). Due to the observation of nonproportional hazards, Cox regressions were not performed for AOs. A significant interaction was observed between the survival impact of RT and histology overall (interaction P<.001) and in a model limited to the anaplastic (WHO grade 3) histologies. (interaction P=.024), characterizing histology as a significant predictive factor for the impact of RT. Subgroup analyses demonstrated greater hazard reductions with RT among patients older than median age for both GBMs and AAs (all interaction P≤.001). No significant interactions were observed between RT and extent of resection. Identical patterns of significance were observed for cause-specific survival and OS across analyses. CONCLUSIONS In this large population-based cohort, glioma histology represented a significant predictor for the survival impact of RT. Adjuvant RT was associated with improved survival for AAs, with benefits comparable to those observed for GBMs over the same 10-year interval. No survival advantage was observed with adjuvant RT for AOs.

A state-of-the-art review and guidelines for tumor treating fields treatment planning and patient follow-up in glioblastoma

Tumor treating fields (TTFields) are an integral treatment modality in the management of glioblastoma and extend overall survival when combined with maintenance temozolomide in newly diagnosed patients. Complexities exist regarding correct selection of imaging sequences with which to perform TTFields treatment planning. Guidelines are warranted first, to facilitate treatment planning standardization across medical disciplines and institutions, to ensure optimal TTFields delivery to the tumor and peritumoral brain zone while maximizing patient safety, and also to mitigate the risk of premature cessation of a potentially beneficial treatment. This summary guideline outlines methods for starting patients on TTFields, for monitoring patient response to therapy and provides a framework for evaluating when therapy should be re-planned, based on the extent of sequential imaging changes.

EGFR Exon 19 Deletion Mutations and Systemic/Central Nervous System Miliary Metastasis: Clinical Correlations and Response to Therapy

A 62 year old male former smoker presented emergently to an outside hospital with acute onset expressive aphasia of unknown etiology and was treated for stroke with tissue plasminogen activator infusion. Additional history revealed a 5 month history of headaches, weight loss, fatigue, poor work performance and episodic symptoms of significant confusion, expressive aphasia, dressing apraxia, gait imbalance, and hypersomnolence. Lumbar puncture revealed hypercellular cerebrospinal fluid (CSF, WBC 39 cells/mL) and increased protein (178g/dL). Computed tomography (CT) demonstrated a mass in the right lower lobe with innumerable ‘miliary’ nodules in bilateral lungs (figure 1A). A positron emitting tomography (PET)/CT and brain magnetic resonance imaging (MRI) with and without contrast re-demonstrated a hypermetabolic right lobe mass with no extrathoracic metastases and diffuse nodular leptomeningeal enhancement with extension along cranial nerves consistent with leptomeningeal metastases (figure 2A). Core needle biopsy of the right lobe nodule demonstrated a moderately differentiated adenocarcinoma that was CK7+ and TTF1+ by immunohistochemistry. Allele-specific real-time PCR EGFR mutational testing (Qiagen, Manchester, UK) revealed an in-frame deletion in exon 19 of EGFR. Dual ALK/ROS1 FISH was negative for either gene rearrangement. The patient was hospitalized for failure to thrive with an Eastern Cooperative Oncology Group (ECOG) performance status of 4 and was started on erlotinib (150 mg/day), dexamethasone and levetiracetam. Marked improvement in his neurologic symptoms occurred within weeks of initiating erlotinib, and restaging CT demonstrated marked decrease in the size of the primary tumor and miliary nodules (figure 1B). Restaging brain MRI showed significant decrease of leptomeningeal enhancement (figure 2B). At this point the patient’s neurological function had improved and he was no longer experiencing abrupt onset spells or seizure activity. He was living independently, driving, and was primarily responsible for all activities of daily living. Montreal Cognitive Assessment score improved from unable to perform to a normal score of 29 out of a possible 30 points. The patient remained on erlotinib with continued partial response in his intrathoracic disease with leptomeningeal progression by MRI and associated cognitive decline after 8 months of sustained clinical and radiographic response. Progression of the leptomeningeal disease caused a significant decline in the patient’s performance status including confusion, short-term memory loss, progressive ataxia, and urinary incontinence. He was determined to be an unsuitable candidate for brain radiation or systemic treatment. After approximately 8 months the dose of erlotinib was increased to 1500mg weekly in an attempt to achieve higher CNS penetration. Treatment was discontinued after 4 weeks of pulsatile high dose erlotinib and dexamethasone for edema related symptoms with no improvement in his neurological status. Hospice care was initiated, and shortly thereafter the patient passed away. 1) Magnified axial Computed Tomography images of the chest (Panels A,B) demonstrating miliary disease burden within the right lower lobe of the lung at initial staging (Panel A). Additional representive axial image of the right lower lobe demostrating near ... 2) Axial T1 post-contrast images of Brain MRI with and without contrast (Panels A and B) demonstrating leptomeningeal enhancement in the subarachnoid spaces prior to erlotinib (A, arrow) with radiographic response approximately 4 months after initiating ... DISCUSSION EGFR tyrosine kinase inhibitors (TKIs, e.g. erlotinib, gefitinib, afatinib) are the preferred first line therapy for patients with activating mutations in EGFR due to superior efficacy and tolerability compared to standard chemotherapy.1-3 Penetration of erlotinib into the CNS is limited by the blood-brain barrier, with one pharmacokinetic trial of NSCLC patients with CNS metastasis reporting mean steady-state cerebrospinal fluid erlotinib (CSF) values of 54 ng/mL (standard deviation +/− 30ng/mL) which is equivalent to 5.1% (standard deviation +/−1 .9%) of the study cohort’s mean steady state plasma concentration. However, steady state CSF values of 54ng/mL well exceed known median inhibitory concentration of (IC50) of cell lines with sensitizing L858R and deletion 19 EGFR mutations treated with erlotinib.4 EGFR TKIs gefitinib and erlotinib have demonstrated activity against leptomeningeal metastases at standard dosages.5, 6 Furthermore, EGFR deletion 19 mutations may be predictive for improved outcomes for leptomeningeal metastasis as suggested by a recent cohort study that demonstrated that patients with EGFR deletion 19 mutations have improved clinical outcomes when compared to EGFR exon 21 mutation and EGFR wild-type cohorts with leptomeningeal metastasis. Median time to progression or symptom deterioration for patients with leptomeningeal metastasis was 7.8 months in the exon 19 deletion subgroup compared to 0.9 and 1.9 months in the wild type and exon 21 mutation cohorts, respectively.7 Where concerns regarding EGFR TKI penetration into the CNS exist or toxicity to standard daily dosages of erlotinib exist, pulsatile weekly erlotinib can improve both CSF drug concentration and CNS response.8, 9 While there was an attempt to recapture CNS response with pulsatile weekly erlotinib in our patient, it was proven unsuccessful with continued cognitive decline. It is unknown if the patient’s leptomeningeal relapse and continued progression was due inadequate delivery of erlotinib into the CNS or development of a secondary resistance mutation within the CNS. Isolated T790M resistance mutations within the CNS and different inter-patient mechanisms of resistance to EGFR inhibition (between the CNS and other areas of visceral metastasis) have been described in other case reports. 10

The Neurologic Assessment in Neuro-Oncology (NANO) Scale as an Assessment Tool for Survival in Patients With Primary Glioblastoma

BACKGROUND The Neurologic Assessment in Neuro-Oncology (NANO) scale is a standardized objective metric designed to measure neurological function in neuro-oncology. Current neuroradiological evaluation guidelines fail to use specific clinical criteria for progression. OBJECTIVE To determine if the NANO scale was a reliable assessment tool in glioblastoma (GBM) patients and whether it correlated to survival. METHODS Our group performed a retrospective review of all patients with newly diagnosed GBM from January 1, 2010, through December 31, 2012, at our institution. We applied the NANO scale, Karnofsky performance score (KPS), Eastern Cooperative Oncology Group (ECOG) scale, Macdonald criteria, and the Response Assessment in Neuro-Oncology (RANO) criteria to patients at the time of diagnosis as well as at 3, 6, and 12 mo. RESULTS Initial NANO score was correlated with overall survival at time of presentation. NANO progression was correlated with decreased survival in patients at 6 and 12 mo. A decrease in KPS was associated with survival at 3 and 6 mo, an increase in ECOG score was associated only at 3 mo, and radiological evaluation (RANO and Macdonald) was correlated at 3 and 6 mo. Only the NANO scale was associated with patient survival at 1 yr. NANO progression was the only metric that was linked to decreased overall survival when compared to RANO and Macdonald at 6 and 12 mo. CONCLUSION The NANO scale is specific to neuro-oncology and can be used to assess patients with glioma. This retrospective analysis demonstrates the usefulness of the NANO scale in glioblastoma.