The incidence of radiation necrosis has increased secondary to greater use of combined modality therapy for brain tumors and stereotactic radiosurgery. Given that its characteristics on standard ...imaging are no different that tumor recurrence, it is difficult to diagnose without use of more sophisticated imaging and nuclear medicine scans, although the accuracy of such scans is controversial. Historically, treatment had been limited to steroids, hyperbaric oxygen, anticoagulants, and surgical resection. A recent prospective randomized study has confirmed the efficacy of bevacizumab in treating radiation necrosis. Novel therapies include using focused interstitial laser thermal therapy. This article will review the diagnosis and treatment of radiation necrosis.
Approximately 40–50% of glioblastomas (GBM) overexpress epidermal growth factor receptor (EGFR). Erlotinib is a specific and potent EGFR tyrosine kinase inhibitor active against refractory GBM. ...Patients with non-small cell lung cancer and ≥grade 2 erlotinib-induced rash have improved survival. This phase 2 study assessed the efficacy and safety of concurrent radiation therapy (RT) and temozolomide with pharmacodynamic dose escalation of erlotinib in patients with newly diagnosed GBM. Patients received RT 60 Gy in 30 fractions with concurrent temozolomide 75 mg/m
2
/day × 42 days, followed in four weeks by temozolomide 150–200 mg/m
2
/day × 5, every 28 days for 12 cycles. Patients received erlotinib, 50 mg/day and increased by 50 mg/day every 2 weeks until the occurrence of grade 2 rash or to a maximum dose of 150 mg/day, from day 1 until disease progression. Twenty-seven patients were treated in this study. Twenty-two (81%) patients came off study for progressive disease (18 67%) or adverse events (4 15%). Eighteen patients (67%) have died. Median progression-free survival was 2.8 months, and the median overall survival was 8.6 months. Five patients remain on study with a median follow-up of 16 months. Grade 3/4 toxicities included thrombocytopenia, anemia, lymphopenia, fatigue, and febrile neutropenia. There were four deaths on study, three definitely treatment-related; therefore, the trial was terminated after accrual of 27 of 30 planned patients. Erlotinib co administered with RT and temozolomide was not efficacious and had an unacceptable toxicity.
Malignant transformation (MT) of adult grade 2 glioma (low-grade glioma LGG) is associated with adverse survival. We sought to describe the incidence, outcomes, and risk factors for MT of molecularly ...classified LGG.
We reviewed a single-institutional database of adults who received a diagnosis of LGG with data allowing for molecular classification from 1980 to 2018 to evaluate time to MT and its associated risk factors. MT was defined as pathologic confirmation of grade 3-4 glioma and/or imaging characteristics consistent with MT by multidisciplinary consensus.
Among the included 486 adults with molecularly classified LGG, median age was 39 years (range, 18-78), median tumor size was 3.9 cm (range, 0.3-13.0), and 262 (54%) were male. Molecular classification was IDH
1p/19q
in 169 (35%), IDH
1p/19q
in 125 (26%), and IDH
in 192 (40%) patients. Adjuvant management was observation in 246 (51%) patients, temozolomide alone in 82 (16%), radiation therapy alone in 63 (13%), and radiation therapy concurrent with temozolomide in 81 (17%). Temozolomide monotherapy was more likely to be given to IDH
1p/19q
patients (P < .001). Median follow-up was 5.3 years. MT occurred in 84 (17%) patients, with a 5-year freedom from MT of 86% (95% confidence interval CI, 82%-90%). Median overall survival after MT was 2.4 years (95% CI, 1.5-3.3) and was associated with molecular classification (P = .03) and grade at MT (P < .001). Factors associated with MT were male sex (hazard ratio HR, 2.1; 95% CI, 1.2-3.6; P = .009), tumor size ≥5 cm (HR, 3.5; 95% CI, 2.0-6.2; P < .001), IDH
1p/19q
(HR, 2.7; 95% CI, 1.3-5.6; P = .009) or IDH
classification (HR, 5.5; 95% CI, 2.5-11.8; P < .001), and adjuvant temozolomide monotherapy (HR, 3.8; 95% CI, 1.4-10.3; P = .008).
MT of LGG has a poor prognosis associated with unfavorable molecular groups. Analysis of our large cohort identified adjuvant temozolomide monotherapy as the only modifiable risk factor for MT and provides the first clinical evidence of temozolomide-associated MT among molecularly classified adult LGG. This novel finding supplements our understanding of temozolomide-induced hypermutation and informs precision management of LGG.
Abstract
Objective
To update the 2000 American Academy of Neurology (AAN) practice parameter on anticonvulsant prophylaxis in patients with newly diagnosed brain tumors.
Methods
Following the 2017 ...AAN methodologies, a systematic literature review utilizing PubMed, EMBASE Library, Cochrane, and Web of Science databases was performed. The studies were rated based on the AAN therapeutic or causation classification of evidence (class I-IV).
Results
Thirty-seven articles were selected for final analysis. There were limited high-level, class I studies and mostly class II and III studies. The AAN affirmed the value of these guidelines.
Recommendations
In patients with newly diagnosed brain tumors who have not had a seizure, clinicians should not prescribe antiepileptic drugs (AEDs) to reduce the risk of seizures (level A). In brain tumor patients undergoing surgery, there is insufficient evidence to recommend prescribing AEDs to reduce the risk of seizures in the peri- or postoperative period (level C). There is insufficient evidence to support prescribing valproic acid or levetiracetam with the intent to prolong progression-free or overall survival (level C). Physicians may consider the use of levetiracetam over older AEDs to reduce side effects (level C). There is insufficient evidence to support using tumor location, histology, grade, molecular/imaging features when deciding whether or not to prescribe prophylactic AEDs (level U).
Little is known on the natural history, recurrence patterns, neurocognitive outcomes and prognostic factors associated with survival in long-term survivors (≥10 years) from brain metastasis (BM). In ...this study, the records of 1953 patients who underwent treatment for BM with a potential for ≥10 years of follow-up were reviewed. Cox regression analysis identified factors predictive for overall survival (OS). The median age at brain metastasis diagnosis was 60 years and the median OS was 6.4 months. The 1-year OS rate was 29.9, 12.1 % at 2 years, 3.0 % at 5 years, and 1.3 % at 10 years. On multivariable analysis, factors associated with worse OS included gender (males, HR 1.2), multiple brain metastases (HR 1.3), no surgery (HR 1.8), and no stereotactic radiosurgery (HR 1.8) (p < 0.0001 each). Fifty-six patients (2.9 %) survived ≥5 years; 23 patients (1.2 %) survived ≥10 years and the median survival for ≥10 year survivors was 18.5 years. Six of the 10-year survivors had an intracranial recurrence, five occurred within 11 years from the first treatment. Presence of a solitary lesion or single lesion at the time of brain metastasis diagnosis was associated with improved survival. Eight of the ≥10 year survivors (34.8 %) had no neurological symptoms at last follow-up; none of the 10-year survivors were documented to have a neurologic death. Our study demonstrates that patients with favorable prognostic features should undergo multimodality treatment. Albeit rare, patients who are alive 10 years after treatment for their brain metastases may be considered cured from their intracranial disease.
The incidence, risk factors, and outcomes of low-grade glioma patients who undergo malignant transformation (MT) in the era of temozolomide are not well known. This study evaluates these factors in a ...large group of World Health Organization grade 2 glioma patients treated at a tertiary-care institution.
Patient, tumor, and treatment factors were analyzed using an institutional review board-approved low-grade glioma database. Characteristics were compared using χ
and Wilcoxon signed rank tests. Time to event was summarized using proportional hazards models. Univariate and multivariate survival analyses were performed.
Of a total of 599 patients, 124 underwent MT; 76 (61.3%) had biopsy-proven MT. The MT incidence was 21%, and the median time to MT was 56.4 months. The 5- and 10-year progression-free survival rates were 30.6% ± 4.2% and 4.8% ± 1.9%, respectively, for MT patients and 60% ± 2.4% and 38% ± 2.7%, respectively, for non-MT patients. The 5- and 10-year overall survival rates were 75% ± 4.0% and 46% ± 5.0%, respectively, for MT patients and 87% ± 1.7% and 78% ± 2.3%, respectively, for non-MT patients. On multivariate analysis, older age (P = .001), male sex (P = .004), multiple tumor locations (P = .004), chemotherapy alone (P = .012), and extent of resection (P = .045) remained significant predictors of MT.
MT affects survival. Risk factors include older age, male sex, multiple tumor locations, use of chemotherapy alone, and presence of residual disease. Our finding that initial interventions could affect the rate of MT is provocative, but these data should be validated using data from prospective trials. In addition to improving survival, future therapeutic efforts should focus on preventing MT.
Purpose
We sought to evaluate the effects of concurrent temozolomide-based chemoradiation therapy on neurocognitive function in patients with low-grade glioma (LGG).
Materials/methods
We included ...adult patients with LGG who were treated postoperatively with radiotherapy (RT) with concurrent and adjuvant temozolomide (TMZ). Patients were evaluated with comprehensive psychometric tests at baseline (prior to RT + TMZ) and at various time intervals following RT + TMZ. Baseline cognitive performance was analyzed by sex, age, education history, history of seizures, IDH mutation status, and 1p/19q codeletion status. Changes in neurocognitive performance were evaluated over time.
Results
Thirty-seven LGG patients (mean age 43.6, 59.5% male) had baseline neurocognitive evaluation. Patients with an age > 40 years old at diagnosis and those with an education > 16 years demonstrated superior baseline verbal memory as assessed by HVLT. No other cognitive domains showed differences when stratified by the variables mentioned above.
A total of 22 LGG patients had baseline and post RT + TMZ neurocognitive evaluation. Overall, patients showed no statistical difference between group mean test scores prior to and following RT + TMZ on all psychometric measures (with the exception of HVLT Discrimination).
Conclusion
Cognitive function remained stable following RT + TMZ in LGG patients evaluated prospectively up to 2 years. The anticipated analysis of RTOG 0424 will provide valuable neurocognitive outcomes specifically for high risk LGG patients treated with RT + TMZ.
Purpose
Low-grade glioma (LGG) exhibits longer median survival than high-grade brain tumors, and thus impact of our therapies on patient quality of life remains a crucial consideration. This study ...evaluated the effects of concurrent temozolomide-based chemoradiation (RT + TMZ) or observation on quality of life (QOL) in patients with low-grade glioma.
Methods
We completed a retrospective cross-sectional study of adults with LGG who underwent surgery with known molecular classification from 1980 to 2018. Postoperatively, patients were either observed or received adjuvant concurrent temozolomide-based chemoradiation. EQ-5D and PHQ-9 depression screen were completed before outpatient visits every 2–3 months. Baseline score was defined as ± 30 days within initial operation.
Results
Of the 63 patients (mean age 44 ± 17 years, 51% female) with baseline EQ-5D or PHQ-9 depression screen data and at least one follow-up measure, 30 (48%) were observed and 33 (52%) received RT + TMZ. No significant decline was seen in EQ-5D or PHQ-9 scores at 3, 6, 9, 12, and 24 months compared to baseline scores for all patients. At each time point, there was no significant difference between those who were observed or received adjuvant therapy. The linear mixed model estimating PHQ-9 value or EQ-5D index demonstrated that there was no significant difference in PHQ-9 or EQ-5D index between treatment groups (p = 0.42 and p = 0.54, respectively) or time points (p = 0.24 and p = 0.99, respectively).
Conclusion
Our study found no significant decline in patient QOL or depression scores as assessed by patient- reported outcome measures for patients with low-grade glioma up to 2 years following surgery. We found no difference between RT + TMZ compared to observation during this time frame. Additional follow-up can help identify the longer-term impact of treatment strategy on patient experience.
Purpose
Distinguishing radiation necrosis from tumor progression among patients with brain metastases previously treated with stereotactic radiosurgery represents a common diagnostic challenge. We ...performed a prospective pilot study to determine whether PET/CT with
18
F-fluciclovine, a widely available amino acid PET radiotracer, repurposed intracranially, can accurately diagnose equivocal lesions.
Methods
Adults with brain metastases previously treated with radiosurgery presenting with a follow-up tumor-protocol MRI brain equivocal for radiation necrosis versus tumor progression underwent an
18
F-fluciclovine PET/CT of the brain within 30 days. The reference standard for final diagnosis consisted of clinical follow-up until multidisciplinary consensus or tissue confirmation.
Results
Of 16 patients imaged from 7/2019 to 11/2020, 15 subjects were evaluable with 20 lesions (radiation necrosis, n = 16; tumor progression, n = 4). Higher SUV
max
statistically significantly predicted tumor progression (AUC = 0.875; p = 0.011). Lesion SUV
mean
(AUC = 0.875; p = 0.018), SUV
peak
(AUC = 0.813; p = 0.007), and SUV
peak
-to-normal-brain (AUC = 0.859; p = 0.002) also predicted tumor progression, whereas SUV
max
-to-normal-brain (p = 0.1) and SUV
mean
-to-normal-brain (p = 0.5) did not. Qualitative visual scores were significant predictors for readers 1 (AUC = 0.750; p < 0.001) and 3 (AUC = 0.781; p = 0.045), but not for reader 2 (p = 0.3). Visual interpretations were significant predictors for reader 1 (AUC = 0.898; p = 0.012) but not for reader 2 (p = 0.3) or 3 (p = 0.2).
Conclusions
In this prospective pilot study of patients with brain metastases previously treated with radiosurgery presenting with a contemporary MRI brain with a lesion equivocal for radiation necrosis versus tumor progression,
18
F-fluciclovine PET/CT repurposed intracranially demonstrated encouraging diagnostic accuracy, supporting the pursuit of larger clinical trials which will be necessary to establish diagnostic criteria and performance.
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