Correlation between Cranial Nerve Microstructural Characteristics and Vestibular Schwannoma Tumor Volume.

BACKGROUND AND PURPOSE: Vestibular schwannomas are common cerebellopontine angle tumors arising from the vestibulocochlear nerve and can result in cranial nerve dysfunction. Conventional MR imaging does not provide information that could correlate with cranial nerve compression symptoms of hearing loss or imbalance. We used multitensor tractography to evaluate the relationship between the WM microstructural properties of cranial nerves and tumor volume in a cohort of patients with vestibular schwannomas. MATERIALS AND METHODS: A retrospective study was performed in 258 patients with vestibular schwannomas treated at the Gamma Knife clinic at Toronto Western Hospital between 2014 and 2018. 3T MR images were analyzed in 160 surgically naïve patients with unilateral vestibular schwannomas. Multitensor tractography was used to extract DTI-derived metrics (fractional anisotropy and radial, axial, and mean diffusivities of the bilateral facial and vestibulocochlear nerves [cranial nerves VII/VIII]). ROIs were placed in the transition between cisternal and intracanalicular segments, and images were analyzed using the eXtended Streamline Tractography reconstruction method. Diffusion metrics were correlated with 3D tumor volume derived from the Gamma Knife clinic. RESULTS: DTI analyses revealed significantly higher fractional anisotropy values and a reduction in axial diffusivity, radial diffusivity, and mean diffusivity (all P < .001) within the affected cranial nerves VII and VIII compared with unaffected side. All specific diffusivities (axial, radial, and mean diffusivity) demonstrated an inverse correlation with tumor volume (axial, radial, and mean diffusivity, P < .01). CONCLUSIONS: Multitensor tractography allows the quantification of cranial nerve VII and VIII WM microstructural alterations in patients with vestibular schwannomas. Our findings support the hypothesis that tumor volume may cause microstructural alterations of the affected cranial nerves VII and VIII. This type of advanced imaging may represent a possible avenue to correlate diffusivities with cranial nerve function.

Re-irradiation for Paediatric Tumours.

Despite best available therapy, many children with cancer develop recurrence after multimodal treatment, including initial radiation therapy. Re-irradiation is defined as the use of a second course of radiation therapy with a retreatment volume that overlaps substantially with that of a previously delivered course of radiation therapy. Re-irradiation is an important part of salvage treatment for patients with recurrent ependymoma, diffuse intrinsic pontine glioma, medulloblastoma and germinoma. In patients with ependymoma, conventionally fractionated re-irradiation (1.8 Gy/day) can provide long-term disease control with low rates of high-grade toxicity. For children with progressive diffuse intrinsic pontine glioma, re-irradiation provides effective palliation of symptoms and a survival gain as compared with those treated without re-irradiation. Repeat radiation therapy that includes craniospinal irradiation, if safe to deliver, may provide long-term tumour control in patients with medulloblastoma. Patients with recurrent intracranial germinoma can be effectively salvaged with re-irradiation that includes craniospinal irradiation. Finally, the emerging role of re-irradiation in non-brainstem high-grade glioma and extracranial solid tumours requires further study regarding its efficacy and safety. When given, re-irradiation should be delivered with care so that doses to organs at risk are minimised. In all cases, re-irradiation should be considered as an option alongside, or concurrently with, other salvage treatments, including surgery or systemic therapy, to maximise the likelihood of durable disease control.

PRODIGE: a randomized placebo-controlled trial of dalteparin low-molecular-weight heparin thromboprophylaxis in patients with newly diagnosed malignant glioma.

BACKGROUND AND OBJECTIVES: Venous thromboembolism (VTE) occurs in 20-30% of patients with malignant glioma per year of survival. We tested the efficacy of long-term dalteparin low-molecular-weight heparin (LMWH) for prevention of VTE in these patients. PATIENTS/METHODS: Adults with newly diagnosed malignant glioma were randomized to receive dalteparin 5000 anti-Xa units or placebo, both subcutaneously once daily for 6 months starting within 4 weeks of surgery. Treatment continued for up to 12 months. The primary outcome was the cumulative risk of VTE over 6 months. The target sample size was 512 patients. Events were adjudicated by a committee unaware of treatment. RESULTS: The trial began in 2002 and closed in May 2006 because of expiration of study medication. Ninety-nine patients were randomized to LMWH and 87 to placebo. Twenty-two patients developed VTE in the first 6 months: nine in the LMWH group and 13 in the placebo group [hazard ratio (HR) = 0.51, 95% confidence interval (CI): 0.19-1.4, P = 0.29]. At 6 months, there were three major bleeds on LMWH and none on placebo; at 12 months, 5 (5.1%) major bleeds on LMWH and 1 (1.2%) on placebo occurred (HR = 4.2, 95% CI: 0.48-36, P = 0.22). All major bleeds were intracranial and occurred while on study medication. The 12-month mortality rates were 47.8% for LMWH and 45.4% for placebo (HR = 1.2, 95% CI: 0.73-2.0, P = 0.48). CONCLUSIONS: Trends suggesting reduced VTE and increased intracranial bleeding were seen in the LMWH thromboprophylaxis group. The role of long-term anticoagulant thromboprophylaxis in patients with brain tumors remains uncertain.

A population-based study of malignant spinal cord compression in Ontario.

DESIGN: Population-based cohort study. BACKGROUND: Malignant spinal cord compression (MSCC) has long been recognized as an important complication of cancer, but its incidence is unknown. OBJECTIVES: To describe the incidence, the management, and the outcome of MSCC in the cancer population of the Canadian province of Ontario. METHODS: Episodes of MSCC, and treatments used for each episode, were identified by linking electronic hospital separation records and cancer centre records to Ontario's population-based cancer registry. The cumulative frequency of MSCC in the last 5 years of life was described in the 121435 patients who died of cancer in Ontario between 1990 and 1995. Survival after the first episode of MSCC, and duration of hospitalization with MSCC, was described. RESULTS: The cumulative probability of experiencing at least one episode of MSCC in the 5 years preceding death from cancer was 2.5% overall, and ranged from 0.2% in cancer of the pancreas to 7.9% in myeloma. Overall, 60.2% of first episodes of MSCC were treated with primary radiotherapy, and 16.1% with surgery +/- postoperative radiotherapy, while in the remaining 23.7%, there was no record of radiotherapy or surgery. Overall, the median survival following the first episode of MSCC was 2.9 months. The diagnosis of MSCC was associated with a doubling of the time spent in hospital in the last year of life. CONCLUSION: MSCC is a fairly common occurrence among patients dying of cancer. There is a 40-fold variation in the cumulative incidence of MSCC among different types of cancer.

A retrospective analysis of 52 cases of spinal cord glioma managed with radiation therapy.

PURPOSE: To describe the outcome of primary spinal cord glioma treated with radiation therapy after surgery and to identify variables predictive of outcome. METHODS AND MATERIALS: A chart review of 52 patients with a diagnosis of spinal cord non-ependymoma glioma at the Princess Margaret Hospital was conducted. Thirty-two patients (62%) were male and 20 (38%) were female. Median age was 32 years (2-76 years). Median follow-up was 3.7 years (2 months to 27 years). Initial surgical management consisted of biopsy alone in 27 (52%) cases, subtotal resection in 20 (38%) cases, and gross total resection in 5 (10%) cases. All patients received postoperative radiation therapy; median total dose was 50 Gy, given in 25 daily fractions (20-60 Gy). Actuarial survival rates were calculated and the influence of patient-, tumor-, and treatment-related variables on outcome was determined. RESULTS: Five-year overall, cause-specific, and progression-free survivals were 54%, 62%, and 58%, respectively. Ten-year survivals were 45%, 50%, and 43%, respectively. A total of 29 (56%) patients died during the period of review. For 23 (79%) of these patients, death was cancer specific. Progression of tumor was documented in 28 of 52 (54%) patients. The following factors predicted for improved outcome on univariate analysis: age < 18 years, low-grade histology, and length of symptoms prior to diagnosis > 6 months. CONCLUSION: The outcome of patients in this series is consistent with that of other similar published reports. Specific recommendations are made for the management of this tumor.

Randomized study of brachytherapy in the initial management of patients with malignant astrocytoma.

PURPOSE: A randomized study was undertaken to assess the role of brachytherapy as a boost to external beam radiation therapy in the initial management of patients with malignant astrocytomas. METHODS AND MATERIALS: Inclusion criteria included the following: biopsy-proven supratentorial malignant astrocytoma of brain < or =6 cm in size, not crossing midline or involving corpus callosum, age 18-70, Karnofsky Performance Status (KPS) > or =70. Patients were randomized to external radiation therapy only delivering 50 Gray (Gy) in 25 fractions over 5 weeks or external radiation therapy plus a temporary stereotactic iodine-125 implants delivering a minimum peripheral tumor dose of 60 Gy. Patients were stratified to age < or =50 or >50, and KPS > or =90 or < or =80. RESULTS: There were 140 patients randomized between 1986 and 1996, 71 to the implant arm and 69 to external irradiation only. Pathologically 125 patients had necrosis noted in their tumor specimen. Factors associated with improved survival in univariate analysis were age < or =50, KPS > or =90, chemotherapy at recurrence, and reoperation at the original tumor site. The Cox proportional hazards model revealed the following significant factors: treatment at recurrence (chemotherapy or reoperation) with a relative risk (RR) of 0.6 (p = 0.004) and KPS > or =90 with a RR 0.6 (p = 0.007). Randomization to the implant arm was associated with a RR of 0.7 (p = 0.07). Median survival for patients randomized to brachytherapy or not were 13.8 vs. 13.2 months, respectively, p = 0.49. CONCLUSIONS: We conclude that stereotactic radiation implants have not demonstrated a statistically significant improvement in survival in the initial management of patients with malignant astrocytoma.

Accelerated radiation therapy for primary lymphoma of the brain.

BACKGROUND AND PURPOSE: We report the results of a pilot study of the use of accelerated radiation therapy for 10 patients with primary lymphoma of the brain. MATERIALS AND METHODS: There were five females and five males with a median age of 60 years (range 31-77 years) and a median Karnofsky performance status of 60 (range 30-90). Nine patients underwent biopsies only and one patient underwent a partial resection. The radiation therapy consisted of 50 Gy in 25 fractions over 13 consecutive days to the whole brain including all meningeal surfaces. Two fractions were delivered daily with a minimum interval of 6 h between fractions. Treatment was delivered daily right through the weekend with no treatment interruptions. RESULTS: To date nine patients have died. The median survival was 17 months. Seven patients have demonstrated definite evidence of recurrence (six in the brain and one with positive CSF cytology only). There have been two autopsies, one of which demonstrated diffusely recurrent tumor and the other showing residual disease and radiation demyelination and small areas of necrosis in the pons which undoubtedly was the cause of death at 5 months. One patient alive and free of recurrence at 69 months has bilateral radiation retinopathy and an undiagnosed degenerative neurologic condition. CONCLUSION: We conclude that this accelerated schedule of radiation therapy is ineffective in improving survival in primary lymphoma of the brain and is associated with unacceptable increased toxicity.

Emergency treatment of malignant extradural spinal cord compression: an evidence-based guideline.

PURPOSE: To review the literature for malignant extradural spinal cord compression (MSCC), produce evidence-based recommendations based on the criteria used by the Canadian Task Force on the Periodic Health Examination, and make suggestions regarding future research directives. METHODS: A systematic review of the literature with explicit study selection and evaluation criteria was performed. Primary outcome measure was posttreatment ambulation rate. RESULTS: There is good evidence to support the use of high-dose dexamethasone (96 mg/d), but inconclusive evidence for the use of moderate-dose steroids (16 mg/d) in conjunction with radiotherapy (RT) for the treatment of MSCC. Fair evidence exists for not using steroids in patients who are nonparetic and ambulatory pretreatment, and to give radiation to patients with subclinical spinal cord compression (SCC). The remainder of the recommendations are based on inconclusive evidence: RT alone should be the first-line treatment for ambulatory patients except when there is spinal instability, bony compression, or paraplegia on presentation, in which case surgery should be performed. Either modality can be used for paraparetic patients who are nonambulatory. Postoperative RT should be considered for tumor in residua. Ambulatory, undiagnosed patients should have needle biopsy attempted first. Patients should be aggressively screened and educated about SCC. CONCLUSION: In general, there were very few papers of high methodologic quality found in the literature. More studies are needed to satisfy the validity of many of the clinical decisions that are made today with regard to the management of MSCC.

Post-operative radiotherapy for recurrent dermoid cysts of the spine: a report of 3 cases.

We report three cases of recurrent, intraspinal dermoid cysts managed with post-operative radical radiotherapy. In all cases, the period between last surgery and cystic re-accumulation has been lengthened by the use of involved-field radiotherapy. This combined-modality approach could be beneficial in decreasing the probability of recurrence associated with incompletely-resected tumours, or in patients whose co-morbidities put them at increased operative risk for serial neurosurgical procedures.

Primary lymphoma of brain: results of management of a modern cohort with radiation therapy.

PURPOSE: To assess the outcome and prognostic factors for patients with primary lymphoma of brain managed with radiation therapy between 1979 and 1988. METHODS AND MATERIALS: A retrospective review was undertaken of 49 patients referred to Princess Margaret Hospital. There were 25 males and 24 females. Median age was 60 years, with a range of 17-80 years. Tumors were located supratentorially in 35, infratentorially in 10, and both in 4 patients. Single masses were demonstrated on CT brain in 36, and multiple lesions in 13 patients. Cranial irradiation was given in 48, and 11 patients received chemotherapy. All patients in this series were immunocompetent. RESULTS: Over a follow-up range of 3-11 years of surviving patients, with a median of 6 years, 40/49 patients have died. Overall median survival was 1.4 years (17 months) and 5-year actuarial survival was 26%. Statistical analysis revealed the following significant factors: Karnofsky performance status (KPS), age, and distribution pattern of disease on presenting CT brain. Five-year actuarial survival for patients with a KPS > 60 or <60 was 56% and 10%, respectively (P = 0.01); for patients with age < 60 or >60, 5-year actuarial survival was 42% and 9%, respectively (P = 0.03); for patients with solitary or multiple lesions, 5-year actuarial survival was 30% and 15%, respectively (P = 0.04). CONCLUSIONS: We conclude that Karnofsky performance status, age, and distribution pattern on pretreatment CT of brain are significant prognostic factors in primary lymphoma of brain, and that new approaches need to be developed for these patients.

Radiotherapy for atypical or malignant intracranial meningioma.

PURPOSE: To study the natural history of intracranial atypical and malignant meningiomas, and the role of radiotherapy in the treatment of these tumors. METHODS AND MATERIALS: The records of the 59 patients who were treated at the Princess Margaret Hospital between 1966 and 1990 with histologically confirmed intracranial atypical or malignant meningiomas were retrospectively reviewed. The median age was 58 years. Twenty-four patients were referred for radiation immediately after diagnosis and the remainder after at least one recurrence. The extent of the most recent surgery prior to radiation was gross total excision in 17, subtotal excision in 35, biopsy in 3, and none or unknown in 4. Seventeen had atypical meningiomas, defined as the presence of mitoses, nuclear atypia, or necrosis. Forty-two had malignant meningiomas on the basis of brain invasion (60%) or a pathologist's designation of malignant or hemangiopericytic meningioma. All patients received megavoltage radiation to a median dose of 50 Gy. RESULTS: Disease progressed in 39 patients (66%) after radiation. Of these, 36 died of meningioma and 3 were alive after further surgery. The 5-year actuarial overall and cause-specific survivals were 28 and 34%, respectively. Age less than 58, treatment after 1975, and a radiation dose of 50 Gy or more were independently associated with higher cause-specific survival by multivariate analysis. CONCLUSIONS: Young age, modern imaging and treatment planning techniques, and a postoperative radiation dose of at least 50 Gy contribute to improved outcome in patients with atypical or malignant meningiomas. We recommend that all patients receive radiotherapy immediately after initial surgery.

Medulloblastoma in adults.

PURPOSE: To assess the outcome and prognostic factors for adult patients with medulloblastoma managed by postoperative radiotherapy between 1958 and 1988 at the Princess Margaret Hospital. METHODS AND MATERIALS: A retrospective review was undertaken of 48 patients age 16 years or older who received radiotherapy for medulloblastoma. The median age at diagnosis was 25 years, with 36 male and 12 female patients. Sixteen tumors were confined to midline structures, and 32 were localized to a cerebellar hemisphere or involved midline and lateral structures. The desmoplastic variant was reported in 12 cases. Complete macroscopic removal was achieved in 22 patients, subtotal removal in 23, and biopsy only in 3. Forty-six patients received craniospinal radiation and 2 patients received local irradiation only. RESULTS: Median overall survival was 7.9 years, and 5- and 10-year overall survival was 62% and 41%, respectively. Significant factors for disease-free survival were M stage (M0 vs. M1-4, p = 0.0005), functional state at the time of radiotherapy (1-2 vs. 3-5, p = 0.005), and the absence or presence of hydrocephalus preoperatively (p = 0.02). Twenty-four patients developed recurrent disease, with 14 relapsing first in the posterior fossa. Subtotal removal of tumor (p = 0.04) was the only factor predictive of posterior fossa relapse. CONCLUSIONS: Patients with disease outside the posterior fossa at diagnosis, symptomatic patients (neurologic functional state 3-5) at the time of radiotherapy, and those who present with hydrocephalus have poorer disease-free survival. Gross total resection improved posterior fossa control.

Radiation myelopathy following single courses of radiotherapy and retreatment.

PURPOSE: To assess the latent time, survival and dose-fractionation factors associated with permanent radiation myelopathy following single and multiple courses of radiotherapy to the spinal cord. METHODS AND MATERIALS: A retrospective analysis was undertaken of all patients who were registered at the Princess Margaret Hospital between 1955 and 1985, and who developed permanent radiation myelopathy. There were 22 males and 13 females with ages ranging from 30 to 72 years. Twenty-four patients developed permanent myelopathy after one course of radiation therapy and 11 patients following retreatment. Seven patients had histological confirmation of radiation myelopathy at autopsy. RESULTS: The actuarial survival was 14% at 5 years (median: 8.3 months) from the date of diagnosis of radiation myelopathy. Latent times for myelopathy following a single course of treatment (mean: 18.5 months, 7-57 months), were significantly longer than those after reirradiation (mean: 11.4 months, 4-25 months), p = 0.03. There was not a single incident of myelopathy in patients who received fractionated radiotherapy given once daily to an extrapolated response dose (ERD) of < or = 100 Gy2 (equivalent to 50 Gy in 25 daily fractions). Four patients who developed myelopathy after an ERD of < 100 Gy2 were all treated on accelerated fractionation protocols with multiple fractions given per day. Patients who were reirradiated received significantly higher doses (mean ERD of 148 Gy2) than those who had a single course of treatment (mean ERD of 121 Gy2), p = 0.001. CONCLUSION: We conclude that the risk of radiation myelopathy following conventionally fractionated radiotherapy to the spinal cord is extremely small; giving multiple fractions per day reduces the spinal cord tolerance; latent time to myelopathy decreases following retreatment; and there is possible long-term recovery of radiation damage in the human spinal cord.

Radiotherapy for brain tumors.

Improved techniques of radiotherapy have led to marked improvement in the results of radiotherapy for certain brain tumors, such as medulloblastoma and pineal germinoma, but results for malignant astrocytoma, the most common brain tumor, have been modest. This article reviews results of radiotherapy for brain tumors in adult patients over the last decade and comments on the new approaches being studied.

Glioma arising after radiation therapy for pituitary adenoma. A report of four patients and estimation of risk.

BACKGROUND: Many case reports in the literature associate cranial radiation therapy with the development of brain tumors. Quantitation of the risk of second brain tumors after irradiation in childhood is available, but it is seldom reported for those treated by radiation therapy as adults. METHODS: A retrospective review was made of 367 patient records registered at the Princess Margaret Hospital with a diagnosis of pituitary adenoma from 1972 to 1986. Three hundred five patients treated with megavoltage radiation therapy form the basis of this report. Second brain tumors were identified and the patient case histories described. The risk of second brain tumor after irradiation was estimated by calculating the observed/expected (O/E) ratio, age- and sex-adjusted to the Ontario population. RESULTS: Of the 305 patients in this study, 4 had glioma of the brain. All gliomas arose within the previous radiation field(s), with a latency of 8-15 years after radiation therapy. Additional treatment was compromised by the location of the glioma and the moderately high doses of radiation received previously; all four patients died of their gliomas. Our cohort of patients had a relative risk of malignant brain tumor 16 times greater than that of the general population in Ontario (P < 0.001; 95% confidence interval, 4.4-41). The cumulative actuarial risk of secondary glioma after radiation therapy was 1.7% at 10 years and 2.7% at 15 years. CONCLUSIONS: There was a clinically significant increased risk of malignant brain tumor developing after radiation therapy for pituitary adenoma. Because there is no reported association between pituitary adenomas and gliomas of brain, this excess risk is attributed to irradiation. Before advising radiation therapy for pituitary adenoma, the risk:benefit ratio, including the risk of secondary brain tumors, should be carefully considered.

Spinal cord ependymomas: a retrospective analysis of 59 cases.

PURPOSE: To determine the outcome of patients with primary spinal ependymoma treated with postoperative radiotherapy and to identify clinical and treatment variables predictive of outcome. METHODS AND MATERIALS: A retrospective chart review was undertaken of 59 spinal ependymoma patients referred to the Princess Margaret Hospital between 1958 and 1987. All patients were treated with radiation therapy to either the site of the primary tumor or the craniospinal axis. There were 23 female and 36 male patients with a median age of 37 years (range: 8-66 years). Median follow-up was 130 months (range: 1-371 months). Clinical variables including age, sex, length of symptoms, functional status, tumor location, and grade as well as treatment variables including extent of surgery, radiation dose and treatment volume were analyzed for influence on outcome. RESULTS: Treatment was well-tolerated with no cases of radiation myelopathy identified. Overall actuarial survival at 5 and 10 years was 83% and 75%, respectively. Eleven patients had recurrent tumor with the 9/11 having a component of their recurrence within the treatment field. Median time to recurrence was 2 years with 9 of the 11 recurrences within the first 3 years. Tumor grade was the only independent variable identified as predictive of outcome. Patients with well differentiated tumors had a 5-year cause-specific survival of 97% compared to 71% for those with intermediate or poorly differentiated tumors (p = 0.005). CONCLUSION: We conclude that postoperative irradiation for patients with spinal ependymomas is associated with a favorable outcome and that tumor grade is a major prognostic factor. Based on results of this series and a review of the literature, specific management recommendations are made for this rare tumor.

Critical appraisal of experimental radiation modalities for malignant astrocytomas.

The management of patients with supratentorial malignant astrocytomas has remained a major problem. Patients continue to die from a lack of local control in 90% of cases despite an improvement of median survival seen with the use of postoperative radiation therapy. Because of this, there has been considerable interest in exploring novel ways of possibly improving results. This paper reviews the rationale and clinical results with the use of altered fractionation schemes, brachytherapy, radiation sensitizers, hyperthermia, particle therapy, and radiosurgery in the treatment of these patients. Currently, there is no demonstrated advantage with the use of these experimental modalities in the initial management of patients. There would appear to be some benefit for selected patients who are treated with brachytherapy at recurrence, but its efficacy as part of initial management remains to be determined determined in ongoing randomized prospective trials.

A critical appraisal of the role of brachytherapy for pediatric brain tumors.

While brachytherapy is increasingly being utilized in adult patients with brain tumors, there has been very little experience with this approach in pediatric patients. This report reviews the current published experience with brachytherapy for brain tumors in children. Intracavitary irradiation with radioactive colloid is quite effective in controlling cystic craniopharyngiomas and represents an alternative approach to this subgroup of patients with craniopharyngiomas. There has been a substantial experience with the use of permanent interstitial implants in cases of low-grade astrocytoma in Europe, but its value is difficult to judge because of the variable natural history of these slow-growing neoplasms. Very few high-grade astrocytomas have been treated with brachytherapy in children, but children with localized recurrences after conventional therapy should be considered for this approach.