Intrinsic Brainstem Tumors Research Articles

There is no role for hyperfractionated radiotherapy in the management of children with newly diagnosed diffuse intrinsic brainstem tumors: results of a pediatric oncology group phase III trial comparing conventional vs. hyperfractionated radiotherapy

Purpose: In June 1992, POG began accrual to a phase III study, POG-9239, designed to compare the time to disease progression, overall survival, and toxicities observed in children with newly diagnosed brainstem tumor treated with 100 mg/m2 of infusional cisplatin and randomized to either conventional vs. hyperfractionated radiotherapy.Methods and Materials: Patients eligible for study were those between 3 and 21 years of age with previously untreated tumors arising in the pons. Histologic confirmation of diagnosis was not mandatory, provided that the clinical and MRI scan findings were typical for a diffusely infiltrating pontine lesion. Treatment consisted of a six-week course of local field radiotherapy with either once a day treatment of 180 cGy per fraction to a total dose of 5400 cGy (arm 1) or a twice a day regimen of 117 cGy per fraction to a total dose of 7020 cGy (the second of the three hyperfractionated dose escalation levels of POG-8495) (arm 2). Because of previously reported poor results with conventional radiotherapy alone, cisplatin was included as a potential radiosensitizer in an attempt to improve progression-free and ultimate survival rates. Based on results of the phase I cisplatin dose escalation trial, POG-9139, 100 mg/m2 was chosen for this trial and was delivered by continuous infusion over a 120-hour period, beginning on the first day of radiotherapy and repeated during weeks 3 and 5. One hundred thirty eligible patients were treated on protocol, 66 on arm 1 and 64 on arm 2.Results: The results we report are from time of diagnosis through October 1997. For patients treated on arm 1, the median time to disease progression (defined as time to off study) was 6 months (range 2–15 months) and the median time to death 8.5 months (range 3–24 months); survival at 1 year was 30.9% and at 2 years, 7.1%. For patients treated on arm 2, the corresponding values were 5 months (range 1–12 months) and 8 months (range 1–23 months), with 1- and 2-year survival rates at 27.0% and 6.7%, respectively. Evaluation of response by MRI at 4 or 8 wks post treatment was available in 108 patients and revealed a complete response in 1 patient of each Rx arm, a partial response (> 50% decrease in size) in 18 patients of arm 1 and 15 patients of arm 2, minimal to no response (stable) in 25 patients of arm 1 and 23 patients of arm 2, and progressive disease in 13 patients of arm 1 and 12 patients of arm 2. The pattern of failure was local in all patients. Morbidity of treatment was similar in both Rx arms, with no significant toxicity (including hearing loss) reported. Autopsy was performed in 6 patients, and confirmed the presence of extensive residual tumor in these cases.Conclusion: The major conclusion from this trial is that the hyperfractionated method of Rx 2 did not improve event-free survival (p = 0.96) nor did it improve survival (p = 0.65) over that of the conventional fractionation regimen of Rx 1, and that both treatments are associated with a poor disease-free and survival outcome.

P251 Surgery of intrinsic brainstem tumors: Electrophysiological monitoring of cranial motor nuclei III–XII

P251 Surgery of intrinsic brainstem tumors: Electrophysiological monitoring of cranial motor nuclei III–XII

REVIEWER'S COMMENTS ON ARTICLE 1

The authors have adapted the long-recognized technology of electromyography as a surgical adjunct and used the information it provides in a relatively novel way. Most of us who have been interested in mapping and monitoring brainstem function during posterior fossa surgery have used the electrophysiological technique to minimize morbidity during removal of intrinsic brainstem tumors. Grabb, et al., have utilized information gleaned from intraoperative electromyographic monitoring of cranial nerves six and seven not to facilitate intrinsic brainstem surgery, but, rather, to warn the surgeon away from entering the brainstem during removal of tumors that are juxtaposed to it. This technique, applicable to this end, would certainly be a worthwhile adjunct to the removal of tumors deep in the cerebellar hemisphere or tumors that are extending through a cerebellar peduncle toward the brainstem. Very often, we are cautious in pursuing a tumor deep within the cerebellar hemisphere for fear of injuring the brainstem and, if this technique obviates that concern, it would certainly be a very worthwhile adjunct.

Hyperfractionated radiotherapy for diffuse intrinsic brain stem tumors in children.

Over the past decade, the principle focus of clinical research in children with diffuse intrinsic brain stem tumors has been on the use of hyperfractionated radiotherapy because of the predominantly local pattern of failure and the evidence for a dose-response relationship with conventional radiotherapy that might suggest an advantage to the use of the higher total radiation doses that can be given using a hyperfractionated schedule. Since 1984, large numbers of children have been accrued to a series of phase I/II studies testing escalating doses of hyperfractionated radiotherapy. At the lowest dose levels of 64.8 and 66 Gy, results were not better than those seen after conventional treatment and no unusual or unexpected toxicity was observed. At intermediate dose levels of 70.2 and 72 Gy there was some suggestion of improved efficacy. At the highest dose level of 75.6 and 78 Gy there were no further gains in efficacy and complications of treatment including steroid dependency and intralesional necrosis were observed with greater frequency. The intermediate dose level was therefore considered to be associated with the best therapeutic ratio and the value of hyperfractionated radiotherapy at this dose level is being tested by the Pediatric Oncology Group in a randomized phase III study that will be completed soon.

Results and expectations with image-integrated brainstem stereotactic biopsy

The histologic diagnosis of an intrinsic brainstem tumor remains problematic due to controversies in methods of biopsy. Despite the widespread use of biopsy techniques, stereotactic brain stem biopsy has received limited attention due to potential morbidity and limited sample size. To evaluate the safety and efficacy of brain stem stereotactic biopsy using a dedicated computed tomography (CT)-stereotactic operating room suite, we reviewed our outcomes in 40 consecutive patients over a 13-year interval. This study included patients with midbrain lesions (n = 20), pontine lesions (n = 18), and medullary lesions (n = 2). Midline lesions were approached via a coronal, transthalamic trajectory; lateral brain stem lesions usually were approached via a transcerebellar route. A histologic diagnosis was achieved in 38 patients (95%). All patients had an immediate, intraoperative, postbiopsy CT scan to check for hemorrhage (none occurred). Morbidity was limited to one patient (2.5%) who developed a transient diplopia; there was no mortality. Stereotactic biopsy for intrinsic brain stem lesions proved as safe and effective as biopsy in the supratentorial compartment. Using high-resolution stereotactic imaging, an appropriate intraparenchymal trajectory, limited sampling, and specific neuropathologic tests, stereotactic techniques within the brain stem were performed with low risk and high accuracy. Biopsy results facilitated specific management strategies for each patient.

Pediatric midbrain tumors: a benign subgroup of brainstem gliomas.

The presentation, radiographic findings and course of 17 children with MRI-documented intrinsic midbrain lesions are reviewed. The anatomic centers of all the lesions were tectal, peritectal, or tegmental. Lesions centered at the pineal gland were excluded. Signs of increased intracranial pressure from hydrocephalus requiring shunt placement were present in 14 patients. Histopathological diagnosis was confirmed in three tumors; these were low grade astrocytomas and all received focal irradiation, as did one unbiopsied tumor. The remaining 13 patients with no histopathological diagnosis received no therapy other than shunt placement in 11. All but one of the lesions have remained clinically and radiographically stable, with a 4-year progression-free and total survival of 94 and 100%, respectively. We conclude that mass lesions originating in the upper midbrain are a subset of intrinsic brainstem tumors with a relatively benign course, usually presenting with hydrocephalus after infancy. They may remain stable for considerable periods and may require no further therapy after treatment of hydrocephalus. Surgical biopsy and/or resection can usually be reserved for progressive or atypical lesions which may also require further adjuvant therapy.

Isolated facial nerve palsy of peripheral type caused by an intrinsic brain stem tumor

Key words: Bell's palsy, brainstem glioma, magnetic reso- nance imaging Introduction Facial palsy of the peripheral type is generally seen in the pain clinic and is often treated with a stellate gang- lion block. The most common cause of peripheral facial nerve palsy is Bell's palsy, although its etiology remains controversial. The diagnosis of Bell's palsy is usually made by exclusion of other conditions such as herpes zoster oticus (Ramsay Hunt syndrome), trauma (including skull base fracture and surgery), otitis media, and neoplasm [1]. Isolated peripheral facial nerve palsy of neoplastic origin is uncommon. We herein describe a case of peripheral facial nerve palsy which was initially diag- nosed as Bell's palsy but was later found to be caused by an intrinsic brain stem tumor. Case report A 9-year-old boy presented to the Pediatric Depart- ment of our University Hospital in August 1990 with left facial weakness. His mother noticed the hyperemic conjunctiva and lacrimation of his left eye at the end of June. Consultation with the ophthalmologist revealed no abnormality in his left eye and the hyperemia im- proved with conservative therapy. In July, facial asym- metry became obvious. He was diagnosed as having Bell's palsy by a pediatrician in August and was referred to. our pain clinic. Address correspondence to: K. Kodama Received for publication on May 31, 1993; accepted on January 6, 1994 Upon examination, the patient had a left facial nerve palsy of the peripheral type (score of the facial paresis was 24/40), however, no other neurological deficits were seen. An audiogram failed to reveal a hearing abnormality. Although repeated stellate ganglion block was given, his facial palsy progressed slowly over a 2- month period, suggesting an etiology other than Bell's palsy. Magnetic resonance imaging (MRI) in September demonstrated a tumor in the left pons and brachium pontis extending into the left cerebellopontine angle (Fig. 1). The lesion was seen as a hypointense and hyperintense area on T1- and T2-weighted images, re- spectively. He was admitted to the Neurosurgical De- partment on September 29. The positive neurological findings on admission were Bruns' nystagmus, absence of left corneal reflex, decreased gag reflex, and mild trunkal ataxia, in addition to left facial nerve palsy. He underwent a wide suboccipital decompressive craniec- tomy, and biopsy of the tumor indicated low-grade glioma. In spite of postoperative radiation (60 Gy) and chemotherapy including Ranimustine and tumor necro- sis factor, he died due to tumor progression 17 months from the time of his initial symptom. Discussion Eighty percent of peripheral facial nerve palsy cases represent idiopathic or Bell's palsy, of which approxi- mately 20% can be demonstrated to have a specific etiology [2]. Peripheral facial nerve palsy with neoplas- tic origin is uncommon, and is estimated to be the cause in approximately 5% of all cases [3]. The diagnosis of Bell's palsy is unjustified unless an accurate history is taken along with a careful examina- tion of the ear and central nervous system (CNS). The differential diagnosis of neoplastic facial palsy is vast

Isolated facial nerve palsy of peripheral type caused by an intrinsic brain stem tumor

Isolated facial nerve palsy of peripheral type caused by an intrinsic brain stem tumor

Pre-irradiation chemotherapy and hyperfractionated radiation therapy 66 Gy for children with brain stem tumors. A phase II study of the pediatric oncology group, protocol 8833

Fewer than 20% of children with intrinsic brain stem tumors survive longer than 2 years. Although some improvement has been noted in recent trials using higher doses of hyperfractionated radiation therapy (HRT), the feasibility of pre-irradiation chemotherapy has not been explored in these patients with poor prognosis. Between February 1988 and March 1989, 37 patients were entered onto a Phase II Pediatric Oncology Group study for evaluating the feasibility, response, and toxicity of treating children with high-risk brain stem tumors with chemotherapy followed by HRT (66 Gy). Chemotherapy consisted of four cycles of cisplatin (100 mg/m2) plus cyclophosphamide (3 g/m2). Of 32 eligible patients, 65% improved clinically during the first 2-3 cycles of chemotherapy; 75% of those improving were weaned from steroids. On neuroradiology review of scans before and after chemotherapy, 3 patients had partial responses (PR, > 50% shrinkage), 23 had stable disease (SD), and 6 had progressive disease (PD). The median survival was 9 months. The three patients who attained a PR on chemotherapy were among the longest survivors at 38 plus, 44 plus, and 40 months. Toxicities included profound but brief marrow suppression, transient electrolyte-renal dysfunction, and ototoxicity. Brain stem swelling from intravenous fluids caused transient deterioration in two patients. Six patients developed an unusual syndrome of transient marrow suppression after HRT. This study suggests that pre-irradiation chemotherapy can be successfully added to the treatment of patients with brain stem tumors with both clinical and objective responses noted, but that other agents must be identified to overcome the apparent development of drug resistance and to improve survival.

Surgical Management of Brain Stem Tumors of Childhood and Adolescence

Intrinsic brain stem tumors are a heterogeneous group of neoplasms that may be classified according to clinical and neurodiagnostic criteria. We have described simple anatomic categories that include focal, diffuse, cystic, and cervicomedullary tumors. Although there is no surgical option for the common diffuse brain stem neoplasms, the other tumors may be operated on if the clinical and neurodiagnostic assessment suggests the possibility of a benign neoplasm. It is important to emphasize that although all tumors that were covered by intact ependyma or pia were considered intrinsic tumors in this series, most of these tumors created a "bulge" that was obvious on visual inspection of the external surface of the brain stem. In all of the tumors that were benefitted by surgery, the neoplasms tended to "bulge" from the brain stem rather than infiltrate it, which was the case with the diffuse neoplasms. It seems likely that many of the focal, cystic, and cervicomedullary tumors are similar to the dorsal exophytic brain stem tumors, which are characteristically low-grade astrocytomas that disrupt the ependymal lining and grow posteriorly into the fourth ventricle. Although surgery has been well tolerated and beneficial in many patients, it would be premature to comment on the duration of remission or the possibility of permanent cure.

Intrinsic brainstem tumors in childhood: surgical indications.

Sixty-six children with intrinsic brainstem gliomas diagnosed between 1980 and 1986 underwent radical surgical resection. Retrospective analysis permitted classification of tumors into four categories: diffuse, focal, cystic and cervicomedullary. All 27 patients with diffuse tumors had malignant neoplasms, were not benefitted by surgery and died within 12-18 months. Five of nine cystic tumors, three of five focal tumors and twenty of twenty-four cervicomedullary tumors had low grade histopathology and are alive one to six years postoperatively. The authors propose a clinical-neuroradiological criteria that accurately predict which patients with brainstem tumors are likely to benefit from radical surgical intervention.

Intrinsic brain-stem tumors of childhood: surgical indications.

This report summarizes the first author's experience with radical excision of intrinsic non-exophytic brain-stem gliomas in 34 pediatric patients. On retrospective analysis, these tumors may be classified into three subgroups: focal, diffuse, and cervicomedullary. A focal neoplasm is a circumscribed mass less than 2 cm in diameter and without associated edema. Tumors of a larger size or in which the "focal" neoplasm is associated with a large area of apparent edema are classified as diffuse. Cervicomedullary neoplasms occur at the junction of the medulla and spinal cord and involve both of the structures but do not extend rostrally into the pons. A radical tumor excision was carried out in all patients, and the only mortality and morbidity occurred in children harboring diffuse gliomas. All of the diffuse gliomas were malignant (grade III or IV astrocytomas), whereas three of the four focal astrocytomas and all of the cervicomedullary tumors were grade II astrocytomas. No patient with a diffuse astrocytoma was benefitted by surgery, while two of the focal astrocytomas and all of the cervicomedullary neoplasms either became stable or improved postoperatively. It is concluded that, although surgery may be accomplished within the substance of the brain stem with low morbidity and mortality rates, it is not indicated for malignant astrocytomas as it has no impact on the biology of the neoplasm. Therefore, while primary radical excision is recommended for cervicomedullary neoplasms, which are often benign, the more traditional radiation therapy and/or chemotherapy remain appropriate for tumors above the medulla.

Brain stem gliomas in childhood. Rational approach and treatment.

Thirty-six infants and children with brain stem glioma diagnosed between 1967 and 1980 were reviewed. Posterior fossa craniotomy was performed in 25, with biopsy or partial resection in 18, cyst aspiration in 2, and exploration alone in 5. The 19 surgical specimens obtained revealed neoplastic cells in 15 but only gliosis or blood clot in 4. There was a significant discrepancy in pathological spectrum between autopsy and surgical specimens. The review of the literature shows that 51.6% of autopsy confirmed tumors were malignant while 26.8% of surgically biopsied tumors were benign. Since biopsy specimens often misrepresent the true pathology, we felt that surgery undertaken to obtain precise histological verification of brain stem gliomas is futile. Rather, we employ computed tomography (CT) with high-resolution metrizamide CT cisternography to distinguish surgically resectable extra-axial tumors adjacent to the brain stem from the unresectable intrinsic brain stem gliomas. Radiation therapy is the choice of treatment should CT indicate clear evidence of intrinsic brain stem tumor. However, posterior fossa craniotomy should be undertaken only for aspiration of cystic intrinsic stem tumors, resection of extra-axial juxtastem tumors and, although rare, in instances when CT is unable to definitively distinguish extra-axial from intra-axial mass for verification of lesion location.