Diagnosis and management of brain metastases.

In the past 15 years, significant advancement has been made in the diagnosis and treatment of brain metastases. The distinction between the management of single and multiple brain metastases is an important one. Although radiotherapy remains a mainstay of treatment, especially in multiple brain metastases, surgical resection and stereotactic radiosurgery also have their place in the management of selected patients. Rarely, interstitial radiation or chemotherapy also may be used to treat brain metastases in the setting of relapse.

The prognostic significance of midline shift at presentation on survival in patients with glioblastoma multiforme.

PURPOSE: While patients with glioblastoma multiforme (GBM) who present with midline shift have a presumably worse prognosis, there is little literature evaluating the prognostic significance of this presentation in multivariate analysis in the context of other known prognostic factors. METHODS AND MATERIALS: From March 1981 to September 1993, 219 patients underwent irradiation for intracranial glioma at our institution. One hundred fourteen patients with a diagnosis of a primary GBM were analyzed for the influence of the presence of midline shift at diagnosis on survival with respect to other known prognostic factors, including age, Karnofsky performance status (KPS), and extent of surgery. Eighty-five patients (74%) presented with midline shift. Surgical treatment consisted of subtotal/total resection in 86 patients (75%). Among patients presenting with midline shift, 68 (80%) underwent subtotal/total resection before irradiation. RESULTS: Multivariate analysis of the entire cohort of patients found none of the potential prognostic factors analyzed to significantly influence survival. The overall median survival was 6 months. However, when multivariate analysis was limited to patients with a KPS of > or = 70, only the presence of midline shift and age were found to significantly influence survival. Patients with a KPS > or = 70 and with midline shift present at diagnosis had a median survival of 8 months, as compared to 14 months for those not having midline shift at presentation (p = 0.04). Patients with a KPS > or = 70 and age > 50 years had a median survival of 5 months as compared to 11 months for those < or = 50 (p = 0.02). CONCLUSION: In this series, where 80% of patients who presented with a midline shift underwent decompressive resection of GBM before irradiation, the presence of midline shift at diagnosis remained an independent prognostic factor influencing survival among good performance status patients. While the role of decompressive surgery in this setting is likely of some benefit, the extent of this benefit remains to be defined.

Substituting proxy ratings for patient ratings in cancer clinical trials: an analysis based on a Southwest Oncology Group trial in patients with brain metastases.

In studies of the effect of cancer treatment in the advanced disease setting, researchers have attempted to avoid missing data for quality of life (QOL) assessments by either substituting proxy for patient assessments from the outset or by interspersing proxy measures when patients are unable to respond. Although poor agreement between patient and proxy assessments has been amply demonstrated in the literature, interest in using proxy measures persists. Completion of the Spitzer QL-Index by a small sample of patients with brain metastases and family member proxies provided data for evaluating the ability to substitute proxy for patient QOL assessments. These data cannot address treatment efficacy due to the modest sample size. Rather, the analyses serve to alert researchers to the important distinction (in a clinical trial setting) between agreement and the use of the proxy as a surrogate. We present several methods for evaluating the accuracy of proxy measures and for identifying other sources of error and bias that may vary with time or with treatment arm. Lin's concordance correlation coefficient suggests that proxies are generally a poor substitute for capturing a patient's perspective of his/her QOL. A longitudinal analysis suggests that the use of proxy rather than patient responses could lead to different conclusions concerning radiation therapy's effect on QOL.

Preliminary report of a phase I study of combined fractionated stereotactic radiosurgery and conventional external beam radiation therapy for unfavorable gliomas.

PURPOSE: To determine the tolerance and toxicities of fractionated stereotactic radiosurgery (FSRS) given in combination with conventional external beam radiation therapy (CEBRT). METHODS AND MATERIALS: From March 1995 to September 1998, 14 patients with previously unirradiated and unfavorable glioma (malignant glioma, n = 8; unfavorable low-grade glioma, n = 5; and recurrent glioma, n = 1) were stratified into 3 groups according to tumor volume (TV) to determine the initial FSRS dose schedule: Group A (n = 3): TV /=50% reduction, n = 2) or minor (>20% reduction, n = 9) imaging response. Follow-up ranged from 9 to 51 months (median 15 months), with 7 patients alive at 22-51 months. CONCLUSIONS: Imaging response and the ability of these patients with unfavorable intracranial gliomas to complete therapy without interruption or experiencing disease progression is very encouraging. Excessive toxicity of combined FSRS and CEBRT as evaluated thus far in this study was seen for patients with group B/C lesions. Evaluation of this novel treatment strategy with dose modification is ongoing.

Combined stereotactic split-course fractionated gamma knife radiosurgery and conventional radiation therapy for unfavorable gliomas: a phase I study.

OBJECT: This investigation was performed to determine the tolerance and toxicities of split-course fractionated gamma knife radiosurgery (FSRS) given in combination with conventional external-beam radiation therapy (CEBRT). METHODS: Eighteen patients with previously unirradiated, gliomas treated between March 1995 and January 2000 form the substrate of this report. These included 11 patients with malignant gliomas, six with low-grade gliomas, and one with a recurrent glioma. They were stratified into three groups according to tumor volume (TV). Fifteen were treated using the initial FSRS dose schedule and form the subject of this report. Group A (four patients), had TV of 5 cm3 or less (7 Gy twice pre- and twice post-CEBRT); Group B (six patients), TV greater than 5 cm3 but less than or equal to 15 cm3 (7 Gy twice pre-CEBRT and once post-CEBRT); and Group C (five patients), TV greater than 15 cm3 but less than or equal to 30 cm3 (7 Gy once pre- and once post-CEBRT). All patients received CEBRT to 59.4 Gy in 1.8-Gy fractions. Dose escalation was planned, provided the level of toxicity was acceptable. All patients were able to complete CEBRT without interruption or experiencing disease progression. Unacceptable toxicity was observed in two Grade 4/Group B patients and two Grade 4/Group C patients. Eight patients required reoperation. In three (38%) there was necrosis without evidence of tumor. Neuroimaging studies were available for evaluation in 14 patients. Two had a partial (> or = 50%) reduction in volume and nine had a minor (> 20%) reduction in size. The median follow-up period was 15 months (range 9-60 months). Six patients remained alive for 3 to 60 months. CONCLUSIONS: The imaging responses and the ability of these patients with intracranial gliomas to complete therapy without interruption or experiencing disease progression is encouraging. Excessive toxicity derived from combined FSRS and CEBRT treatment, as evaluated thus far in this study, was seen in patients with Group B and C lesions at the 7-Gy dose level. Evaluation of this novel treatment strategy with dose modification is ongoing.

Expression of p53, bcl-2, E-cadherin, matrix metalloproteinase-9, and tissue inhibitor of metalloproteinases-1 in paired primary tumors and brain metastasis.

The objectives of this study were to: (a) characterize the immunohistochemical expression of p53, bcl-2, E-cadherin (EC), matrix metalloproteinase-9 (MMP-9), and tissue inhibitor of metalloproteinases-1 (TIMP-1) in brain metastases; (b) compare immunohistochemical (IHC) expression of brain metastases with their primary tumors; and (c) assess the prognostic value of expression of these markers. Tumors from 35 patients with brain metastasis were studied for IHC expression of p53, bcl-2, EC, MMP-9, and TIMP-1. In 17 cases, primary tumors were also available for study. In brain metastases, p53 was positive in 91% of cases and intermediate in 9%, MMP-9 was positive in all cases, TIMP-1 was intermediate in 6% and negative in 94% of cases, EC expression was positive in 86% of cases and intermediate in 14%, and bcl-2 was variable. All primary tumors were positive for p53 and MMP-9, 3% were intermediate for TIMP-1 and 97% were negative, 65% were positive for EC and 35% were intermediate, whereas bcl-2 expression was variable. Neither p53, bcl-2, TIMP-1, or EC staining correlated with overall survival or survival with brain metastases. No assessment of survival differences could be made for MMP-9 because of its overexpression in all tissues. This study found that MMP-9 and p53 were markedly overexpressed in primary tumors and matched brain metastasis, TIMP-1 expression was negative in the majority of specimens, whereas EC expression was maintained in both primary tumors and brain metastases and bcl-2 expression was variable. This study suggests that the functional balance of MMP-9 and TIMP-1 is shifted toward extracellular matrix degradation in brain metastases and that deregulation of cell cycle control by p53 also exists in brain metastases. The high expression of EC may indicate the importance of adherence at late stages of metastasis but requires further study.

Neurological complications of childhood malignancies.

UNLABELLED: Between Jan 1982 to Jun 1994, 154 children with malignant non-central nervous system tumors, excluding leukemias and lymphomas, were admitted and treated at the UKMC. Fifty-one (33%) of these cases suffered with 64 neurological complications during the course of their diseases. Nine cases suffered with multiple neurological complications. Nervous system metastasis was the most common neurological complication (n = 24; 15.6%), which was followed by nervous system infection (n = 17; 11%). Twelve (7.7%) cases had treatment related peripheral or cranial neuropathies. Seven (4.5%) cases had new onset of grand-mall seizures. One case had paraneoplastic syndrome, one case had panhypopituitarism secondary to whole brain radiation, and one case had Horner's syndrome secondary to tumor removal. Ten cases suffered with neurological sequelae secondary to neurological complications. Three of these cases suffered with developmental delay and mental retardation. Fifty-one patients with neurological complications were followed for 9 to 102 months. While 30 (19.7%) patients were alive, 20 (13%) patients died and one case was lost during the analysis of the results. Neuroblastoma/ganglioneuroblastoma has the highest rate for causing neurological complication. IN CONCLUSION: neurological complications were seen on 33% of childhood solid malignant tumors. Nervous system metastasis had the worst prognosis and the most frequent neurological complication. Neurological complications did not increase the mortality rate, but one-third of surviving patients with neurological complications suffered with neurological sequelae.

Postoperative radiotherapy in the treatment of single metastases to the brain: a randomized trial.

CONTEXT: For the treatment of a single metastasis to the brain, surgical resection combined with postoperative radiotherapy is more effective than treatment with radiotherapy alone. However, the efficacy of postoperative radiotherapy after complete surgical resection has not been established. OBJECTIVE: To determine if postoperative radiotherapy resulted in improved neurologic control of disease and increased survival. DESIGN: Multicenter, randomized, parallel group trial. SETTING: University-affiliated cancer treatment facilities. PATIENTS: Ninety-five patients who had single metastases to the brain that were treated with complete surgical resections (as verified by postoperative magnetic resonance imaging) between September 1989 and November 1997 were entered into the study. INTERVENTIONS: Patients were randomly assigned to treatment with postoperative whole-brain radiotherapy (radiotherapy group, 49 patients) or no further treatment (observation group, 46 patients) for the brain metastasis, with median follow-up of 48 weeks and 43 weeks, respectively. MAIN OUTCOME MEASURES: The primary end point was recurrence of tumor in the brain; secondary end points were length of survival, cause of death, and preservation of ability to function independently. RESULTS: Recurrence of tumor anywhere in the brain was less frequent in the radiotherapy group than in the observation group (9 [18%] of 49 vs 32 [70%] of 46; P<.001). Postoperative radiotherapy prevented brain recurrence at the site of the original metastasis (5 [10%] of 49 vs 21 [46%] of 46; P<.001) and at other sites in the brain (7 [14%] of 49 vs 17 [37%] of 46; P<.01). Patients in the radiotherapy group were less likely to die of neurologic causes than patients in the observation group (6 [14%] of 43 who died vs 17 [44%] of 39; P=.003). There was no significant difference between the 2 groups in overall length of survival or the length of time that patients remained functionally independent. CONCLUSIONS: Patients with cancer and single metastases to the brain who receive treatment with surgical resection and postoperative radiotherapy have fewer recurrences of cancer in the brain and are less likely to die of neurologic causes than similar patients treated with surgical resection alone.

Intracranial germinoma: treatment with radiosurgery alone--a case report.

The management of intracranial germinomas is controversial, with treatment options including conventional wide-field irradiation with or without chemotherapy or primary chemotherapy alone. The potential role of radiosurgery in the treatment of these lesions, although appealing, remains to be defined. We report a case whose initial management plan included radiosurgery to be followed by chemotherapy; however the patient subsequently refused chemotherapy. The presentation, diagnosis, treatment and results are discussed.

Neurologic complications of the primary pediatric extracranial neuroblastomas.

Between January 1982 and June 1994, 32 children with primary extracranial neuroblastomas (n = 24) and ganglioneuroblastomas (n = 8) were admitted and treated at the UKMC. Twenty-two (68.7%) of these patients suffered with 29 neurological complications (up to 3 complications per case) during the course of their disease. Fourteen cases had nervous system metastases or invasion. Nonmetastatic complications, such as nervous system infections (n = 4) and new onset of seizures secondary to brain metastasis, hypertensive and metabolic encephalopathies (n = 3) were seen on 7 cases. Five cases had treatment related complications, one case first presented with opsoclonus-polymyoclonus syndrome. Eight of these 22 patients died, due to relapse or progression of the disease. The mean follow-up period of 14 surviving patients was 44.9 months (range, 12-110 months). Five of these 14 patients suffered with neurologic sequelae. The incidence of neurologic complications was 68.7%. Nervous system metastasis was the most common neurologic complication. Although 5 patients suffered with neurologic sequelae, outcome was not influenced by presence of neurologic complication.

Cerebral metastases in childhood malignancies.

Between January 1982 to June 1994, 154 children with non-CNS malignant tumours excluding leukaemias and lymphomas were admitted and treated at the UKMC. Symptomatic (10 cases; 6.5%) and non-symptomatic (2 cases; 1.2%) cranial metastases (calvarial, dural and/or parenchymal) were seen in 12 (7.8%) cases. Among these 12 cases, 7 had intracranial parenchymal metastases (4.5%). Three cases had multiple intracranial parenchymal metastases. Only one case had infratentorial (cerebellar) metastasis. The patients' ages ranged from 1 to 18 years (mean age was 7.3 years). The male:female ratio was 5:2. While six patients' brain metastases diagnosed during subsequent relapses, one patient first presented with brain metastasis. Time elapsed between the diagnosis of the primary disease and intracranial metastasis ranged from 0 to 755 days (mean 327 days). Histopathological diagnoses were confirmed in 4 cases who had craniotomy and tumour removal. Mean survival following the diagnosis of intracranial lesion was 157 days (ranged from 0 to 412 days). Despite the aggressive treatment, including surgery, chemotherapy and radiotherapy, 6 cases died with progression or relapse of the intracranial disease. In conclusion, the incidence of paediatric intracranial parenchymal metastasis is 4.5%. Prognosis is poor and intracranial disease is the primary cause of death.

A phase I trial of neutron brachytherapy for the treatment of malignant gliomas.

We performed a phase I trial to test the feasibility of neutron brachytherapy using californium-252 (252Cf) as the sole source of radiation, and to determine the maximum tolerable dose (MTD), for the treatment of malignant gliomas. Previous studies using external beam neutron radiation have shown that neutrons are capable of totally eradicating malignant gliomas. However, in most cases, fatal widespread radiation necrosis resulted. Radioactive implants are a logical method of increasing the dose to the tumour and decreasing the dose to normal brain. 252Cf is a relatively stable neutron-emitting isotope suitable for implant therapy. The study was an open ended dose-escalation study. All radiation was delivered by using only 252Cf implants, without external beam therapy of any type. The first dose step was 900 neutron cGy (ncGy); each subsequent step was increased by 100 ncGy. Three patients with newly diagnosed malignant gliomas were entered at each dose step, and the number was increased to six patients in dose steps at which necrosis of brain occurred. The study ended when two patients at any dose step developed radiation necrosis of brain outside the prescribed radiation field. 33 patients were entered into the study. 10 patients developed scalp necrosis associated with scalp doses above 900 ncGy. The study ended when two patients at the 1300 ncGy dose step developed radiation necrosis of brain. We conclude: (1) neutron brachytherapy using 252Cf as the sole source of radiation is a feasible treatment for malignant gliomas; (2) the scalp tolerates less neutron radiation than the brain; (3) the MTD (and the recommended dose for a phase II trial) of interstitial neutron brachytherapy is 1200 ncGy.

Primary spinal column sarcomas.

Five cases of primary spinal column sarcomas are presented. Sarcomas primarily originating from paravertebral soft tissues were excluded. Patients' age ranged from 1 to 14 years (mean 8.4 years). The male:female ration was 2:3. Two patients had Ewing's sarcoma (ES) originating from L5-S1 and L4-5 pedicles, respectively; two patients had mesenchymal chondrosarcoma (MCS) originating from L1-2 pedicles and L5 body, respectively; and one patient had osteogenic sarcoma (OS) of C4 body. All patients clinically presented with pain and progressive weakness of the extremities. The time that elapsed between the onset of symptoms and diagnoses ranged from one to five months. All cases were treated with chemotherapy, radiotherapy and subtotal tumour resection with spinal canal decompression. Two cases received posterior spinal fusion operations. Three patients were alive 10 to 98 months following diagnosis. Only the case with ES of L5-S1 pedicles was in complete remission and off therapy at the 98th postoperative month. The two MCS cases were in partial remission, and were receiving chemotherapy at the time of analysis. These tumours caused similar clinical findings and prognoses, and required combined treatment, which consisted of surgery, radiotherapy and chemotherapy; histologically three different types of malignant tumours are presented in the same category. We preferred surgical decompression and stabilization procedures especially for neurologically symptomatic patients, even if they had extensive tumours with high grades. By spinal canal decompression and stabilisation, we did not intend to cure the disease; however, we intended to provide neurological improvement, spinal stabilisation, improved quality of life, early mobilisation of the patient, and cytoreduction by means of surgical tumour ablation, which could render the chemotherapy more effective.

Radiosurgical management of meningiomas.

The management of residual, recurrent, or small skull base meningiomas is controversial. Stereotactic radiosurgery has emerged as an alternative treatment. We report our experience from September 1991 to August 1994 of treatment of 20 such patients [18 females -age 19-82 years, followed for 6-36 months (mean 15.5 months)] with the Leksell Gamma Knife. Nine patients were treated either with recurrent (2 patients-2 operations each) or residual tumor. Twelve patients had skull base, 3 optic nerve, 3 parasagittal, and 1 residual torcular tumor. Mean volume/diameter was 9.172 mm3/25 mm.

Metastatic brain tumors.

Significant advances have been made in the diagnosis and treatment of brain metastases, and the therapeutic nihilism of the past is not warranted for most patients with brain metastases. With currently available treatments, most patients do not die of their brain metastases and usually experience effective palliation of neurologic symptoms and meaningful extension of life.

Neurological complications of organ transplantation.

Over the last thirty years, organ transplantation has become a practical treatment option for many otherwise fatal diseases. New immunosuppressive agents, advances in tissue matching, and improvements in surgical technique have increased both the number and type of transplants performed. Kidney, bone marrow, heart, lung, liver, and pancreas transplants are now used regularly in the treatment of end-stage disease. However, these advances have come at a price. Transplant recipients are subject to numerous complications, many of which involve the nervous system. Depending on the type of organ transplanted, 30 to 60% of transplant recipients experience neurological problems. Most neurological complications, especially those related to immunosuppression, are common to all transplant types; other complications are associated predominantly with specific transplant types. This report reviews the general categories of neurological complications as well as the specific problems associated with each kind of transplant.

Neurologic complications of anorexia nervosa.

The records of 100 patients with anorexia nervosa were reviewed. Neurologic complications were present in 47 patients. Neuromuscular abnormalities were most common and were present in 45% of patients. Generalized muscle weakness was detected in 43% of patients and peripheral neuropathies in 13%. Less common neurologic complications included headaches (6%), seizures (5%), syncope in the absence of orthostatic hypotension (4%), diplopia (4%), and movement disorders (2%). Neurologic problems due to chronic deficiency diseases were rare; only one patient had symptoms directly attributable to a vitamin B12 deficiency and none had evidence of Wernicke's encephalopathy. In most patients, the neurologic complications were reversed completely after correction of nutritional deficiencies and fluid and electrolyte imbalances.

A template for rigid stereotaxic afterloading brachytherapy of the brain.

PURPOSE: This paper describes a system for the implantation of rigid stainless steel afterloading tubes into the brain using a stereotaxic head frame for both localization and treatment. METHODS AND MATERIALS: The stereotaxic frame is attached to the skull throughout the treatment, and the afterloading tubes are both rigid and fixed to the frame. The source positions are therefore fixed relative to the skull throughout the irradiation. Design and construction of templates, afterloading tubes and clamps are discussed in detail. RESULTS: The rigidity of the resulting implant provides accurate and immobile positioning of the planned isodose distribution relative to the defined treatment volume and makes it possible to carefully and rapidly plan a source loading which will best cover the volume of interest. The source template is not in contact with the patient at any time. The afterloading tubes are held strictly parallel during treatment, allowing for rapid and versatile preplanning prior to surgical placement. Placement options are enhanced by using a set of rotating templates. CONCLUSION: This system has been used for over 60 procedures without any mechanical or safety problems and has provided a significant improvement in both the speed and confidence of localization and treatment planning. There are significant advantages of such a system for High Dose Rate Afterloading Brachytherapy.