Brain tumors in children under 2 years: treatment, survival and long-term prognosis.

Survival for children with brain tumors less than 2 years of age at diagnosis is dismal, and the quality of life of long-term survivors poor. Between 1975 and 1987, 78 (13%) of 579 patients with brain tumors treated at Children's Hospital of Philadelphia were under 2 years of age. Tumor site was posterior fossa in 31 (40%) and supratentorial in 47 (60%). Nine of 37 patients (24%) with malignant tumors, and 30 of 41 (73%) patients with benign tumors are alive with a mean follow-up of 116 months. Long-term survival after treatment with chemotherapy alone occurred in 10 patients, including 3 with malignant tumors. In 5 additional patients, chemotherapy delayed the need for irradiation a mean of 30 months. Of the 29 patients who relapsed after initial therapy, 12 are alive without progressive disease (2 patients with malignant tumors and 10 with benign tumors) a mean of 80 months after relapse, 2 children are alive with progressive disease, and 14 died a median of 48 months (range 9-115 months) after relapse. Twenty-one of the 39 survivors have minimal or no neurological or intellectual dysfunction. Surviving patients treated with surgery and chemotherapy have better intellectual function than patients treated with surgery and radiation (with or without chemotherapy) in that 8 of 10 children treated with surgery and chemotherapy have normal or above normal intelligence compared with 5 of 12 children receiving irradiation before their second birthday.

Results of treatment of children with recurrent medulloblastoma/primitive neuroectodermal tumors with lomustine, cisplatin, and vincristine.

Primitive neuroectodermal tumors/medulloblastoma (PNET/MB) are the most common posterior fossa tumors in childhood. Despite surgery and radiation therapy, 40% to 50% of children with PNET/MB will have recurrent disease. Various chemotherapeutic agents are transiently effective in recurrent PNET/MB, but long-lasting responses are rarely attainable. To increase the rate and duration of response in children with recurrent PNET/MB, the authors treated seven patients (ages 2-18 years; median, 10 years) with lomustine (CCNU) (100 mg/m2), cisplatin (CPDD) (90 mg/m2) and vincristine (VCR) (1.5 mg/m2; maximum, 2 mg) in a 6-week cycle for a maximum of eight cycles. Six of six evaluable patients responded to chemotherapy. Four patients had a complete response; three with complete disappearance of tumor by imaging studies; and one with eradication of extraneural disease for a median of 24 months from relapse (13-29 months). Overall disease-free survival was 18.5 months. All six patients have subsequently died of recurrent tumor. Major toxicities consisted of reversible bone marrow suppression (six of six), high frequency hearing loss (six of six) and decreased renal function (three of six). All patients required dosage modification for toxicity. A regimen of CCNU, VCR, and CPDD is effective therapy in children with relapsed PNET/MB and can produce relatively long-term disease control with good quality of life. Further investigation into the efficacy of this combination as adjuvant chemotherapy in newly diagnosed high-risk PNET/MB is now being performed.

A prospective study of cognitive function in children receiving whole-brain radiotherapy and chemotherapy: 2-year results.

As survival rates have risen for children with malignant primary brain tumors, so has the concern that many survivors have significant permanent cognitive deficits. Cranial irradiation (CRT) has been implicated as the major cause for cognitive dysfunction. To clarify the etiology, incidence, and severity of intellectual compromise in children with brain tumors after CRT, a prospective study was undertaken comparing the neuropsychological outcome in 18 consecutive children with malignant brain tumors treated with CRT to outcome in 14 children harboring brain tumors in similar sites in the nervous system who had not received CRT. Children with cortical or subcortical brain tumors were not eligible for study. Neuropsychological testing was performed after surgery prior to radiotherapy, after radiotherapy, and at 1- and 2-year intervals thereafter. Children who had received CRT had a mean full-scale intelligence quotient (FSIQ) of 105 at diagnosis which fell to 91 by Year 2. Similar declines were noted in their performance intelligence quotient (IQ) and verbal IQ. After CRT, patients demonstrated a statistically significant decline from baseline in FSIQ (p less than 0.02) and verbal IQ (p less than 0.04). Children who had not received CRT did not demonstrate a fall in any cognitive parameter over time. The decline between baseline testing and testing performed at Year 2 in patients who had CRT was inversely correlated with age (p less than 0.02), as younger children demonstrated the greatest loss of intelligence. Children less than 7 years of age at diagnosis had a mean decline in FSIQ of 25 points 2 years posttreatment. No other clinical parameter correlated with the overall IQ or decline in IQ. After CRT, children demonstrated a wide range of dysfunction including deficits in fine motor, visual-motor, and visual-spatial skills and memory difficulties. After CRT, children with brain tumors also demonstrated a fall in a wide range of achievement scores and an increased need, over time, for special help in school. The 2-year results of this study suggest that children with brain tumors treated with CRT are cognitively impaired and that these deficits worsen over time. The younger the child is at the time of treatment, the greater is the likelihood and severity of damage. These children, although not retarded, have a multitude of neurocognitive deficits which detrimentally affects school performance. New treatment strategies are needed for children with malignant brain tumors.

Efficacy of adjuvant chemotherapy for patients with poor-risk medulloblastoma: a preliminary report.

Recent studies have demonstrated that preoperative and postoperative factors can broadly stratify patients with medulloblastoma/primitive neuroectodermal tumors (MB/PNET) into risk groups. For children with factors that suggest poor outcome after treatment with surgery and radiotherapy, the addition of chemotherapy can improve survival. Since 1983, 26 children with poor-risk posterior fossa MB/PNET have been treated at our institution with craniospinal radiation therapy and adjuvant chemotherapy. Chemotherapy consisted of vincristine during radiotherapy and eight 6-week cycles of vincristine, cis-platinum, and 1-(2-chloroethyl)-3-cyclohexyl-1-nitrosourea (CCNU). Twenty-five of 26 patients (96%) who have been entered on this protocol remain alive and free of disease at a median of 24 months from diagnosis (range 6 to 50 months). Twenty patients have completed all therapy and are at a median of 32 months from initial diagnosis with no evidence of disease. These patients were compared to a group of children with similar prognostic features treated at our institution between 1975 and 1983. Actuarial disease-free survival was statistically significantly better for protocol patients than for historical control subjects (p less than 0.002). This difference was most marked in patients who had received radiation therapy alone (p less than 0.0003). Actuarial 2-year disease-free survival was 96% for patients on protocol as compared to 59% for historical control patients who had been treated with radiotherapy alone. The chemotherapy given in this protocol was well tolerated. The results of this study, although preliminary, suggest that adjuvant chemotherapy is at least transiently effective in improving the rate of disease-free survival for children with poor-risk MB/PNET.

Pathology, treatment and management of posterior fossa brain tumors in childhood.

Brain tumors are the second most common childhood malignancy. Between 1975 and 1985, 462 newly diagnosed patients were treated at the Children's Hospital of Philadelphia; 207 (45%) tumors arose in the posterior fossa and 255 (55%) appeared supratentorially. A wide variety of histological subtypes were seen, each requiring tumor-specific treatment approaches. These included primitive neuroectodermal tumor (n = 86, 19%), astrocytoma (n = 135, 30%), brainstem glioma (n = 47, 10%), anaplastic astrocytoma (n = 32, 7%), and ependymoma (n = 30, 6%). Because of advances in diagnostic abilities, surgery, radiotherapy, and chemotherapy, between 60% and 70% of these patients are alive today. Diagnostic tools such as computed tomography and magnetic resonance imaging allow for better perioperative management and follow-up, while the operating microscope, CO2 laser, cavitron ultrasonic aspirator and neurosurgical microinstrumentation allow for more extensive and safer surgery. Disease specific treatment protocols, utilizing radiotherapy and adjuvant chemotherapy, have made survival common in tumors such as medulloblastoma. As survival rates increase, cognitive, endocrinologic and psychologic sequelae become increasingly important. The optimal management of children with brain tumors demands a multidisciplinary approach, best facilitated by a neuro-oncology team composed of multiple subspecialists. This article addresses incidence, classification and histology, clinical presentation, diagnosis, pre-, intra- and postoperative management, long-term effects and the team approach in posterior fossa tumors in childhood. Management of specific tumor types is included as well.

Results of the treatment of children with recurrent gliomas with lomustine and vincristine.

Gliomas comprise over 50% of all childhood brain tumors. Treatment of recurrent childhood gliomas has been disappointing and the effectiveness of therapy has been difficult to judge because of the variable natural history of the disease. Information gathered recently has suggested that treatment with [1-(2-chloroethyl)-3-cyclohexyl-1-nitrosourea)] (CCNU) and vincristine (VCR) after radiotherapy is effective in prolonging survival in children with newly diagnosed anaplastic gliomas. The authors have used these same drugs--CCNU (100 mg/m2) and VCR (1.5 mg/m2 up to a maximum dose of 2 mg)--in 6-week cycles for a maximum of eight cycles in children with recurrent gliomas. To date, 15 patients have been treated; five patients had malignant gliomas and ten low-grade gliomas. Three children showed improvement, five had stable disease, and seven had progressive disease. Of the five patients with malignant gliomas, four progressed within two cycles of treatment and one had stable disease for 7 months on treatment and then relapsed. Seven of ten children with low-grade gliomas benefitted from treatment and six remain in continuous remission a median of 16 months after initiation of therapy. Three of these children are off all therapy 21, 30, and 30 months after treatment, respectively. Therapy was well tolerated and toxicity consisted primarily of reversible bone marrow suppression. The authors conclude that CCNU and VCR chemotherapy is effective in children with recurrent low-grade gliomas and can result in relatively long-term disease stabilization. In limited experience of the authors, it is not of benefit in children with recurrent anaplastic lesions.

Treatment of chiasmatic/hypothalamic gliomas of childhood with chemotherapy: an update.

Chiasmatic/hypothalamic gliomas (CHG) of childhood may cause progressive neurological and visual deterioration. Radiotherapy results in at least transient stabilization of tumor growth in most patients but may also have adverse long-term effects, especially in young children. Since 1977, children with progressive CHG under 5 years of age at diagnosis have been treated with combination chemotherapy (actinomycin D and vincristine) without radiotherapy. Twenty-four patients, a median of 1.6 years of age at diagnosis, have been treated and followed for a median of 4.3 years (range, 0.3-10 years). All patients are alive. Nine have developed radiographic or clinical progression, occurring a median of 3 years (range, 2-6.5 years) after initiation of treatment. Fifteen of 24 (62.5%) have remained free of progressive disease and have received no other therapy. Tumor shrinkage was documented in 9 of 24 patients but did not clearly relate to long-term outcome. Full-scale intelligence quotient (IQ) obtained a median of 3.5 years after diagnosis in patients who received only chemotherapy was a mean of 103 (range 84-133). We conclude that chemotherapy can significantly delay the need for radiotherapy in children with CHG and such a delay may be beneficial regarding long-term outcome.

Significance of basal ganglia calcification on computed tomography in children.

We reviewed 6,428 head computed tomography (CT) scans performed on 4,283 children at our institution over a 3-year period and found basal ganglia calcification (BGC) in 48 (1.1%) of the patients. Their mean age at the time of detection was 5.3 years (range: 0.5-20 years); 16 (33%) patients had cancer, 14 (29%) had tuberous sclerosis or congenital infection and 18 (38%) had other medical conditions. All patients with cancer had been treated with radiation therapy, receiving a mean dose of 4,583 cGy (range: 1,800-5,500 cGy) to the diencephalon, and calcifications first became apparent at a median of 10 months after treatment. Other medical conditions included neonatal asphyxia (3), metabolic disease (3) (Kearns Sayre, MELAS, Krabbe's), congenital anomalies (3), meningitis (2), Fahr's disease (1) and others (6). Neurologic symptoms were common in children of all groups, but could not be correlated to BGC changes. Calcium and phosphorus metabolism was evaluated in 19 patients and was abnormal in 1. We conclude that BGC on CT in childhood occur primarily as an aftermath of the cancer treatment or in children with generalized neurologic dysfunction. Many children with BGC are delayed in their development, but calcifications are not directly related to specific forms of neurologic dysfunction. Rather, ther appear to serve as markers for more extensive brain damage.

Intracranial visual pathway gliomas in children with neurofibromatosis.

The association between neurofibromatosis and visual pathway gliomas is well documented. The introduction of computed tomography and magnetic resonance imaging has heralded a new era in the understanding of visual pathway gliomas. Both of these noninvasive neuroinvestigative techniques have demonstrated extensive abnormalities throughout the visual pathway in children with visual pathway gliomas, especially in those with neurofibromatosis. The clinical significance of these abnormal areas of brain, especially in asymptomatic patients, is unknown. In an attempt to clarify the incidence, natural history, and clinical course of patients with neurofibromatosis and visual pathway lesions, we reviewed our experience with 24 patients managed consecutively at Children's Hospital of Philadelphia over the past 12 years. The patients in this series were compared to 29 children with visual pathway gliomas without neurofibromatosis who were evaluated at our institution over the same period of time. Visual pathway gliomas in children with neurofibromatosis differ from those in children without neurofibromatosis. In general, lesions tended to be more extensive in patients with neurofibromatosis and the clinical course of these patients is more variable. Twelve of the 24 patients with neurofibromatosis in our series had symptoms of progressive disease at the time of diagnosis and underwent treatment with variable results. Twelve children with neurofibromatosis and visual pathway lesions had static lesions at the time of diagnosis and, to date, 3 have developed progressive disease. From our review we can make some recommendations concerning the management of children with neurofibromatosis and visual pathway gliomas, but many questions remain unanswered. Sequential follow-up of a large cohort of both asymptomatic and symptomatic children with neurofibromatosis and visual pathway lesions is needed to more definitively outline the best management approach for these patients.

Massive gastrointestinal hemorrhage in children with posterior fossa tumors.

Over a 12-month period (September 1984 to September 1985), 64 children with newly diagnosed brain tumors were admitted to the Neurosurgical Service at The Children's Hospital of Philadelphia. Of these children, 29 had posterior fossa tumors. Of this population of children with posterior fossa tumors, three patients aged 4 months, 22 months, and 4 years old developed massive exsanguinating upper gastrointestinal hemorrhage within seven days of their primary neurosurgical procedure. In each instance, large posterior duodenal ulcers were encountered and were treated with oversewing of the duodenal ulcer and vagotomy-pyloroplasty. Follow-up currently ranges from 18 to 26 months. All three children have survived and none have had any gastrointestinal bleeding since then. Massive exsanguinating hemorrhage was not seen in children with brain tumors in locations other than the posterior fossa. In this population of patients, we advocate the use of prophylactic cimetidine and titration of gastric acidity with antacids.

Quality of life in children with primitive neuroectodermal tumors (medulloblastoma) of the posterior fossa.

We reviewed our experience in 43 consecutive patients with primitive neuroectodermal tumors (medulloblastoma), PNET (MB), treated between 1975 and 1984, to characterize their quality of life and identify factors which impacted on long-term function. Twenty-four of forty-three (56%) of children are alive and free of disease, a median of 4.5 years after diagnosis. The quality of life was analyzed for the 24 long-term survivors. 79% (19 of 24) were functioning well in everyday activities. The median full-scale intelligence quotient (FSIQ), obtained a median of 3.5 years after diagnosis for those tested (n = 17) was 97, with all but 3 (12%) of the patients functioning in the normal range. Specific learning, memory and fine-motor disabilities were found in over one half of patients. Factors associated with poorer performance and lower FSIQ included preoperative obtundation, the need for a permanent shunt, younger age at diagnosis, and a complicated postoperative course. It is concluded that (1) the majority of long-term survivors have 'normal' intellectual function, but may have specific intellectual and academic disabilities, and (2) preoperative and postoperative factors strongly impact on the quality of life of survivors.

Cerebrovascular accidents in children with cancer.

During a 4-year period, 26 children with systemic malignancies suffered cerebrovascular accidents. These occurred in 17 patients with lymphoreticular malignancy and nine patients with solid tumors. They were the presenting signs of malignancy in three patients and were the direct cause of death in six. Cerebrovascular accidents were directly related to disseminated intravascular coagulation in eight patients, to chemotherapy in eight patients, to metastatic tumor in three patients, to thrombocytopenia in three patients, and to fungal meningitis in one patient. All patients with disseminated intravascular coagulation had leukemia and at times, cerebrovascular thrombosis predated systemic or laboratory evidence of disseminated intravascular coagulation. This review indicates that four major syndromes are apparent in children with cancer: vascular thrombosis associated with disseminated intravascular coagulation, acute arterial or sagittal sinus thrombosis secondary to L-asparaginase in children with leukemia, acute neurologic dysfunction in patients with osteogenic sarcoma treated with high-dose methotrexate, and obtundation, seizures, and focal neurologic deficits in patients with neuroblastoma metastatic to the torcular region. Although elevated WBC counts and thrombocytopenia occur frequently in children with cancer, in themselves they uncommonly result in strokes. It is concluded that cerebrovascular accidents are a relatively frequent cause of acute neurologic compromise in children with cancer and that certain types of malignancies and their treatment predispose patients to this complication.

Leptomeningeal dissemination of primary central nervous system tumors of childhood.

Presymptomatic craniospinal radiation therapy improves the rate of survival for children with brain tumors, which frequently metastasize to the leptomeninges. Radiotherapy may cause neurological damage and should be used only in patients considered to be at highest risk for leptomeningeal dissemination (LMS) at either the time of initial diagnosis or onset of disease relapse. We reviewed 314 consecutive patients with brain tumors to determine the incidence, timing, and importance of LMS. LMS occurred in 60 (19%) children. LMS occurred before diagnosis in 30 patients, as the only site of relapse or simultaneously with local first disease recurrence in 17 patients, and after local disease recurrence in 13 patients. Children with primitive neuroectodermal tumors, anaplastic gliomas, and ependymomas most frequently had LMS. Patients with primitive neuroectodermal tumors and posterior fossa anaplastic gliomas frequently had LMS before diagnosis or at the onset of relapse, whereas patients with ependymomas had LMS after local disease relapse. Both myelography and cerebrospinal fluid cytological examination are required to diagnose LMS.

Brain stem necrosis after preradiation high-dose methotrexate.

Both cranial radiation therapy (RT) and high-dose systemic methotrexate (MTX) are used to treat intracranial neoplasmas, but both may cause neurologic damage. MTX may be less neurotoxic if given before rather than after radiotherapy. We cared for a 5-year-old girl with a pineocytoma who had progressive brain stem dysfunction 4 months after MTX therapy, followed by local radiation therapy. CT studies were consistent with radiation necrosis that was confirmed at autopsy. MTX used in conjunction with cranial irradiation can result in severe neurotoxicity, even if the drug is given first.