The role of stereotactic radiation therapy in the management of children with brain tumors.

Conventional radiation therapy plays an important role in the management of intracranial tumors in children. For certain tumors radiation therapy serves as the primary mode of treatment, and for others it plays an adjuvant role with surgery and/or chemotherapy. Improvements in long-term survival rates have focused attention on the long-term sequelae of brain tumors and their treatment, and the sequelae, in turn, have become important targets for clinical investigation. Long-term side effects of particular concern in children include cranial nerve damage, memory and intellectual deficits, pituitary-hypothalamic dysfunction, demyelinization of brain tissue, and secondary malignancies. A new form of radiation therapy, stereotactic radiotherapy (SRT), merges the technologies of stereotactic surgery and conventional fractionated radiotherapy. The intent is to deliver maximum tumoricidal doses to the target while limiting the dose to normal surrounding brain tissue. The key feature of SRT is a noninvasive, relocatable immobilization system to assure accurate and reproducible positioning during planning and treatment. The headframes used for children have been modified to address their specific needs. The complexities of this process require careful preparation of patients and their families and the participation of many disciplines. Long-term follow-up will be essential to evaluate the effectiveness of this innovative treatment.

Neurobehavioral and neurologic outcome in long-term survivors of posterior fossa brain tumors: role of age and perioperative factors.

We evaluated the neuropsychological and neurologic outcome of 15 long-term survivors of posterior fossa tumors who were treated between 1970 and 1984 with cranial irradiation (n = 15) and surgery (n = 14). The interval between diagnosis and evaluation ranged from 4 to 20 years (median = 10 years). Earlier age at diagnosis (< 6 years) was associated with an increased incidence of severe neurologic and neuropsychological sequelae. Hydrocephalus, obtundation, and tumor extension outside the vermis also were more prevalent in the younger group. Poor neurobehavioral outcomes in young children with posterior fossa tumors may be related to more aggressive tumor growth or complications of the initial therapy and not solely due to toxicity from craniospinal irradiation.

Advances in radiation therapy for craniopharyngiomas.

The overall survival for patients with craniopharyngioma is excellent. However, conventional treatments that include aggressive surgery and standard irradiation have been associated with significant morbidity. Focal radiation treatment with stereotactic radiosurgery has a role in selected cases, but may also be damaging to sensitive normal tissues such as the optic chiasm. Stereotactic radiotherapy (SRT) is a technique that allows for conventionally fractionated radiation under stereotactic guidance. Thus, highly focal and precise radiotherapy is now coupled with fractionation, enabling the treatment of selected tumors with a potentially improved therapeutic index. Dose optimization with SRT for focally discrete tumors should result in equivalent local control and survival compared to patients treated with conventional irradiation. We anticipate a significant decrease in late effects, especially neuropsychological and neuroendocrine sequelae.

Stage III neuroblastoma over 1 year of age at diagnosis: improved survival with intensive multimodality therapy including multiple alkylating agents.

PURPOSE: A nonrandomized, single-arm trial was conducted to assess the efficacy of multimodality therapy including intensive chemotherapy with multiple alkylating agents in the treatment of children with Evans stage III neuroblastoma older than 1 year at diagnosis. PATIENTS AND METHODS: Twenty-five patients with a median age of 18 months at diagnosis were treated with multimodality therapy including surgery and chemotherapy using either nitrogen mustard (mechlorethamine), doxorubicin, cisplatin, dacarbazine (DTIC), vincristine, and cyclophosphamide (MADDOC) or cisplatin and cyclophosphamide induction followed by maintenance MADDOC (induction MADDOC) protocols. Sixteen of 25 patients also received radiotherapy to the tumor bed and primary lymph nodes. Event-free survival (EFS) was compared with that reported previously in the literature. N-myc amplification was evaluated prospectively and the Shimada classification was evaluated retrospectively as potential prognostic factors. RESULTS: We report a 72% EFS (95% confidence interval +/- 18%) with a median follow-up of 85 months. EFS was significantly worse for patients with tumors demonstrating N-myc amplification (P = .018). Patients classified as favorable according to the Shimada system experienced a significantly better EFS (P = .04), but unfavorable patients still maintained a 60% EFS. CONCLUSION: Intensive multimodality treatment including MADDOC and induction MADDOC chemotherapy provides a very good EFS for children older than 1 year who have stage III neuroblastoma. Children classified as favorable according to the Shimada system have a better prognosis. Patients whose tumors demonstrate N-myc amplification have a poor prognosis despite therapy.

The change in patterns of relapse in medulloblastoma.

The authors reviewed 89 patients treated for cerebellar medulloblastoma between 1970 and 1989 to determine the impact of changing treatment (high-dose posterior fossa radiation therapy and chemotherapy) on the pattern of failure in medulloblastoma. Between 1970 and 1983, 50 patients (median follow-up, 110 months) were treated with surgery and postoperative craniospinal irradiation (CSI). Nineteen of the 50 (38%) recurred in the central nervous system (CNS). Isolated systemic (bone) metastases occurred in six. The median time to the development of bone metastases was 12 months. Since 1984, 39 patients (median follow-up, 27 months) were treated with preradiation chemotherapy consisting of cisplatin and vincristine for 9 weeks before initiation of CSI. Nine of the 39 (23%) patients recurred in the CNS. There were no systemic failures in this cohort. The actuarial 5-year disease-free survival was 55 +/- 7% for the earlier cohort and 72 +/- 8% for the later cohort (P equals 0.3). Posterior fossa recurrence was associated with radiation therapy to this area. The cumulative incidence of posterior fossa relapse was 50 +/- 13% in patients who received less than 5300 cGy and 18 +/- 7% in those who received 5300 cGy or more (P equals 0.005). All six bone relapses were in patients treated with CSI alone and 5300 cGy or more to the posterior fossa for a 5-year cumulative incidence of bone metastases of 18 +/- 7% compared with 0% for patients treated with 5300 cGy or more and chemotherapy (P equals 0.03). The authors concluded that high-dose radiation therapy has altered the pattern of relapse with an increase in systemic recurrence after radiation therapy alone that is now equivalent to the risk of recurrence in the posterior fossa. Chemotherapy may be indicated in an attempt to decrease this high risk of systemic metastases.

Stage IV neuroblastoma in infants. Long-term survival.

Before the advent of multiagent chemotherapy, the prognosis for patients with Stage IV neuroblastoma of all ages was dismal. More recently, marked improvement in infants with Stage IV neuroblastoma has been reported. Twenty-four infants with Stage IV neuroblastoma have been treated at the Dana-Farber Cancer Institute/The Children's Hospital, and the Joint Center For Radiation Therapy, Boston, Massachusetts, between 1970 and 1988. Twenty-three of these patients were treated with multiagent chemotherapy and one with a single drug. In the initial report, ten of 11 patients were alive without evidence of disease after intensive therapy. In this report the authors update their initial series of patients and include 13 additional patients who subsequently presented to our institutions with Stage IV neuroblastoma younger than 1 year of age. The 5-year actuarial event-free survival for the 24 patients is 75%. No patient without bone metastases died from neuroblastoma, and 12 of 16 patients with bone metastases remained disease free. These results confirm that infants with Stage IV neuroblastoma have a very good prognosis when treated with intensive multiagent chemotherapy.

Choroid plexus tumors in the breast cancer-sarcoma syndrome.

Choroid plexus neoplasms are rare epithelial tumors of the central nervous system. A carcinoma of the choroid plexus occurred in a child from a family with the breast cancer-sarcoma syndrome (Li-Fraumeni or SBLA syndrome), an inherited condition characterized by the development of diverse neoplasms (sarcoma, breast cancer, brain tumors, leukemia, adrenal cortical carcinoma, and others). Choroid plexus carcinomas were identified in two kindreds previously reported with the syndrome. The literature contains reports of choroid plexus neoplasms occurring in families and in individuals with multiple primary tumors. Choroid plexus neoplasm may be a manifestation of the inherited proclivity to tumor development in the breast cancer-sarcoma syndrome.

Ototoxicity of preradiation cisplatin for children with central nervous system tumors.

From March 1984 through March 1989 we performed 235 audiometric tests on 39 children with malignant brain tumors who were treated with cisplatin 100 mg/m2 every 3 weeks for three courses and vincristine weekly for 9 weeks followed by cranial irradiation. Twenty-eight of the 39 children had sufficient serial testing for evaluation of ototoxicity secondary to cisplatin. Following the third cisplatin treatment (300 mg/m2 cumulative dose), 20% of the assessable children had hearing loss limited to the high frequencies of 6,000 to 8,000 Hz, 16% had hearing loss beginning at 3,000 to 4,000 Hz, and three children (11%) had loss within the speech frequencies beginning at 1,000 to 2,000 Hz. Eighteen of 19 children (95%) who were evaluated comparatively at a median of 15 months following radiation showed no significant change from preradiation testing. There was no correlation between hearing loss and patient age. We conclude that cisplatin ototoxicity was acceptable and that radiation therapy does not increase the ototoxicity of cisplatin when the drug is given before, instead of following, cranial irradiation.

Pre-irradiation chemotherapy for infants and children with medulloblastoma: a preliminary report.

From March, 1984, through June, 1987, 21 newly diagnosed children with high-risk medulloblastoma (Chang Stage T3 to T4) were treated on a 9-week postoperative, pre-irradiation chemotherapy regimen consisting of vincristine and cisplatin. The children over 2 years old then received radiation therapy. Six infants (aged 6 to 18 months) were maintained on chemotherapy consisting of MOP (nitrogen mustard, vincristine, and procarbazine) until the age of 2 years, at which time they were referred for irradiation. Of 13 children with measurable disease following surgery, five showed a definite response on computerized tomography scans to vincristine and cisplatin (one complete response and four partial responses) and five others showed clear marginal responses. Four of the six infants were disease-free at 19, 32, 35, and 57 months from diagnosis. One infant developed progressive disease at the completion of the vincristine and cisplatin course, and a second infant had progression during MOP administration. Three of the 21 children developed hearing loss within the speech frequencies during cisplatin treatments, but there were no other major toxicities. Fifteen children remained disease-free with a median follow-up period of 35 months (range 19 to 57 months). Chemotherapy given between surgery and radiotherapy may allow for the direct evaluation of a specific drug regimen and permit the postponement of radiation therapy in infants. Pre-irradiation vincristine and cisplatin was well tolerated and effective in shrinking the tumor in most children with medulloblastoma. Such chemotherapy regimens have the potential for extending long-term survival in high-risk children.

Pre-radiation chemotherapy for infants and poor prognosis children with medulloblastoma.

Beginning in 1984, we started a prospective study to evaluate the role of postoperative, pre-radiation chemotherapy in the treatment of infants and poor prognosis children with medulloblastoma. The study was designed to evaluate the role of pre-radiation chemotherapy in two specific patient populations: (a) children under the age of 2 years in which there was an attempt to delay definitive radiation and thus reduce the risk of toxicity to the developing nervous system; and (b) children over age 2 years with Stage T3 and T4 disease who were known to have a relatively poor prognosis with surgery and radiation. The five patients under age 2 years received cisplatinum (100 mg/m2) every 3 weeks and weekly vincristine (1.5 mg/m2) for a total of 9 weeks. Nitrogen mustard (6 mg/m2), procarbazine (100 mg/m2), and vincristine (1.5 mg/m2) (MOP) were given in 28 day cycles as long as there was no disease progression or until the child's second birthday, at which time the children were referred for radiation therapy. The 13 patients over 2 years of age received the 9 week course of cisplatinum and vincristine and then began radiation. Responses measured by computed tomography were obtained in 10 of 12 children with measurable disease at the start of chemotherapy. With a median follow-up of 22 months, 15 of 18 children were alive and free of disease. Except for mild ototoxicity in one child, the acute side effects have been well tolerated. In conclusion, it appears that some infants can have their radiation delayed until the age of 2 years. Although the follow-up time was short, all but three patients were free of disease, time exceeding the median time to failure with radiation alone. Pre-radiation chemotherapy might improve local control and survival in children with advanced stage medulloblastoma.