Edward H. Kovnar

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.

High risk of recurrent stroke after discontinuance of five to twelve years of transfusion therapy in patients with sickle cell disease

Although long-term transfusion therapy is at least 90% effective in preventing recurrent strokes after an initial cerebrovascular accident in patients with sickle cell disease, it is unknown how long transfusion therapy should be continued. To address this question, we prospectively discontinued transfusions in 10 patients with sickle cell disease whose median duration of transfusion therapy after an initial stroke was 9 1/2 years (range 5 to 12 years). Before the transfusions were discontinued, patients were examined by cerebral angiography, magnetic resonance imaging of the head, neuropsychologic testing, electroencephalography, and a complete neurologic examination. Within 12 months after transfusion therapy was stopped, 5 of 10 patients had had an ischemic event. Three events caused relatively mild deficits in the same areas as those originally affected. Two were associated with massive intracranial hemorrhage, including one on the contralateral side of original involvement. An additional patient died suddenly of unknown causes. Of the four remaining patients, three declined to resume transfusion and are relatively well at greater than or equal to 18 months after therapy was stopped. The studies performed before transfusions were stopped were not predictive of recurrent stroke. The risk of recurrent cerebrovascular accident in this group was significantly greater than the estimated risk of 10% in patients who are receiving long-term transfusion therapy (p = 0.002). This adverse outcome suggests that patients with sickle cell disease who have had a stroke must receive long-term transfusion indefinitely or a suitable therapeutic alternative must be devised.

Preirradiation cisplatin and etoposide in the treatment of high-risk medulloblastoma and other malignant embryonal tumors of the central nervous system: a phase II study.

Medulloblastoma, pineoblastoma, and cerebral neuroblastoma are malignant embryonal tumors of the CNS that may demonstrate similar histologic features, a propensity for neuraxis dissemination and sensitivity to radiation therapy and, in certain cases, chemotherapy. To evaluate the activity of preirradiation chemotherapy in such tumors, 11 newly diagnosed children with measurable residual disease and characteristics indicative of poor prognosis were treated postoperatively with cisplatin (CDDP) and etoposide (VP-16). Responses graded on the basis of radiographic findings in areas of either macroscopic residual tumor or metastatic disease included two complete responses (CRs), eight partial responses (PRs), and one stable disease (SD). Acute and subacute toxicity consisted of high-frequency hearing loss in four patients, reversible signs and symptoms of increased intracranial pressure in two patients, and transient neutropenia. Seven of eight patients with high-risk medulloblastoma and two of two with pineoblastoma remain free of tumor progression following neuraxis irradiation at 8 to 48 months postdiagnosis (median, 18 months). CDDP and VP-16 is a highly active drug combination when given before irradiation in children with high-risk medulloblastoma and other malignant embryonal tumors of the CNS, producing objective responses in at least one site of measurable disease in 10 of 11 newly diagnosed patients, including all of five with gross neuraxis dissemination.

Medulloblastoma in very young children: outcome of definitive craniospinal irradiation following incomplete response to chemotherapy.

PURPOSE To evaluate survival and neurodevelopmental outcomes following radiation therapy in infants and young children with residual or progressive medulloblastoma after primary chemotherapy. PATIENTS AND METHODS Thirteen young patients (< or = 36 months old) with medulloblastoma were treated with preirradiation multiagent chemotherapy and maximal surgical resection. Patients were scheduled to receive radiation therapy at the time of documented disease progression or upon completion of chemotherapy with residual disease. All patients underwent neurodevelopmental evaluation at the time of diagnosis, before receiving radiation therapy, and at yearly intervals posttreatment. RESULTS Two patients completed the scheduled chemotherapy with residual disease and received delayed radiation therapy. The remaining 11 patients had either local or leptomeningeal progression during chemotherapy (median time to progression, 5 months). Six patients had a complete response (CR) to radiation therapy, and three of these children are alive 48 to 104 months postdiagnosis. Of the five patients who had progressive disease (PD) during radiation therapy or residual imaging abnormalities after treatment, only one is alive (with stable enhancing leptomeningeal abnormalities) 48 months postirradiation. Two additional survivors were rendered disease-free by surgical resection before radiation therapy and are without evidence of disease at 91 and 107 months after diagnosis. Thus, six of 13 patients are alive at 48 to 107 months postdiagnosis. Neurodevelopmental scores tended to be below age norms at diagnosis; scores improved during chemotherapy, but then decreased during posttreatment follow-up evaluation. CONCLUSION Radiation therapy appears to produce long-term disease-free survival in a proportion of very young patients who have progressive or residual medulloblastoma during or after primary chemotherapy. However, neurodevelopmental deficits are frequent among long-term survivors.

Predominance of Pilocytic Histology in Dorsally Exophytic Brain Stem Tumors

We report the magnetic resonance imaging (MRI) and clinico-histologic characterization of dorsally exophytic brain stem gliomas (DEBSGs). Between 1983 and 1991, 12 of 51 patients evaluated for the diagnosis of brain stem glioma were found to have DEBSGs emanating from the pons, pontomedullary junction or medulla. Eleven of the 12 patients had classic juvenile pilocytic astrocytomas. Unlike most other brain stem tumors, these patients were young (median 38 months, range 17-75), had a relatively long duration of symptoms (median 7 months, range 2-24) and displayed signs of increased intracranial pressure with limited cranial nerve paresis, absence of pyramidal tract findings, and near normal brain stem auditory-evoked potentials. MRI characteristically showed sharply demarcated lesions with decreased signal intensity on T1, and increased intensity on T2 sequences. Except for cystic areas, these tumors showed bright, uniform enhancement after gadolinium-DTPA. In all patients, 50-100% of the tumor volume could be resected. Three of 10 patients who received no immediate postoperative treatment eventually demonstrated disease progression, and 2 patients with subtotal resections who were treated with radiation and/or chemotherapy postoperatively remain disease-free for extended periods of time. The only death occurred in the 1 patient treated with chemotherapy who died of secondary leukemia. The overall and progression-free survival of these patients at 2 years is 100 and 67% as compared to 18 and 21%, respectively, for other concomitantly treated nonexophytic brain stem gliomas.2+ the ability to achieve significant degrees of resection.

High-dose chemotherapy and autologous bone marrow rescue followed by interstitial and external-beam radiotherapy in newly diagnosed pediatric malignant gliomas.

PURPOSE Evaluation of high-dose chemotherapy with autologous bone marrow rescue (ABMR) in pediatric malignant gliomas. PATIENTS AND METHODS Newly diagnosed (n = 11) and recurrent (n = 2) malignant glioma patients received high-dose chemotherapy within 4 weeks of surgery; three had near total and 10 had subtotal resection/biopsy. High-dose thiotepa (300 mg/m2) and cyclophosphamide (2 g/m2) daily for 3 days were followed by ABMR; response was evaluated at day 30. At day 60, patients with at least stable disease received hyperfractionated (n = 9) or conventional external-beam radiotherapy (n = 2) preceded by local radioactive iodine 125 implantation (n = 2) or radiosurgery (n = 1). RESULTS Grade III and IV toxicities after ABMR consisted of mucositis (n = 12), cardiomyopathy (n = 1), acute abdomen (n = 1), pneumonitis (n = 2), and infection (n = 2). One complete and three partial responses were observed; the objective response rate was 31% (95% confidence interval, 9% to 61%). Seven had stable disease, one had disease progression, and one died of toxicity before response evaluation. The median overall and progression-free survival durations after combined modality therapy were 14 months (range, 4 to 30+) and 9 months (range, 0 to 30+), respectively. One patient remains progression-free at 30+ months. Radionecrosis and white matter changes occurred in three patients: one after hyperfractionated irradiation, and two after 125I implants. CONCLUSION For patients with bulky residual disease after surgery, survival with this aggressive chemotherapy and radiation regimen is not better than that reported for conventional treatment regimens.

Brain tumors in the very young child: Postoperative chemotherapy in combined-modality treatment

Twelve consecutively diagnosed children with brain tumors, ages 7 to 27 months, were treated by a combined‐modality approach featuring aggressive surgical resection followed by chemotherapy and delayed irradiation. Patients received multiple clinical neurologic examinations and psychological evaluations, as well as diagnostic imaging studies, to monitor the efficacy of chemotherapy and toxic effects of therapy. Six of the eight children with residual tumor evident postoperatively on computed tomography scans had objective responses to chemotherapy. The efficacy of chemotherapy was further demonstrated by the lack of disease progression for 7 months or longer in eight children, seven of whom remain free of tumor 19 to 57 months (median, 28 months) from the date of diagnosis. The neurologic status of ten patients improved during treatment. Developmental progress was normal in two, low average in three, and frankly deficient in four of ten children formally evaluated. These results indicate that postoperative chemotherapy, added to a regimen of surgical resection and delayed irradiation, prolong survival with only minimal short term neurotoxicity in the majority of very young children with malignant brain tumors.

Preirradiation chemotherapy with carboplatin and etoposide in newly diagnosed embryonal pediatric CNS tumors.

PURPOSE We evaluated the clinical efficacy of preirradiation carboplatin (CARBO) and etoposide (VP-16) in 25 patients with newly diagnosed embryonal CNS tumors. PATIENTS AND METHODS Sixteen patients with high-risk medulloblastoma and nine with other embryonal tumors were treated with two daily doses of CARBO 350 mg/m2 and VP-16 100 mg/m2 (CARBO/VP) every 21 days for four cycles before standard craniospinal irradiation. Patients with disease progression (PD) before radiation therapy were additionally treated with intensive postirradiation cyclophosphamide (CYCLO) and vincristine (VINC). RESULTS Among 23 assessable patients, 48% (95% confidence interval, 27% to 69%) had a complete response (CR) or partial response (PR) to CARBO/VP; eight had PD. Among the subgroup of 15 assessable patients with medulloblastoma, 53% had a CR or PR (95% confidence interval, 27% to 79%) and five PD. The toxicity of CARBO/VP was predominantly hematologic; although grade IV neutropenia was common, only five episodes of febrile neutropenia occurred. Only thrombocytopenia was a more common toxicity than in other reported chemotherapy regimens; ototoxicity was less common than in cisplatin (CDDP) regimens. CONCLUSION The responses and survival associated with neoadjuvant CARBO/VP are similar to those with CDDP-containing and other neoadjuvant drug regimens. Although the rate of progression with this regimen may be higher than with similar CDDP-containing regimens, the numbers of patients in other published studies of these agents are too small to detect meaningful statistical differences. Future studies must balance the apparently comparable efficacy of CARBO and CDDP with their differing toxicities.

Primary extracranial neuroblastoma with central nervous system metastases characterization by clinicopathologic findings and neuroimaging

The authors report the clinicopathologic and neuroimaging findings in ten children with primary abdominal or thoracic neuroblastoma who relapsed in the central nervous system (CNS) without evidence of concurrent intracranial extension from adjacent bone, dura, or dural sinus metastases. At diagnosis, the patients ranged in age from 0.3 to 4.5 years (median, 2 years). Their times to CNS relapse ranged from 2 to 34 months from diagnosis. In seven patients the relapse occurred from 1 to 14 months after elective discontinuation of therapy. In four patients, the CNS relapse was the primary (isolated) adverse event. Four patients could not be treated at the time of relapse, and they died within 7 days of progressive CNS disease. In the remaining group, craniospinal irradiation with or without administration of a platinum compound and an epipodophyllotoxin caused complete CNS remissions lasting 4, 5, 16, and 62+ months. Neuroimaging and autopsy findings indicated that cerebrospinal fluid is the major pathway for neuraxis dissemination by neuroblastoma cells. There was no evidence of dural penetration in any patient. The possibility of relapse in the neuraxis should be considered for any patient with neuroblastoma who has neurologic deterioration. A combination of craniospinal radiation and administration of a platinum compound and an epipodophyllotoxin will induce complete responses in some patients with neuraxis involvement by neuroblastoma, but the risk of subsequent failure outside the CNS remains high.

Neuraxis dissemination in pediatric brain tumors. Response to preirradiation chemotherapy

Of 29 consecutive children treated for malignant primary tumors of the central nervous system (CNS) at this institution, postoperative examination showed radiographic or cytologic evidence of neuraxis dissemination in 10 (34%). Given the historically poor results in disseminated CNS tumors treated with surgery and radiation therapy alone, these ten patients were treated prospectively with an investigational Phase II protocol consisting of preirradiation cisplatin (90 mg/m2 on day 1) and etoposide (150 mg/m2 on days 3 and 4). The diagnoses included medulloblastoma (n = 4), malignant glioma (n = 3), cerebral primitive neuroectodermal tumor (n = 1), pineoblastoma (n = 1), and mixed glioma of the brainstem (n = 1). Postoperative neuraxis scanning with computed tomography, magnetic resonance imaging, or spinal myelography showed measurable intracranial or spinal me‐tastases in all children. The cerebrospinal fluid (CSF) cytologic examination was positive for tumor cells in five. The best responses, based on serial imaging of neuraxis metastases, included two complete responses, four partial responses, and three stable disease states. One patient had progressive disease at the primary site despite stable disease in the spine; progressive neuraxis disease was documented in only one patient during chemotherapy. Clearance of tumor cells from the CSF was documented in three patients. The adverse effects of chemotherapy, consisting of transient myelosuppression and mild ototoxicity, were minimal. Reversible neurologic deterioration occurred in two patients; one patient became acutely quadriplegic after a prolonged convulsive seizure without radiographic evidence of tumor progression. Cancer 1992; 69:1061–1066.