BACKGROUND: PTC299 is a novel, orally bioavailable small molecule that selectively inhibits vascular endothelial growth factor receptor protein synthesis at the post-transcriptional level.METHODS: A phase I and pharmacokinetic study was performed in children between aged 3-21 years, inclusive, with recurrent brain tumors.PTC299 was given 2-3 times per day every day based on body weight.Six patients were enrolled at each dose level.Four dose levels were planned, beginning at 1.2 mg/kg/dose BID up to 2.0 mg/kg/dose TID; escalation was based on tolerability and mandatory pharmacokinetic data.RESULTS: A total of 28 patients (median age 11.6 years [range 5.5-21.1])were enrolled, with a wide variety of tumors including 8 low-grade gliomas, 9 high-grade gliomas, and 4 brainstem gliomas; 21 patients were evaluable for toxicity.One dose-limiting toxicity (DLT) possibly related to treatment (hyponatremia) was identified during the first course of treatment.Possibly related grade 3 toxic effects of hypernatremia (1), hypertension (1), and lethargy (1) were noted with prolonged use.Pharmacokinetic analysis in cycle 1 demonstrated the expected rise in drug concentrations with increasing doses.Concentrations at dose level three were similar to adult phase II levels.With prolonged use, some patients had drug accumulations without associated toxicity.Objective radiographic responses were not seen, but prolonged (greater than 6 months) stable disease was seen in 5 of 8 patients with low-grade gliomas, 2 of whom maintained disease control for more than 1 year.Four evaluable patients were entered at dose level 4, but the study was suspended pending evaluation of toxicity seen in the adult trials.CONCLUSIONS: PTC299 was well tolerated and prolonged disease control was seen in children with low-grade gliomas.Further study, possibly in combination with other agents, is reasonable, although the pharmacokinetic profile may be challenging, and the adult toxicity profile must be taken into account.

PURPOSE:To describe the pattern of survival and late mortality among contemporary long-term survivors of pediatric CNS tumor.PATIENTS AND METHODS:The study population comprised 643 pediatric patients with primary CNS tumor treated at St Jude Children's Research Hospital (Memphis, TN) from 1985 to 2000 who survived > or = 5 years from diagnosis. Patients were classified according to primary tumor type, location of tumor, and survival. Cause of death was obtained from the medical record and categorized as progression, malignant transformation, second malignancy, medical complication, or external cause.RESULTS:Overall survival estimates for patients who survived at least 5 years postdiagnosis was 91.3% +/- 2% and 86% +/- 3% at 10 and 15 years postdiagnosis, respectively. A significant difference in the survival rates according to original tumor type (P = .001) was seen. Sixty-six (10%) of 643 patients experienced late mortality: 38 patients (58%) died of progressive disease while 14 patients (21%) died of second malignant tumor. Twelve patients (18%), predominantly with diencephalic tumor location, died of a specific medical cause: cardiovascular disease (n = 2), cerebrovascular accident (n = 1), metabolic collapse and/or sepsis (n = 7), respiratory failure (n = 1), or shunt malfunction (n = 1).CONCLUSION:Late mortality occurs in a substantial number of long-term survivors of pediatric CNS tumors and is most influenced by the initial tumor histopathology. Progressive disease remains the most common cause of death within the first decade of diagnosis. Teenage patients requiring treatment for panhypopituitarism may be especially vulnerable and deserve significant medical surveillance.

Purpose/Objective: To evaluate event-free (EFS) and overall survival (OS) and to assess early and late complications in children and adolescents with favorable, early stage Hodgkin's disease (HD) who are treated with vinblastine, doxorubicin, methotrexate, and prednisone (VAMP) chemotherapy and low–dose, involved–field radiation therapy (IF RT). Materials/Methods: 110 children from three participating institutions (St. Jude, Stanford, Dana Farber) who presented with nonbulky, clinical stage I–II, favorable, (low risk) HD underwent clinical staging and were treated with four cycles of VAMP and 15 Gy IF RT for those who achieved a complete response, or 25.5 Gy for those with a partial response after two cycles of chemotherapy. Results: Patient characteristics included: 75 boys, 35 girls; 77 had classic HD, 33 lymphocyte predominant disease. The stage was I in 36 children, II in 74; 53 had a mediastinal mass. Involved nodal sites were: 1 site–34 children, 2 sites–46, 3 sites– 20, 4–6 sites–10. Laboratory studies revealed: ESR > 20 mm/h in 46 children; hemoglobin 10.5 g/dl in 4 children. The median age at study entry was 13 years (range 3–20). The response to 2 cycles of VAMP was 100 %; 49 achieved a complete response, 61 a partial response. With median follow-up of 8.9 years (range 1.7–13.7 years), the 5 year and 10 year OS are 99 % (SE 0.009) and 97 % (SE 0.029). The 5 year and 10 year EFS are 93 % (SE 0.026) and 91 % (SE 0.047). This out patient treatment is well tolerated. Blood product transfusions and hospital admissions for neutropenic fever are rare. Hair thinning is uncommon. There have been no serious bacterial infections. Two malignant tumors have been observed: One thyroid cancer 8 years after 25.5 Gy to the neck occurring within the RT field; one Ewing 's sarcoma occurring 4 years after treatment, outside the RT field. Offspring include 14 healthy babies among 107 survivors, indicating maintenance of fertility. One–quarter of irradiated patients developed laboratory evidence of hypothyroidism, easily corrected with medication. Growth abnormalities are subtle and appear to be restricted to children < 10 years old, who received doses > 15 Gy, to volumes that included the entire clavicle. There have been no cardiac, neurologic or symptomatic pulmonary abnormalities observed. Conclusions: Four cycles of VAMP and 15–25.5 Gy IF RT is effective in pediatric low–risk HD confirming that these children can be cured with limited therapy that does not include an alkylating agent, bleomycin, etoposide, or high–dose, extended field RT. With this favorable outcome, our current low–risk protocol now tests the need for RT in children/adolescents who achieve an early complete response to 2 cycles of VAMP chemotherapy.

Purpose/ObjectiveControversy persists on the association of radiation (RT) dose and volume with the occurrence of second malignancies (SMN) following treatment of children with Hodgkin lymphoma (HL). The impact must be defined in order to devise treatment strategies that diminish the risk and appropriately screen for such cancers.Materials/MethodsAll 930 children (<18 years old) treated for HL between 1960–1990 at 5 institutions were evaluated. Mean age at diagnosis was 13.6 years, median follow-up was 16.7 years (maximum 39), and male:female ratio was 1.3:1. Treatment included RT alone (43%), chemotherapy alone (9%), or both (48%). Standardized incidence ratio (SIR) for a SMN was calculated from age- and sex-matched SEER data.ResultsSMNs occurred in 102 (11%) patients, with an actuarial rate of 19% at 25 years. With 15154 patient years (PY) of follow-up, only 7.18 cancers would be expected, resulting in a SIR of 14.2 and an absolute excess risk (AER) of 63 cases per 10,000 PY. Increasing RT dose was associated with an increasing SIR (p = .0085). Mean RT dose was marginally greater for patients who developed a SMN (32.5 Gy vs. 29.2 Gy, p = .0099). The SIR for patients treated with mantle RT <25 Gy, 25–34 Gy, and ≥35 Gy was 11.7, 12.1, and 16.5, respectively; the AER was 38.8, 50.8, and 77.8 respectively. 77% of SMNs occurred within, 9% outside, and 3% at a margin (within 2 cm) of a RT field, and 9% were indeterminant or non-applicable (i.e. ANLL). Nevertheless, calculated RT volume was not associated with risk. Alkylator or anthracycline dose was not significant. Of note, only 1 of 82 girls irradiated to the pelvis developed breast cancer (BC), vs. 28 of 288 girls not irradiated to the pelvis (p = 0.015). On univariate analysis, increased risk of SMN was associated with female gender and increasing RT dose. Splenectomy, RT volume, chemotherapy, time since treatment, and relapse did not have statistically significant associations with risk. On multivariate logistic analysis, only mantle RT dose and female gender were significantly associated with risk. Stratified analyses demonstrated no significant risk factors in males, whereas mantle RT >35 Gy increased risk by 2.5 fold in females, predominately relating to BC. Most solid SMNs are curable, and their impact on survival is shown in the figure.Conclusions Purpose/ObjectiveControversy persists on the association of radiation (RT) dose and volume with the occurrence of second malignancies (SMN) following treatment of children with Hodgkin lymphoma (HL). The impact must be defined in order to devise treatment strategies that diminish the risk and appropriately screen for such cancers. Controversy persists on the association of radiation (RT) dose and volume with the occurrence of second malignancies (SMN) following treatment of children with Hodgkin lymphoma (HL). The impact must be defined in order to devise treatment strategies that diminish the risk and appropriately screen for such cancers. Materials/MethodsAll 930 children (<18 years old) treated for HL between 1960–1990 at 5 institutions were evaluated. Mean age at diagnosis was 13.6 years, median follow-up was 16.7 years (maximum 39), and male:female ratio was 1.3:1. Treatment included RT alone (43%), chemotherapy alone (9%), or both (48%). Standardized incidence ratio (SIR) for a SMN was calculated from age- and sex-matched SEER data. All 930 children (<18 years old) treated for HL between 1960–1990 at 5 institutions were evaluated. Mean age at diagnosis was 13.6 years, median follow-up was 16.7 years (maximum 39), and male:female ratio was 1.3:1. Treatment included RT alone (43%), chemotherapy alone (9%), or both (48%). Standardized incidence ratio (SIR) for a SMN was calculated from age- and sex-matched SEER data. ResultsSMNs occurred in 102 (11%) patients, with an actuarial rate of 19% at 25 years. With 15154 patient years (PY) of follow-up, only 7.18 cancers would be expected, resulting in a SIR of 14.2 and an absolute excess risk (AER) of 63 cases per 10,000 PY. Increasing RT dose was associated with an increasing SIR (p = .0085). Mean RT dose was marginally greater for patients who developed a SMN (32.5 Gy vs. 29.2 Gy, p = .0099). The SIR for patients treated with mantle RT <25 Gy, 25–34 Gy, and ≥35 Gy was 11.7, 12.1, and 16.5, respectively; the AER was 38.8, 50.8, and 77.8 respectively. 77% of SMNs occurred within, 9% outside, and 3% at a margin (within 2 cm) of a RT field, and 9% were indeterminant or non-applicable (i.e. ANLL). Nevertheless, calculated RT volume was not associated with risk. Alkylator or anthracycline dose was not significant. Of note, only 1 of 82 girls irradiated to the pelvis developed breast cancer (BC), vs. 28 of 288 girls not irradiated to the pelvis (p = 0.015). On univariate analysis, increased risk of SMN was associated with female gender and increasing RT dose. Splenectomy, RT volume, chemotherapy, time since treatment, and relapse did not have statistically significant associations with risk. On multivariate logistic analysis, only mantle RT dose and female gender were significantly associated with risk. Stratified analyses demonstrated no significant risk factors in males, whereas mantle RT >35 Gy increased risk by 2.5 fold in females, predominately relating to BC. Most solid SMNs are curable, and their impact on survival is shown in the figure. SMNs occurred in 102 (11%) patients, with an actuarial rate of 19% at 25 years. With 15154 patient years (PY) of follow-up, only 7.18 cancers would be expected, resulting in a SIR of 14.2 and an absolute excess risk (AER) of 63 cases per 10,000 PY. Increasing RT dose was associated with an increasing SIR (p = .0085). Mean RT dose was marginally greater for patients who developed a SMN (32.5 Gy vs. 29.2 Gy, p = .0099). The SIR for patients treated with mantle RT <25 Gy, 25–34 Gy, and ≥35 Gy was 11.7, 12.1, and 16.5, respectively; the AER was 38.8, 50.8, and 77.8 respectively. 77% of SMNs occurred within, 9% outside, and 3% at a margin (within 2 cm) of a RT field, and 9% were indeterminant or non-applicable (i.e. ANLL). Nevertheless, calculated RT volume was not associated with risk. Alkylator or anthracycline dose was not significant. Of note, only 1 of 82 girls irradiated to the pelvis developed breast cancer (BC), vs. 28 of 288 girls not irradiated to the pelvis (p = 0.015). On univariate analysis, increased risk of SMN was associated with female gender and increasing RT dose. Splenectomy, RT volume, chemotherapy, time since treatment, and relapse did not have statistically significant associations with risk. On multivariate logistic analysis, only mantle RT dose and female gender were significantly associated with risk. Stratified analyses demonstrated no significant risk factors in males, whereas mantle RT >35 Gy increased risk by 2.5 fold in females, predominately relating to BC. Most solid SMNs are curable, and their impact on survival is shown in the figure. Conclusions

BACKGROUND. Medullomyoblastoma (MMB) is a rare cerebellar embryonal neoplasm that occurs almost exclusively in children. It is biphasic by microscopy, containing myoblastic and primitive neuroectodermal components.METHODS. The authors conducted a retrospective review of the radiographic and pathologic characteristics, treatment, and clinical outcomes of six children with MMB who were treated at St. Jude Children's Research Hospital (Memphis, TN) between 1984 and 2003. Fluorescence in situ hybridization (FISH) data were available for four children. A literature review also was conducted and focused on imaging and pathologic findings.RESULTS. The median age at diagnosis was 4.5 years (range, 0.83-7.5 years). Radiographically, all tumors were cerebellar and exhibited variable enhancement, and 50% of tumors had necrotic foci. Three tumors contained discrete, magnetic resonance imaging (MRI) T2-weighted-hypointense/computed tomography (CT)-hyperdense enhancing regions and separate hyperintense/hypodense nonenhancing regions, which correlated microscopically with geographic islands of primitive neuroectodermal and rhabdomyoblastic cells. Large cell/anaplastic (five tumors), nodular/ desmoplastic (two tumors), and classic (two tumors) medulloblastoma histologies were encountered either alone (five tumors) or in combination with each other (two tumors). All 4 tumors that were tested exhibited alterations in chromosome 17 or c-myc amplification. All patients underwent macroscopic total resection and subsequently received chemotherapy and craniospinal (five patients) or local conformal (one patient) radiotherapy. At a median follow-up of 92 months (range, 23-187 months), 3 patients remain alive with no evidence of disease, 2 patients have died of disease, and 1 patient has died of secondary acute lymphocytic leukemia.CONCLUSIONS. The results of the current study demonstrated the frequent correlation of biphasic nodularity (as determined by MRI or CT) with discrete rhabdomyoblastic and primitive neuroectodermal islands (as revealed by microscopy) in MMB. These results also support the view that MMB and medulloblastoma may have common tumorigenic origins, given their similar histologic and molecular features. (C) 2004 American Cancer Society.

Children with intrinsic brain stem gliomas and incompletely resected supratentorial malignant gliomas have a dismal prognosis. Over-expression of EGFR has been reported in these tumors, and preclinical data suggests radiation sensitizing activity of EGFR inhibition. We investigated the safety of ZD1839, an EGFR tyrosine kinase inhibitor, administered in conjunction with irradiation (RT) in children with newly diagnosed brainstem gliomas and incompletely resected STMG. Children with newly diagnosed intrinsic brain stem gliomas (BSG) and incompletely resected supratentorial malignant gliomas (STMG) with residual tumor on imaging were eligible for this dose-finding study of ZD1839 given concomitantly with involved field irradiation. Two strata were identified: patients receiving and not receiving enzyme-inducing anticonvulsants. In the absence of disease progression or dose-limiting toxicity, treatment was to continue for one year. In each stratum, the beginning dose of ZD1839 was 100 mg/m2/day commencing with the start of RT. Daily doses of ZD1839 to be studied subsequently were 250 mg/m2, 375 mg/m2, 500 mg/m2, 650 mg/m2 and 850 mg/m2. The toxicity observation period for the purpose of establishing safety during RT concluded two weeks following completion of RT. Because of concern for potential increased toxicity in patients with BSG, formal dose finding was limited to this group. 33 patients were entered on study (20 BSG and 13 STMG), A maximum tolerated dose (MTD) of ZD1839 was not established according to the design of the dose-finding phase of this trial. Only one of five evaluable patients treated at 375 mg/m2 experienced a DLT during the observation period, none of the 6 patients at 250 mg/m2 experienced DLT during this period. However, there have been 5 instances of symptomatic intratumoral hemorrhage (ITH) noted (2BSG, 3 STMG). Three occurred among 12 patients 1 to 4 months after starting the 375 mg/m2/day dose, and 2 among 10 patients 4–8 months after starting the 250 mg/m2/day dose. Two cases occurred during the initial 2 months of therapy (during or immediately following radiation) and three occurred after course 3 (course 4, 5 and 6). No patient treated at 100 mg/m2 experienced ITH. No relationship to dexamethasone administration or thrombocytopenia or coagulation abnormality was noted. The incidence of ITH noted in this trial appears to exceed that reported for patients with CNS tumors receiving RT. There is little such data in children. There is a suggestion of increased frequency and earlier onset at the highest dose level. Based on these observations, the Phase 1 trial was concluded, and the dose of 250 mg/m2 was chosen for use in Phase 2 testing with RT in newly diagnosed patients with brain stem gliomas.