Joachim Kuehl

Treatment of young children with localized medulloblastoma by chemotherapy alone: results of the prospective, multicenter trial HIT 2000 confirming the prognostic impact of histology.

This study was designed to confirm the previously observed favorable survival rates and prognostic factors in young children with nonmetastatic medulloblastoma (MB) treated with postoperative chemotherapy alone. Patients who received a diagnosis during the period January 2001 through December 2005 and who were aged <4 years received 3 cycles of postoperative systemic multiagent chemotherapy and intraventricular methotrexate. In cases of complete remission, treatment was terminated after 2 additional cycles of chemotherapy. Otherwise, secondary surgery, radiotherapy, and consolidation chemotherapy were recommended. At a median follow-up of 4.5 years, the 5-year event-free survival (EFS) and overall survival (OS) rates (± standard error) for 45 patients (median age, 2.5 years) were 57% ± 8% and 80% ± 6%, respectively. Nineteen patients with desmoplastic/nodular MB variants had better 5-year EFS and OS rates (90% ± 7% and 100% ± 0%, respectively) than did 23 patients with classic MB (30% ± 11% and 68% ± 10%, respectively; P < .001 for EFS; P = .008 for OS). Five-year EFS and OS rates for 3 children with anaplastic MB were 33% ± 27%. Desmoplastic/nodular histology was an independent prognostic factor for EFS. Twenty-nine of 30 patients without postoperative residual tumor remained in continuous complete remission. Our results confirm that histology of MB variants is a strong prognostic factor in this age group. Sustained tumor control can be achieved by this chemotherapy regimen in young children with desmoplastic/nodular MB variants. For children with non-desmoplastic/nonnodular MB variants, for which predominantly local relapses lead to less favorable survival rates, local radiotherapy has been introduced after chemotherapy since 2006.

Frequency, risk-factors and survival of children with atypical teratoid rhabdoid tumors (AT/RT) of the CNS diagnosed between 1988 and 2004, and registered to the German HIT database.

To analyze the frequency, prognostic factors, and outcome of children with atypical teratoid/rhabdoid tumors (AT/RT), a rare and highly malignant embryonal brain tumor.

Treatment of young children with CNS-primitive neuroectodermal tumors/ pineoblastomas in the prospective multicenter trial HIT 2000 using different chemotherapy regimens and radiotherapy

BACKGROUND Especially in young children, primitive neuroectodermal tumors of the central nervous system (CNS-PNET) and pineoblastomas are associated with an unfavorable outcome, and only a few prospective trials have been conducted thus far. METHODS From January 2001 through January 2005, 17 eligible children aged <4 years with CNS-PNET not otherwise specified (n = 8), ependymoblastoma (n = 1), or pineoblastoma (n = 8) confirmed by central review were prospectively treated in the trial HIT 2000. In nonmetastatic disease (n = 11), up to 5 postoperative cycles of HIT-SKK systemic multiagent chemotherapy (8 months duration), followed by craniospinal radiotherapy (CSI), were given. In metastatic disease (M1-M3, n = 6), treatment consisted of a shorter induction chemotherapy (2-3 months) with carboplatin and etoposide, followed by tandem high-dose chemotherapy (HDCT) in case of good response to induction. During induction and HDCT, patients received intraventricular methotrexate. CSI was applied to all patients with poor response to induction or residual disease after HDCT and was optional for patients with residual disease before HDCT. RESULTS Five-year event-free survival and overall survival rates ± standard error for all eligible patients were 24% ± 10% and 40% ± 12%, respectively (median follow-up of survivors: 8.3 years). Only one patient with nonmetastatic disease remained free of relapse/progressive disease during induction. Three of 6 patients with metastatic disease responded to induction and received tandem-HDCT, followed by preventive CSI, and remain in continuous complete remission. CONCLUSIONS Short intensive induction chemotherapy followed by tandem-HDCT in young children with CNS-PNET/pineoblastomas seems to be superior to the prolonged and less intensive induction regimen.

Treatment of adult nonmetastatic medulloblastoma patients according to the paediatric HIT 2000 protocol: A prospective observational multicentre study

BACKGROUND Medulloblastoma in adulthood is rare. Knowledge is limited, and the efficacy and toxicity of chemotherapy--especially in nonmetastatic disease--is still elusive. METHODS Seventy adults aged ≥21 years (median age: 28.5 years) with nonmetastatic medulloblastoma were followed as observational patients within the prospective paediatric multicentre trial HIT 2000. Treatment consisted of radiotherapy (35.2 Gy to the craniospinal axis and a boost to 55.2 Gy to the posterior fossa) followed in most patients by maintenance chemotherapy (lomustine (CCNU), vincristine and cisplatin, n=49). RESULTS The implementation of maintenance chemotherapy was feasible. Peripheral neuropathy (74%) and haematotoxicity (55%) during maintenance chemotherapy appear to be more common in adults than in children. At a median follow-up of 3.7 years, the 4-year event-free survival (EFS) and overall survival (OS) rates±standard error (SE) were 68%±7% and 89%±5%. Patients with desmoplastic medulloblastoma and lateral tumour location (n=19) had a lower EFS compared to patients with centrally located desmoplastic tumours (n=10) (p=0.011). Absence of residual postoperative tumour (n=40) was associated to a lower rate of progression/relapse compared to present (n=11) or unknown (n=12) residual tumour status (p=0.006). Lateral tumour location and unknown residual tumour status were independent negative prognostic factors. CONCLUSIONS Maintenance chemotherapy is applicable in adults with nonmetastatic medulloblastoma. Histological subtype and tumour location were newly identified risk factors in this age-group, and should be further analysed in prospective trials.

Intraventricular methotrexate as part of primary therapy for children with infant and/or metastatic medulloblastoma: Feasibility, acute toxicity and evidence for efficacy

BACKGROUND To assess feasibility, acute toxicity, and efficacy of intraventricular methotrexate administered as part of the primary therapy in medulloblastoma. METHODS From 2001 to 2007, 240 patients < 22 years from 61 treatment centres were registered. Patients received 2-3 cycles of intraventricular methotrexate with systemic chemotherapy in three different treatment arms of the prospective multicentre trial HIT2000 (150 children > 4 years with metastatic, 59 < 4 years with non-metastatic, 31 < 4 years with metastatic medulloblastoma). RESULTS 211 patients received an intraventricular access device with a subcutaneous reservoir for the application of chemotherapy. Reservoir-associated complications were documented in 57 (27%) patients, mostly due to infection (n = 32) and reservoir malfunction (n = 19), requiring removal in 39 (18%) patients. Acute neurotoxicity likely associated with intraventricular MTX was observed in 9/202 documented patients. Toxicity was usually mild, apart from one therapy-associated death due to toxic oedema followed by seizures. Of 519 treatment cycles including intraventricular methotrexate, 226 (43%) were reduced or omitted, most frequently due to the absence of an intraventricular device. Survival rates were higher in patients receiving ⩾ 75% of the scheduled intraventricular methotrexate dose compared to those receiving < 75% in both univariate and multivariate models (event-free survival (EFS), 61.5 versus 46.2%, p = 0.004; OS, 75.5% versus 60.4%, p = 0.015; hazard ratio: EFS 1.723, p = 0.016; OS 1.648, p = 0.051). CONCLUSION Intraventricular methotrexate therapy was feasible and mostly well tolerated. Infections were the most frequent complication. A higher cumulative dose of intraventricular methotrexate was associated with better survival. Further evaluation of efficacy and late effects is warranted.

Treatment of children with central nervous system primitive neuroectodermal tumors/pinealoblastomas in the prospective multicentric trial HIT 2000 using hyperfractionated radiation therapy followed by maintenance chemotherapy.

PURPOSE The prognosis for children with central nervous system primitive neuroectodermal tumor (CNS-PNET) or pinealoblastoma is still unsatisfactory. Here we report the results of patients between 4 and 21 years of age with nonmetastatic CNS-PNET or pinealoblastoma diagnosed from January 2001 to December 2005 and treated in the prospective GPOH-trial P-HIT 2000-AB4. METHODS AND MATERIALS After surgery, children received hyperfractionated radiation therapy (36 Gy to the craniospinal axis, 68 Gy to the tumor region, and 72 Gy to any residual tumor, fractionated at 2 × 1 Gy per day 5 days per week) accompanied by weekly intravenous administration of vincristine and followed by 8 cycles of maintenance chemotherapy (lomustine, cisplatin, and vincristine). RESULTS Twenty-six patients (15 with CNS-PNET; 11 with pinealoblastoma) were included. Median age at diagnosis was 11.5 years old (range, 4.0-20.7 years). Gross total tumor resection was achieved in 6 and partial resection in 16 patients (indistinct, 4 patients). Median follow-up of the 15 surviving patients was 7.0 years (range, 5.2-10.0 years). The combined response rate to postoperative therapy was 17 of 20 (85%). Eleven of 26 patients (42%; 7 of 15 with CNS-PNET; 4 of 11 with pinealoblastoma) showed tumor progression or relapse at a median time of 1.3 years (range, 0.5-1.9 years). Five-year progression-free and overall survival rates (± standard error [SE]) were each 58% (± 10%) for the entire cohort: CNS-PNET was 53% (± 13); pinealoblastoma was 64% (± 15%; P=.524 and P=.627, respectively). CONCLUSIONS Postoperative hyperfractionated radiation therapy with local dose escalation followed by maintenance chemotherapy was feasible without major acute toxicity. Survival rates are comparable to those of a few other recent studies but superior to those of most other series, including the previous trial, HIT 1991.

Late complete remission of supratentorial primitive neuroectodermal tumor (CNS-PNET) after multiple relapses.

To the Editor: Central primitive neuroectodermal tumors (CNSPNET) are highly malignant WHO grade IV brain tumors accounting for 3% of childhood CNS tumors. Besides surgery, a variety of therapeutic strategies including craniospinal radiotherapy, chemotherapy and high-dose chemotherapy with autologous stem cell transplantation are currently followed by different protocols [1]. A localized brain tumor (Fig. 1A,B) was diagnosed in a 7-yearold female with a 2-month history of headache and right hemiparesis (Table I). The tumor was completely removed, and the hemiparesis was partially reversible. Histology from this and all following neurosurgical interventions were compatible with a CNS-PNET WHO grade IV and were confirmed by central review. The patient was recommended to be treated by a combination of craniospinal radiotherapy and chemotherapy according to the HIT 91 protocol [2], but the parents refused chemotherapy and irradiation of the craniospinal axis. Therefore, the patient received local radiotherapy only (Table I). The patient experienced nine local relapses/progressive diseases (PD), had seven re-surgeries, was locally re-irradiated twice, received standard chemotherapy according to HIT 91 sandwichchemotherapy, and other systemic chemotherapy, and more experimental treatment (gene therapy, carmustine wafers, and tumor vaccination) (Table I). After the sixth relapse (Fig. 1C,D) local hypofractionated radiotherapy was used (9 4 Gy), and temozolomide was given for

Abstract 3463: Treatment of young children with localized medulloblastoma by chemotherapy alone: Final results of the prospective multicenter trial HIT 2000 confirming the prognostic impact of histology

Background: This study was designed to confirm the previously observed favorable survival rates and prognostic factors in young children with non-metastatic medulloblastoma (MB) treated by postoperative chemotherapy alone. Methods: Patients diagnosed between January 2001 and December 2005 and younger than 4 years received three cycles of postoperative systemic multiagent chemotherapy and intraventricular methotrexate. In case of complete remission, treatment was terminated after two additional cycles of chemotherapy. Otherwise secondary surgery, radiotherapy and consolidation chemotherapy were recommended. Results: The 5-year event-free survival (EFS) and overall survival (OS) (±SE) rates of 45 patients were 57 ± 8% and 80 ± 6% (median follow-up: 4.5 years, median age: 2.5 years). Nineteen patients with desmoplastic / nodular MB variants had better EFS and OS (5-year rates: 90 ± 7% and 100 ± 0%) compared to 23 patients with classic MB (30 ± 11% and 68 ± 10%; p Conclusions: Our results confirm histology of MB variants as a strong prognostic factor in this age-group. Sustained tumor control and favorable survival rates can be achieved by this chemotherapy regimen in young children with desmoplastic / nodular MB variants. For children with non-desmoplastic / non-nodular MB variants, where predominantly local relapses lead to less favorable survival rates, local radiotherapy has been introduced after chemotherapy since 2006. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 3463. doi:10.1158/1538-7445.AM2011-3463