Joachim Kühl

Postoperative neoadjuvant chemotherapy before radiotherapy as compared to immediate radiotherapy followed by maintenance chemotherapy in the treatment of medulloblastoma in childhood: results of the german prospective randomized trial hit ’91

Purpose: The German Society of Pediatric Hematology and Oncology (GPOH) conducted a randomized, prospective, multicenter trial (HIT ’91) in order to improve the survival of children with medulloblastoma by using postoperative neoadjuvant chemotherapy before radiation therapy as opposed to maintenance chemotherapy after immediate postoperative radiotherapy. Methods and Materials: Between 1991 and 1997, 158 patients were enrolled and 137 patients randomized. Seventy-two patients were allocated to receive neoadjuvant chemotherapy before radiotherapy (arm I, investigational). Chemotherapy consisted of ifosfamide, etoposide, intravenous high-dose methotrexate, cisplatin, and cytarabine given in two cycles. In arm II (standard arm), 65 patients were assigned to receive immediate postoperative radiotherapy, with concomitant vincristine followed by 8 cycles of maintenance chemotherapy consisting of cisplatin, CCNU, and vincristine (“Philadelphia protocol”). All patients received radiotherapy to the craniospinal axis (35.2 Gy total dose, 1.6 Gy fractionated dose / 5 times per week followed by a boost to posterior fossa with 20 Gy, 2.0 Gy fractionated dose). Results: During chemotherapy Grade III/IV infections were predominant in arm I (40%). Peripheral neuropathy and ototoxicity were prevailing in arm II (37% and 34%, respectively). Dose modification was necessary in particular in arm II (63%). During radiotherapy acute toxicity was mild in the majority of patients and equally distributed in both arms. Myelosuppression led to a mean prolongation of treatment time of 11.5 days in arm I and 7.5 days in arm II, and interruptions in 35% of patients in arm I. Quality control of radiotherapy revealed correct treatment in more than 88% for dose prescription, more than 88% for coverage of target volume, and 98% for field matching. At a median follow-up of 30 months (range 1.4–62 months), the Kaplan-Meier estimates for relapse-free survival at 3 years for all randomized patients were 0.70 ± 0.08; for patients with residual disease: 0.72 ±0.06; without residual disease: 0.68 ± 0.09; M0: 0.72 ± 0.04; M1: 0.65 ± 0.12; and M2/3: 0.30 ± 0.15. For all randomized patients without M2/3 disease: 0.65± 0.05 (arm I) and 0.78 ± 0.06 (arm II) (p < 0.03); patients between 3 and 5.9 years: 0.60 ± 0.13 and 0.64 ± 0.14, respectively, but patients between 6 and 18 years: 0.62 ± 0.09 and 0.84 ± 0.08, respectively (p < 0.03). In a univariate analysis the only negative prognostic factors were M2/3 disease (p < 0.002) and an age of less than 8 years (p < 0.03). Conclusions: Maintenance chemotherapy would seem to be more effective in low-risk medulloblastoma, especially in patients older than 6 years of age. Neoadjuvant chemotherapy was accompanied by increased myelotoxicity of the subsequent radiotherapy, causing a higher rate of interruptions and an extended overall treatment time. Delayed and/or protracted radiotherapy may therefore have a negative impact on outcome. M2/3 disease was associated with a poor survival in both arms, suggesting the need for a more intensive treatment. Young age and M2/3 stage were negative prognostic factors in medulloblastoma, but residual or M1 disease was not, suggesting a new stratification system for risk subgroups. High quality of radiotherapy may be a major contributing factor for the overall outcome.

Diagnostic Cerebrospinal Fluid Examination in Children With Acute Lymphoblastic Leukemia: Significance of Low Leukocyte Counts With Blasts or Traumatic Lumbar Puncture

PURPOSE To determine the significance of leukemic blasts or traumatic lumbar puncture (TLP) in diagnostic CSF of children enrolled in the Berlin-Frankfurt-Münster (BFM) Acute Lymphoblastic Leukemia-BFM-95 trial. PATIENTS AND METHODS A total of 2,021 patients were retrospectively evaluated according to initial central nervous system (CNS) status. Patients were classified as follows: CNS1 (CNS negative, n = 1,605), CNS2 (< or = 5 WBC/ micro L CSF with blasts, n = 103), CNS3 (CNS positive, n = 58), TLP+ (TLP with blasts, n = 135), or TLP- (TLP without blasts, n = 111). Patients with CNS2 and TLP+ status were eligible for two additional doses of intrathecal (IT) methotrexate (MTX). CNS3 patients received additional IT MTX and cranial irradiation (18 Gy). RESULTS CNS2, CNS3, and TLP+ groups contained a higher percentage of patients with unfavorable characteristics. Cox regression analysis identified TLP+ and CNS3 status as prognostically significant (CNS3): risk ratio (RR) = 2.3; 95% confidence interval [CI], 1.4 to 3.6; P =.0005; TLP+: RR = 1.5; 95% CI, 1.02 to 2.2; P =.04. Overall 5-year event-free survival (EFS) is 79%, for CNS1 it is 80%, and for TLP- it is 83%. CNS2 patients have an EFS of 80%, but the cumulative incidence of relapses with CNS involvement is higher compared with CNS1 patients (0.10 v 0.04). TLP+ patients have a significantly reduced EFS (73%, P =.003) because of an increased incidence of CNS relapses. CNS3 patients suffer from more systemic and CNS relapses (EFS 50%). CONCLUSION CNS2 patients have the same prognosis as patients with CNS1 status, whereas the EFS of TLP+ patients is inferior to CNS1 but superior to CNS3 patients (P =.001). Both subgroups may have benefitted from additional IT MTX.

Combined postoperative irradiation and chemotherapy for anaplastic ependymomas in childhood: results of the german prospective trials hit 88/89 and hit 91

PURPOSE To evaluate the outcome in children with anaplastic ependymomas after surgery, irradiation, and chemotherapy; and to identify prognostic factors for survival. METHODS AND MATERIALS Fifty-five children (n = 27 girls, 28 boys; median age at diagnosis, 6.2 years) with newly diagnosed anaplastic ependymomas were treated in the multicenter, prospective trials HIT 88/89 and HIT 91. Macroscopic complete resection was achieved in 28 patients; 27 patients underwent incomplete resection. All patients received chemotherapy before (n = 40) or after irradiation (n = 15). The irradiation volume encompassed either the neuraxis followed by a boost to the primary tumor site (n = 40) or the tumor region only (n = 13). No radiotherapy was administered in two patients. RESULTS Median follow-up was 38 months. The overall survival rate at 3 years after surgery was 75.6%. Disease progression occurred in 25 children with local progression occurring in 20. The median time to disease progression was 45 months. The only significant prognostic factor was the extent of resection (estimated progression-free survival [EPFS] after 3 years was 83.3% after complete resection and 38.5% after incomplete resection) and the presence of metastases at the time of diagnosis (0% vs. 65.8% 3-year EPFS in localized tumors). Age, sex, tumor site, mode of chemotherapy, and irradiation volume did not influence survival. CONCLUSIONS Treatment centers should be meticulous about surgery and diagnostic workup. Because the primary tumor region is the predominant site of failure it is important to intensify local treatment. Dose escalation by hyperfractionation or stereotactic radiotherapy might be a promising approach in macroscopically residual disease. The role of adjuvant chemotherapy requires further study.

Surgery and adjuvant dendritic cell-based tumour vaccination for patients with relapsed malignant glioma, a feasibility study.

Patients with relapsed malignant glioma have a poor prognosis. We developed a strategy of vaccination using autologous mature dendritic cells loaded with autologous tumour homogenate. In total, 12 patients with a median age of 36 years (range: 11–78) were treated. All had relapsing malignant glioma. After surgery, vaccines were given at weeks 1 and 3, and later every 4 weeks. A median of 5 (range: 2–7) vaccines was given. There were no serious adverse events except in one patient with gross residual tumour prior to vaccination, who repetitively developed vaccine-related peritumoral oedema. Minor toxicities were recorded in four out of 12 patients. In six patients with postoperative residual tumour, vaccination induced one stable disease during 8 weeks, and one partial response. Two of six patients with complete resection are in CCR for 3 years. Tumour vaccination for patients with relapsed malignant glioma is feasible and likely beneficial for patients with minimal residual tumour burden.

Role of Radiotherapy in the Treatment of Supratentorial Primitive Neuroectodermal Tumors in Childhood: Results of the Prospective German Brain Tumor Trials HIT 88/89 and 91

PURPOSE To evaluate the outcome of children with supratentorial primitive neuroectodermal tumors after surgery, irradiation, and chemotherapy and to identify factors predictive for survival. PATIENTS AND METHODS Sixty-three children in the prospective trials HIT 88/89 and HIT 91 were eligible. Complete resection was performed in 21 patients. Patients were randomized for preirradiation chemotherapy, consisting of two cycles of ifosfamide, etoposide, methotrexate, cisplatin, and cytarabine (n = 40), or chemotherapy after irradiation, consisting of eight cycles with cisplatin, vincristine, and lomustine (n = 23). Irradiation volume was recommended to encompass the neuraxis with 35.2-Gy total dose followed by a boost (20.0 Gy) to the primary tumor site (n = 54). Seven patients were irradiated to the tumor region only with a total dose of 54.0 Gy. RESULTS Overall survival at 3 years was 48.4%. Progression occurred in 38 children, with local recurrences in 27 patients. The only significant prognostic factor was dose and volume of radiotherapy (progression-free survival after 3 years was 49.3% with correct treatment compared with 6.7% for 15 children with major violations of radiotherapy). Ten early progressions occurred during adjuvant therapy (eight before and two during radiotherapy), nine of them treated with preirradiation chemotherapy. There was a positive trend in outcome for nonmetastatic and pineal tumors. CONCLUSION Significant predictive factors were dose and volume of radiotherapy. Volume of irradiation should encompass the whole CNS with additional boost to the tumor region. Local doses of at least 54 Gy and a craniospinal dose of 35 Gy are necessary. Preirradiation chemotherapy seems to increase risk of early progression.

Preradiation chemotherapy for pediatric patients with high-grade glioma

To evaluate the feasibility and efficacy of intensive chemotherapy given prior to irradiation in pediatric patients with malignant glioma, the Society of Pediatric Oncology in Germany started a randomized trial in 1991. The high‐grade glioma strata had to be closed because of insufficient patient accrual. The follow‐up data from these patients are reported.

Role of Radiotherapy in Supratentorial Primitive Neuroectodermal Tumor in Young Children: Results of the German HIT-SKK87 and HIT-SKK92 Trials

PURPOSE To assess the outcome of young children with supratentorial primitive neuroectodermal tumor (stPNET) treated by intensive postoperative chemotherapy alone compared with treatment with chemotherapy and delayed radiotherapy (RT). PATIENTS AND METHODS From 1987 to 1992, children younger than 3 years of age with stPNET were enrolled in the HIT-SKK87 trial in Germany and Austria. After surgery, low-risk patients received maintenance chemotherapy before RT. In high-risk patients, intensive induction chemotherapy was followed by maintenance chemotherapy until delayed RT was initiated. In the following trial, HIT-SKK92 methotrexate-based chemotherapy was applied. In children with complete remission after three cycles, therapy was finished without irradiation. Otherwise, radiotherapy or salvage chemotherapy was administered. RESULTS Twenty-nine children were eligible (age, 3.0 to 37.0 months). All children received chemotherapy. In 15 children, no RT was administered. Four children had tumor progression during chemotherapy and underwent irradiation. In 10 patients, RT was given after chemotherapy. Overall survival (OS) and progression-free survival (PFS) rates after 3 years were 17.2% and 14.9%, respectively. Twenty-four children relapsed (13 at the tumor site only, three at distant site, and eight at both local and distant sites). Positive impact on survival was observed in children with complete resection but without statistical significance. Administration of RT was the only significant predictive factor for OS and PFS. Only one child not having RT survived. CONCLUSION Outcome of infants and babies with stPNET is unsatisfactory. Omission of RT jeopardizes survival, even if intensive chemotherapy is applied. We suggest to limit any delay of RT to a maximum of 6 months even in young children.

A possible role for somatostatin receptor scintigraphy in the diagnosis and follow-up of children with medulloblastoma

The surgical resection of medulloblastoma (MB), the most frequent malignant brain tumor in children, often remains subtotal. To estimate the response to further treatment the residual tumor is monitored by CT or MRI. The interpretation of both imaging techniques is complicated by disturbances resulting from surgery and radiation. Our study searched for alternative imaging techniques and asked the following questions. 1) Do MB express somatostatin receptors (SSTR), 2) is SSTR scintigraphy a sensitive imaging technique for the follow-up and the detection of vital tumor tissue in children with MB, and 3) do the results of SSTR scintigraphy correlate with the in vitro analysis of MB tissue by SSTR autoradiography. We analyzed the SSTR status in 20 children with MB, aged 1 to 15 years. Sixteen SSTR scintigraphies using Indium-111-DTPA-D-Phel-pentetreotide were performed in 14 children. MB tissue of 14 children was analyzed by SSTR autoradiography using Iodine-125-Tyr3-octreotide. In 8 cases SSTR were measured by both methods in vivo and in vitro. In comparison with conventional imaging, results of SSTR scintigraphy were true positive in 7 of 7 patients, true negative in 9 of 9 patients, including one patient with false positive findings in MRI, false negative in only one patient with small spinal metastases (diameter < 3 mm) and false positive in none of the analyzed patients. In all cases with residual tumor (n = 3) and suspected relapse (n = 4) the diagnosis could be confirmed (n = 4) or excluded (n = 3), consistent with the results of MRI and tumor histology. All MB tissues analyzed by SSTR autoradiography (n = 14) showed an extremely high density of SSTR ranging from 4047 to 15526 dpm/mg MB tissue. MB (n = 8) which were analyzed by SSTR scintigraphy and autoradiography demonstrated consistent results in evaluation by both methods. In cases where the integrity of the blood-brain barrier was tested by Tc-99m-DTPA scintigraphy (n = 10), the SSTR-to-brain scintigraphy index confirmed the tumor specificity of radionuclide uptake. We conclude that 1) MB tissue expresses a particularly high density of SSTR, 2) the high density of SSTR in autoradiography correlates with a sensitive imaging of these tumors by SSTR scintigraphy, 3) SSTR scintigraphy might be a valuable imaging method for detection of vital MB tissue in patients with residual tumor or relapse.

Aktuelle und zukünftige Strategien in der interdisziplinären Therapie von Medulloblastomen, supratentoriellen PNET und intrakraniellen Keimzelltumoren im Kindesalter

Hintergrund Die Chancen auf Heilung haben sich beim Medulloblastom und bei intrakraniellen Keimzelltumoren im Kindesalter in den letzten Jahrzehnten durchgreifend verbessert. So werden heute langfristige Überlebensraten von 60–80% bzw. mehr als 90% erreicht. Das seltene Vorkommen und die Notwendigkeit ärztlicher Erfahrung in der Steuerung der Therapie und ihrer Nebenwirkungen auf hohem Niveau haben dazu geführt, dass heute über 90% der Kinder innerhalb von nationalen und internationalen Studien behandelt werden, um eine ständige Verbesserung der Resultate zu erreichen. Die Weiterentwicklung operativer Verfahren ermöglicht eine zunehmend bessere und schonendere Resektion von Hirntumoren. Methode: Die systematische Strahlenbehandlung des gesamten Liquorraums ist unverändert wesentlicher Therapiebestandteil bei Medulloblastom, supratentoriellen primitiv neuroektodermalen Tumoren (stPNET) und intrakraniellen Keimzelltumoren. Die Einführung von Qualitätssicherungsprogrammen in der Radioonkologie gewährleistet eine präzise Bestrahlung der Zielvolumina und bildet die Grundvoraussetzung für eine Anhebung der Überlebenszeiten. Ergebnisse: Hyperfraktionierte Strahlenbehandlungen bieten beim Medulloblastom und bei stPNET die Möglichkeit, die wirksame Tumordosis anzuheben, ohne gleichzeitig das Nebenwirkungspotential zu erhöhen. Pilotstudien ergaben eine akzeptable Akuttoxizität und eine ausgezeichnete Tumorkontrolle mit Langzeitüberlebensraten von bis zu 96%. Stereotaktische Bestrahlungstechniken zeigen nach vorläufigen Ergebnissen beim Medulloblastom sowohl eine gute Verträglichkeit als auch vielversprechende Tumorkontrollraten bei Rückfall sowie im Rahmen der Primärtherapie und haben ihren Weg bei persistierendem Resttumor in zukünftige Studienprotokolle gefunden. Die alleinige Bestrahlung der reinen Germinome führt nach reduzierten Dosierungen unverändert zu hohen Heilungsraten (100% SIOP CNS GCT 96). Mit cisplatinhaltigen Chemotherapien lassen sich bei sezernierenden Keimzelltumoren zusammen mit Radiotherapie heute Überlebensraten von 80% erreichen. Chemotherapien sind vor allem beim Medulloblastom mit hohen Risikofaktoren und sezernierenden Keimzelltumoren zu einem festen Bestandteil der interdisziplinären Therapie geworden. Von der Weiterentwicklung chemotherapeutischer Protokolle und der Einführung neuer Substanzen kann eine weitere Verbesserung der bisherigen Behandlungsergebnisse erhofft werden. Schlussfolgerungen: Die Bestrebungen der beteiligten Fachgebiete gehen dahin, Modifikationen der einzelnen Therapiekomponenten innerhalb der interdisziplinären Behandlungskonzepte zu entwickeln, um die bisherigen Ergebnisse weiter zu verbessern. Zukünftig sollten die betroffenen Kinder und Jugendlichen möglichst in die bevorstehende prospektive multizentrische Studie HIT 2000 bzw. in die laufende Studie SIOP CNS GCT 96 aufgenomen werden, um die entsprechenden Ergebnisse zu verbessern und adäquate Entscheidungen für zukünftige optimierte Vorgehensweisen zu ermöglichen.Background The chances for cure in medulloblastoma, supratentorial primitive neuroetodermal tumors (stPNET) and intracranial germ cell tumors have decisively improved within the tast decades. Today long-term survival in the range between 60% and 80% and more than 90%, respectively, can be achieved. The low incidence of brain tumors in childhood and the necessity for optimal patient care has led to the fact that more than 90% of children are treated within national and international controlled studies today in order to assure a constant improvement of therapeutic outcome. Recent developments in neurosurgery achieved complete tumor resections in the majority of children at a low risk for morbidity and mortality. Methods: Systemic irradiation of neuroaxis is an essential part in the management of medulloblastoma, stPNET and intracranial germ cell tumors. The introduction of quality assurance programs in radiooncology assures a precise radiotherapy of target volumes and is a prerequisite to improve survival. Results: Hyperfractionated radiotherapy has the potential of increasing dose to tumor more safely without increasing the risk for late adverse effects. Pilot studies revealed excellent tumor control in medulloblastoma with acceptable acute toxicity and a long-term survival of up to 96%. In medulloblastoma stereotactic radiation techniques reveal an acceptable toxicity and promising results in tumor control in recurrent disease or as primary treatment. They are now part of future treatment protocols in case of persisting residual tumor. Radiotherapy alone in pure germinoma is continuously yielding high cure rates. In secreting germ cell tumors cisplatin containing chemotherapies in conjunction with radiotherapy achieve a long-term survival rate of 80% today. Especially in high risk medulloblastoma and secreting germ cell tumors chemotherapies are playing an increasingly important role in the interdisciplinary management. It can be expected that future developments of chemotherapeutic protocols and the introduction of new cytostatic substances will further improve the therapeutic outcome. Conclusions: The therapeutic endeavors of all those caring for children are aiming to study modifications of the therapeutic components in the interdisciplinary approach in order to optimize the therapeutic strategies. In future the affected children and young adolescents should be accrued for the forthcoming cooperative, prospective trial HIT 2000 and ongoing trial SIOP CNS GCT 96, respectively, in order to provide the body of data supporting the selection of novel and optimized approaches for future treatment strategies.

HIT '91 (prospective, co-operative study for the treatment of malignant brain tumors in childhood): accuracy and acute toxicity of the irradiation of the craniospinal axis. Results of the quality assurance program.

BackgroundIt was the aim of the quality control program of the randomized trial HIT ’91 (intensive chemotherapy before irradiation versus maintenance chemotherapy after irradiation) to assess prospectively the quality of neuroaxis irradiation with respect to the protocol guidelines and to evaluate acute toxicity with respect to treatment arm.Patients, Materials and MethodsData of 134 patients undergoing irradiation of the craniospinal axis were available. Positioning aids, shielding techniques, treatment machines, choice of energy, total dose and fractionation were evaluated. A total of 651 simulation and verification films were analyzed to assess the coverage of the clinical target volume (whole brain, posterior fossa, sacral nerve roots) and deviations of field alignment between simulation and verification of first treatment. Field matching between whole brain and adjacent cranial spinal fields was analyzed with respect to site and width of junction. Acute maximal side effects were evaluated according to a modified WHO score for neurotoxicity, infections, skin, mucosa and myelotoxicity.ResultsIn 91.3% of patients contemporary positioning aids and individualized shielding techniques were used to assure a reproducible treatment. In 98 patients (73.1%) linear accelerators and in 36 patients (26.8%) 60Cobalt machines were used. Single and total dose were administered according to the protocol guidelines in more than 90% of patients. In 20.2% of patients the cribriform plate, in 1.4% the middle cranial fossa and in 21.1% the posterior fossa and in 4.5% the 2nd sacral segment were incompletely encompassed by the treatment portals. Ninety-five percent of deviations of field alignment were less than 13.0 mm (whole brain) and 12 mm (cranial spinal field) with a random error between 4.9 and 7.6 mm (whole brain) and 6.9 mm and 9.9 mm (spinal canal), respectively. In 77.5% of patients the junctions between whole brain and cranial spinal fields were placed without a gap. A gap between 5 and 10 mm was left in 15 patients (18.7%), exceeding 10 mm in 3 patients. Acute neurotoxicity and skin reactions were mild, the rate of infections was low in both treatment arms. However, myelotoxicity resulted in interruptions of radiotherapy in 31.9% after intensive chemotherapy as compared to 20.0% without preceding chemotherapy.ConclusionsIn the HIT ’91 trial a precise radiotherapy of craniospinal axis has been performed in the majority of patients. Our findings indicate that the high quality is possibly an important contributing factor for the therapeutic outcome. However, preceding intensive chemotherapy caused marked toxicity of subsequent irradiation leading to a high rate of interruptions. Our database is subject to a future analysis of recurrences.ZusammenfassungHintergrundDas Ziel des Qualitätskontrollprogramms der randomisierten Studie HIT ’91 (intensive Chemotherapie vor Strahlenbehandlung vs. Erhaltungschemotherapie nach Strahlenbehandlung) bestand darin, prospektiv die Qualität der Neuroachsenbestrahlung unter Berücksichtigung der Protokollrichtlinien und die akute Toxizität in Abhängigkeit vom Behandlungsarm zu untersuchen.Patienten, Materialien und MethodenDaten von 134 Patienten, die eine Strahlenbehandlung der kraniospinalen Achse erhielten, wurden ausgewertet. Lagerungshilfen, Ausblockungstechniken, Bestrahlungsgeräte, Auswahl der Strahlungsenergie, der Gesamtdosis und Fraktionierung wurden beurteilt. 651 Simulations- und Verifikationsaufnahmen wurden analysiert, um die Erfassung des klinischen Zielvolumens (Ganzhirn unter Einschluβ der Meningen, hintere Schädelgrube, Duralsack) und Abweichungen der Feldanordnungen zwischen Simulation und Verifikation zum ersten Bestrahlungstermin zu ermitteln. Die Feldanschluβ zone zwischen Ganzhirn und kranialem spinalen Feld wurde unter Berücksichtigung der Lokalisation und der Breite des Feldanschlusses analysiert. Akute maximale Nebenwirkungen wurden entsprechend einem modifizierten WHO-Score für Neurotoxizität, Infektionen, Hautreaktionen, Schleimhautreaktionen und Knochenmarkfunktion ausgewertet.ErgebnisseBei 91,3% der Patienten wurden derzeit gebräuchliche Lagerungshilfen und individualisierte Abschirmtechniken eingesetzt, um eine reproduzierbare Behandlung zu gewährleisten. Bei 98 Patienten (73,1%) erfolgte die Behandlung mit Linearbeschleunigern, bei 36 Patienten (26,8%) mit 60Co-Geräten. Einzel- und Gesamtdosis wurden entsprechend den Protokollrichtlinien bei mehr als 90% der Patienten appliziert. Bei 20,2% der Patienten war die Lamina cribrosa, bei 1,4% die mittlere Schädelgrube, bei 21,1% die hintere Schädelgrube und bei 4,5% der Duralsack unvollständig durch die Bestrahlungsfelder erfaβ t. 95% der Feldabweichungen lagen unterhalb von 13,0 mm (Ganzhirn) und 12 mm (kraniales spinales Feld) mit einem mittleren zufälligen Fehler zwischen 4,9 und 7,6 mm (Ganzhirn) und 6,9 und 9,9 mm (spinales Feld). Bei 77,5% der Patienten erfolgte der Feldanschluβ zwischen Ganzhirn und kranialem spinalen Feld ohne Lücke. Ein Abstand zwischen 5 und 10 mm wurde bei 15 Patienten (18,7%) belassen und überschritt 10 mm bei drei Patienten. In beiden Behandlungsarmen waren die akute Neurotoxizität und Hautreaktionen diskret, die Häufigkeit von Infektionen niedrig. Die Myelotoxizität resultierte jedoch in Unterbrechungen der Strahlentherapie bei 31,9% der Patienten nach der intensiven Chemotherapie im Vergleich zu 20% ohne vorangehende Chemotherapie.Schluß folgerungenIn der Studie HIT ’91 wurde bei der Mehrheit der Patienten eine präzise Strahlenbehandlung der kraniospinalen Achse durchgeführt. Unsere Ergebnisse zeigen, daβ ein hoher Qualitätsstandard das therapeutische Ergebnis möglicherweise wesentlich beeinfluβ t. Eine vorangehende intensive Chemotherapie verursachte eine deutliche Akuttoxizität der Strahlenbehandlung, die zu einer hohen Rate von Unterbrechungen führte. Die erhobenen Daten bilden die Grundlage für eine zukünftige Rezidivanalyse.