Rolf-Dieter Kortmann

German Cancer Society Neuro‐Oncology Working Group NOA‐03 multicenter trial of single‐agent high‐dose methotrexate for primary central nervous system lymphoma

The prospective multicenter NOA‐03 trial, conducted by the Neuro‐Oncology Working Group (NOA) of the German Cancer Society, was initiated to define the feasibility and efficacy of single‐agent high‐dose methotrexate therapy without concomitant radiotherapy in immunocompetent patients with primary central nervous system lymphoma. Thirty‐seven patients (median age, 60 years) received 179 biweekly courses of 8g/m2 methotrexate. Response was assessed after 3 and 6 courses. We had planned to enter 105 patients into the trial. Since fewer than the projected 18 of 37 patients achieved a complete response after an intermediate analysis, the trial was closed. In intention‐to‐treat analysis, 11 of 37 patients (29.7%) achieved complete response, whereas 14 of 37 patients (37.8%) were found to have progressive disease. The median relapse‐free survival among complete response patients was 13.7 months. Multivariate logistic regression analysis revealed that corticosteroid application during the first methotrexate course was associated with complete response. The regimen was well tolerated, but, unlike previously reported results, the activity of high‐dose methotrexate was only moderate.

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

PURPOSEnTo evaluate the outcome in children with anaplastic ependymomas after surgery, irradiation, and chemotherapy; and to identify prognostic factors for survival.nnnMETHODS AND MATERIALSnFifty-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.nnnRESULTSnMedian 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.nnnCONCLUSIONSnTreatment 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.

Malignant glioma: patterns of failure following individually tailored limited volume irradiation

Treatment outcome was analyzed for 66 patients with malignant glioma treated with individually CT-planned multifield irradiation techniques. Total doses of 60 Gy were given, with the planning target volume (PTV) including 2 cm beyond the tumour indicated by preoperative CT examination. Median survival was 14 months, and 86% of recurrences occurred in the treated volume. Our results suggest that the used PTV and radiation technique should be appropriate in radiotherapy of malignant glioma.

Radiochemotherapy of Malignant Glioma in Adults

Background: Standard treatment in patients with malignant glioma consists of surgery and postoperative radiotherapy. A high early recurrence rate, particularly in glioblastoma, has led to the investigation of additional chemotherapy.nMaterial and Methods: Recent results of radiochemotherapy published in the literature were reviewed with respect to outcome in phase II and III trials. Based on these experiences, aspects of future strategies were discussed.nResults: 3 decades of intensive research had, unfortunately, little impact on the overall results. While early prospective studies established adjuvant nitrosoureas, particularly BCNU, as suitable adjuvant to surgery and postoperative radiotherapy, further studies largely concentrated on combined chemotherapeutic protocols, mostly procarbazine, CCNU and vincristine (PCV), which was shown to prolong survival in anaplastic astrocytoma. The recent MRC study, however, showed no effect for adjuvant PCV in grade III and IV malignant glioma. Only in high-grade glioma with an oligodendroglial component, additional chemotherapy may be of a decisive benefit. The introduction of newer drugs such as paclitaxel, temozolomide, or gemcitabine demonstrated no decisive advantage. Different modes of application and sequencing of radiotherapy and chemotherapy are presently actively investigated, but failed to substantially improve outcome.nConclusions: Therefore, search for newer and more effective drugs continues, as well as for “optimal” administration and sequencing, especially from the standpoint of accompanying acute and late toxicity. Finally, recent endeavors focused on basic research such as angiogenesis, migration and invasion, or induction of cell differentiation, but these strategies are still away from broader clinical investigation.Hintergrund: Die Standardtherapie bei Patienten mit malignen Gliomen besteht aus Operation und postoperativer Bestrahlung. Hohe frühe Rückfallraten, insbesondere beim Glioblastom, führten zur Untersuchung zusätzlicher Chemotherapien.nMaterial und Methodik: In der Literatur veröffentlichte Ergebnisse der Radiochemotherapie wurden unter Berücksichtigung des therapeutischen Ergebnisses von Phase-II- und -III-Studien analysiert. Basierend auf diesen Erfahrungen wurden zukünftige Strategien diskutiert.nErgebnisse: 3 Jahrzehnte intensiver Forschung hatten nur einen geringen Einfluss auf das therapeutische Gesamtergebnis. Während frühere prospektive Studien die adjuvante Gabe von Nitrosoharnstoffen, insbesondere BCNU, als geeignete adjuvante Therapie zu Operation und Strahlentherapie etablierten, konzentrierten sich folgende Studienprotokolle auf kombinierte Behandlungen, insbesondere Procarbazin, CCNU und Vincristin (PCV), die ein verlängertes Überleben bei anaplastischen Astrozytomen zeigten. Die neuere Studie des MRC erbrachte jedoch keinen Effekt einer adjuvanten Behandlung mit PCV, weder bei Grad-III- noch Grad-IV-Gliomen. Lediglich bei hochmalignen Gliomen mit oligodendroglialer Komponente besitzen zusätzliche Chemotherapien möglicherweise einen entscheidenden therapeutischen Vorteil. Die Einführung neuerer viel versprechender Agenzien wie Paclitaxel, Temozolomid oder Gemcitabin zeigte keinen durchgreifenden Vorteil. Alternative Applikationsweisen und die Reihenfolge von Bestrahlung und Chemotherapie werden derzeit untersucht, konnten jedoch keine substantielle Verbesserung des therapeutischen Ergebnisses erreichen.nSchlussfolgerungen: Die Suche nach neueren und effektiveren Substanzen wird fortgesetzt, ebenso wie nach der optimalen Applikationsweise und Reihenfolge, vor allem vor dem Hintergrund der begleitenden akuten maximalen Nebenwirkungen und Therapiefolgen. Aktuelle Bestrebungen konzentrieren sich auf Grundlagenforschung in den Bereichen Angiogenese, Migration und Invasion oder die Induzierung von Differenzierungsprozessen. Diese Strategien sind jedoch von einer breiten klinischen Anwendung noch weit entfernt.

Chemotherapy in the treatment of recurrent glioblastoma multiforme: ifosfamide versus temozolomide

Purpose: Despite the progress made in neurosurgery and radiotherapy, the prognosis of glioblastoma multiforme (GB) is poor, due to the lack of an effective salvage therapy. In vitro analysis revealed activity for ifosfamide and temozolomide. The usefulness of these agents in recurrent disease was investigated. Methods: Six adult patients with recurrent GB received one to four courses of 1,500u2009mg/m2 ifosfamide given over 5 days intravenously. Furthermore, temozolomide (100–200u2009mg/m2) was given orally over 5 days to 14 patients. Results: After ifosfamide treatment, one partial response and two cases of stable disease were observed. The median survival time was 24 weeks (range of 9–52 weeks). Toxicity analysis revealed one paranoid reaction, three grade III leukocytopenia, and one grade I–II nausea, anemia, and hematuria. Temozolomide therapy resulted in three partial responses and four cases of stable disease. The median survival time (Kaplan-Meier) was 21 weeks (range 4–64 weeks). The major toxicities were grade I–II nausea and hematological side effects (one case of grade IV leuko- and thrombocytopenia). Conclusions: Ifosfamide treatment might be a feasible approach, but it necessitates hospitalization. Temozolomide showed promising results. Due to its oral application, the patients quality of life (time out of hospital) is favorable. Subgroups with improved survival were observed.

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.

Atypical and anaplastic meningiomas — does the new WHO-classification of brain tumours affect the indication for postoperative irradiation?

SummaryWe retrospectively analysed 13 patients (pts.) treated at the University of Tübingen from 1985 to 1993 to evaluate the results of radiation therapy (XRT) given as an adjuvant to totally or subtotally resected meningiomas. The overall survival was 38% at five years with a probability of relapse of 50% at this time. Reclassification of the tumours according to the new WHO-classification of brain tumours [14] revealed 10 grade-II-tumours (atypical meningioma) and 3 grade-III-tumours (anaplastic meningioma). Radiotherapy failed in all 3 pts. with macroscopically incomplete resection (Simpsons grade IV), who died with relapse between 4 and 51 months after radiotherapy. 5 out of 10 pts. with grade-II-tumours relapsed. All 3 pts. with grade-III-tumours died with relapse between 6 and 21 months after XRT. Morbidity was seen in 2 pts. after irradiation with 60 GY (ICRU dose specification).Complete surgical exstirpation offers the best possibility of tumour control. Grade-III-tumours should be irradiated whatever the extent of the primary surgery was. Our results might indicate a possible indication for XRT in pts. with atypical grade-II-tumours especially when radical surgery must be in doubt. Prospective multicentre trials are warranted to prove the prognostic value of the new WHO-classification for atypical and anaplastic meningiomas and to define the ultimate role of radiotherapy in this setting.

Is the standardized helmet technique adequate for irradiation of the brain and the cranial meninges

PURPOSEnTo evaluate whether the standardized helmet technique is adequate to reliably cover the clinical target volume (whole brain including cranial meninges) during treatment planning and treatment delivery.nnnMETHODS AND MATERIALSnIn 21 patients undergoing irradiation of the brain in acute lymphoblastic leukemia or primary cerebral lymphoma, the coverage of the clinical target volume was checked with a repeat computed tomography (CT) in the treatment position (head fixation with face mask). The accuracy of field alignment was quantitatively assessed with sequential verification films. For each patient, linear and rotational discrepancies were measured between the simulation and first check film, and between five consecutive verification films.nnnRESULTSnCoverage of clinical target volume. In 11 cases (52%), the CT examinations showed that parts of the subfrontal region and midcranial fossa were not included by the field assigned under simulation. Accuracy of field alignment. For the total group of patients, all deviations were normally distributed with mean values between -1.2 mm and 1.5 mm and standard deviations of 2.9 mm to 3.7 mm for linear discrepancies, and 0.3 degrees +/- 3.2 degrees for rotational discrepancies. For all patients, deviations were similar for the transition from simulation to the treatment machine and for subsequent treatment delivery, with 50% and 95% of absolute differences being less than 2.0 mm and 6.5 mm, respectively. Maximum linear deviations were less than 9.5 mm.nnnCONCLUSIONSnThe currently used helmet technique is inadequate to cover the clinical target volume. Repeat CT examinations are a useful method to delineate the clinical target volume on an individual patient basis. In addition, statistical fluctuations of field displacements up to 1.0 cm have to be considered when prescribing safety margins for reliable coverage of the clinical target volume during treatment planning and delivery.

Reproducibility of field alignment in difficult patient positioning.

PURPOSEnQuantitative assessment of the accuracy of field alignment in a homogeneous group of patients with difficult positioning (postoperative irradiation after total hip replacement).nnnMETHODS AND MATERIALSnIn 95 patients linear and rotational discrepancies were measured between the simulation and first check film and between five consecutive verification films.nnnRESULTSnFor the total group of patients, all deviations were normally distributed with mean values of approximately zero and standard deviations of 4.0-8.0 mm (linear discrepancies) and 3.5-5 degrees (rotational discrepancies). Deviations were similar for the transition from simulator to the treatment machine and for subsequent treatment delivery, with 50% and 95% of absolute differences being less than 5 mm and 15 mm, respectively.nnnCONCLUSIONSnOur analysis indicates that statistical fluctuations are considerably more important than errors introduced at start of treatment. Therefore, a first check film seems to be inadequate to predict the expected inaccuracies for the whole course of treatment. In addition, our results should help to prescribe appropriate safety margins for patients with difficult positioning.

Immediate postoperative radiotherapy or "watch and wait" in the management of adult low-grade glioma?

Background:The EORTC Trial 22845 on the role of immediate postoperative radiotherapy in patients with supratentorial lowgrade glioma revealed an advantage of immediate postoperative radiotherapy for progression-free survival, but not for overall survival. It is still an open question in which clinical setting immediate radiotherapy should be considered and whether chemotherapy may become a useful alternative.Material and Methods:Reports in the literature spanning 60 years of radiation therapy were reviewed with respect to timing of radiotherapy, prognostic factors, dose prescriptions, modern treatment techniques, and late effects. Data on chemotherapy were also reviewed. Based on these data, the role of immediate postoperative radiotherapy or chemotherapy in adult low-grade glioma is presented.Results:Radiotherapy is able to control symptoms in up to 80% of cases. Malignant transformation occurs in 36–86% of cases upon progressive disease. Long-term median survival crucially depends on prognostic factors and ranges between 12 months and 10 years. Radiotherapy does not cause neurocognitive deficits, provided that modern treatment techniques and moderate dose prescriptions are used. Recent series with small patient numbers indicate that chemotherapy using PCV or temozolomide may prolong median survival and induces response rates of 50% in oligodendroglial tumors.Conclusion:The arguments for immediate postoperative irradiation include: low-grade gliomas respond to radiotherapy; the tumors often display an aggressive pathobiological behavior; patients with high risk profile may benefit from immediate radiotherapy in terms of progression-free and overall survival; modern focal radiotherapy is far less toxic than feared; radiotherapy might be more effective at diagnosis than at progression. Chemotherapy might be an alternative in immediate postoperative treatment. Its role, however, is unclear. The forthcoming prospective trial of the EORTC will address this issue in a randomized setting.Hintergrund:Die kürzlich publizierte EORTC-Studie 22845, die den Stellenwert der sofortigen Strahlentherapie bei Patienten mit supratentoriellen niedrigmalignen Gliomen randomisiert untersuchte, zeigte, dass die sofortige postoperative Strahlenbehandlung einen Vorteil für das progressionsfreie Überleben zeigt, dass sich dieser Zugewinn jedoch nicht in einem Vorteil bezüglich des Gesamtüberlebens widerspiegelt. Unverändert offen ist die Frage, in welcher klinischen Konstellation dennoch die sofortige Strahlentherapie indiziert ist. Ist die Chemotherapie eine nützliche Alternative?Material und Methodik:Literaturberichte, die 60 Jahre Strahlentherapie umfassen, wurden unter den Aspekten Zeitpunkt der Radiotherapie, prognostische Faktoren, Dosisverschreibungen, moderne Bestrahlungstechniken und Spätfolgen analysiert. Erfahrungen zur Chemotherapie wurden ebenfalls gesichtet. Auf der Basis dieser Daten wird die Rolle der sofortigen postoperativen Bestrahlung oder Chemotherapie bei niedrigmalignen Gliomen im Erwachsenenalter vorgestellt.Ergebnisse:Die Radiotherapie ist in der Lage, Symptome in bis zu 80% der Fälle zu kontrollieren. Eine maligne Transformation tritt in 36–68% der Fälle bei progredienter Erkrankung auf. Das mediane Langzeitüberleben hängt eng von prognostischen Faktoren ab und bewegt sich zwischen 12 Monaten und 10 Jahren. Die Strahlentherapie verursacht keine wesentlichen neurokognitiven Störungen, vorausgesetzt, dass moderne Bestrahlungstechniken und moderate Dosisverschreibungen angewandt werden. Neuere Serien mit geringen Patientenzahlen lassen vermuten, dass die Chemotherapie nach dem PCV-Schema oder mit Temozolomid das mediane Überleben verlängert und zumindest bei oligodendroglialen Tumoren Ansprechraten von 50% erreicht.Schlussfolgerung:Die Argumente für eine sofortige postoperative Strahlenbehandlung lauten: Niedrigmaligne Gliome sprechen auf Bestrahlung an; die Tumoren zeigen häufig ein aggressives pathobiologisches Verhalten; Patienten mit Hochrisikoprofil werden von einer sofortigen Strahlentherapie profitieren; moderne lokale Strahlentherapien sind deutlich weniger toxisch als von vielen Autoren befürchtet; die Strahlenbehandlung könnte zum Zeitpunkt der Diagnose effektiver sein. Die Chemotherapie ist möglicherweise eine Alternative zur sofortigen postoperativen Behandlungssituation. Ihr Stellenwert ist jedoch unklar. Die bevorstehende prospektive Studie der EORTC wird diese Fragestellung randomisiert untersuchen.