Beate Timmermann

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.

Treatment planning and verification of proton therapy using spot scanning: Initial experiences

Since the end of 1996, we have treated more than 160 patients at PSI using spot-scanned protons. The range of indications treated has been quite wide and includes, in the head region, base-of-skull sarcomas, low-grade gliomas, meningiomas, and para-nasal sinus tumors. In addition, we have treated bone sarcomas in the neck and trunk--mainly in the sacral area--as well as prostate cases and some soft tissue sarcomas. PTV volumes for our treated cases are in the range 20-4500 ml, indicating the flexibility of the spot scanning system for treating lesions of all types and sizes. The number of fields per applied plan ranges from between 1 and 4, with a mean of just under 3 beams per plan, and the number of fluence modulated Bragg peaks delivered per field has ranged from 200 to 45 000. With the current delivery rate of roughly 3000 Bragg peaks per minute, this translates into delivery times per field of between a few seconds to 20-25 min. Bragg peak weight analysis of these spots has shown that over all fields, only about 10% of delivered spots have a weight of more than 10% of the maximum in any given field, indicating that there is some scope for optimizing the number of spots delivered per field. Field specific dosimetry shows that these treatments can be delivered accurately and precisely to within +/-1 mm (1 SD) orthogonal to the field direction and to within 1.5 mm in range. With our current delivery system the mean widths of delivered pencil beams at the Bragg peak is about 8 mm (sigma) for all energies, indicating that this is an area where some improvements can be made. In addition, an analysis of the spot weights and energies of individual Bragg peaks shows a relatively broad spread of low and high weighted Bragg peaks over all energy steps, indicating that there is at best only a limited relationship between pencil beam weighting and depth of penetration. This latter observation may have some consequences when considering strategies for fast re-scanning on second generation scanning gantries.

Effectiveness and Safety of Spot Scanning Proton Radiation Therapy for Chordomas and Chondrosarcomas of the Skull Base: First Long-Term Report

PURPOSE To evaluate effectiveness and safety of spot-scanning-based proton radiotherapy (PT) in skull-base chordomas and chondrosarcomas. METHODS AND MATERIALS Between October 1998 and November 2005, 64 patients with skull-base chordomas (n = 42) and chondrosarcomas (n = 22) were treated at Paul Scherrer Institute with PT using spot-scanning technique. Median total dose for chordomas was 73.5 Gy(RBE) and 68.4 Gy(RBE) for chondrosarcomas at 1.8-2.0 Gy(RBE) dose per fraction. Local control (LC), disease specific survival (DSS), and overall survival (OS) rates were calculated. Toxicity was assessed according to CTCAE, v. 3.0. RESULTS Mean follow-up period was 38 months (range, 14-92 months). Five patients with chordoma and one patient with chondrosarcoma experienced local recurrence. Actuarial 5-year LC rates were 81% for chordomas and 94% for chondrosarcomas. Brainstem compression at the time of PT (p = 0.007) and gross tumor volume >25 mL (p = 0.03) were associated with lower LC rates. Five years rates of DSS and OS were 81% and 62% for chordomas and 100% and 91% for chondrosarcomas, respectively. High-grade late toxicity consisted of one patient with Grade 3 and one patient with Grade 4 unilateral optic neuropathy, and two patients with Grade 3 central nervous system necrosis. No patient experienced brainstem toxicity. Actuarial 5-year freedom from high-grade toxicity was 94%. CONCLUSIONS Our data indicate safety and efficacy of spot-scanning based PT for skull-base chordomas and chondrosarcomas. With target definition, dose prescription and normal organ tolerance levels similar to passive-scattering based PT series, complication-free, tumor control and survival rates are at present comparable.

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.

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.

Current and Future Strategies in Radiotherapy of Childhood Low-Grade Glioma of the Brain

Background:For more than 60 years, radiation therapy has been an integral part in the management of childhood low-grade glioma. As this tumor carries an excellent long-term prognosis, the risk of late effects is of particular clinical importance and impinges upon radiotherapeutic treatment strategies.Material and Methods:Studies on the use of radiation therapy in children with low-grade glioma were systematically reviewed for data on radiotherapy-induced side effects on brain parenchyma, endocrine dysfunction, growth retardation, neurocognitive dysfunction, vasculopathy, and secondary neoplasms.Results:Data on late effects are scarce and heterogeneous. Past reports included only retrospective series from the 1930s to present days, a time during which treatment policies and radiation techniques widely varied and considerably changed in recent years. Often, considerable uncertainty existed regarding pretreatment health status and radiotherapy-related factors (e. g., total dose, dose per fraction, treatment fields). In spite of these shortcomings and often conflicting observations, it appears that especially younger children and children with neurofibromatosis (NF) are at risk of endocrinopathies in terms of growth retardation and developmental abnormalities, as well as neurocognitive dysfunction expressed as problems in the psychosocial environment such as in education and occupation. However, both observations may be attributed to the higher proportion of NF in the very young who frequently develop large tumors spreading along the entire supratentorial midline. The risk of radiation-induced disturbances in visual function is low (no case reported). Young children with NF appear to have an increased risk of vasculopathies. 33 cases of moyamoya disease were found (preferably in the very young), 18 of whom were NF-positive. Other cerebrovascular accidents (24 cases, of whom 14 were NF-positive) and secondary neoplasms (15 cases, of whom only five occurred in field—four were high-grade astrocytomas) are a rare condition. The latter cannot be distinguished from late relapses with malignant transformation. Modern treatment techniques appear to reduce the risk of radiation-induced late effects.Conclusions:More studies and clear definitions of clinical endpoints such as neurocognitive and endocrinological outcome are needed in order to clarify the impact of radiation therapy on the risk of late sequelae. Presently, the strategy to postpone radiotherapy in the younger children, especially with NF, is justified to reduce the risk of late effects. These information and the contribution of tumor, surgery and chemotherapy will help to define the role of radiation therapy in the future management of childhood low-grade glioma and whether the use of highly sophisticated and expensive treatment techniques is justifiable. The recently initiated prospective study of the APRO (Pediatric Radiooncology Working Party) on documentation of dose prescription to organs at risk and the network of the GPOH to explore late effects as well as the forthcoming prospective SIOP/GPOH (International Society of Pediatric Oncology/German Society of Pediatric Oncology and Hematology) LGG 2003 trial are addressing these issues.Hintergrund:Seit mehr als 60 Jahren bildet die Bestrahlung einen integralen Therapiebestandteil bei der Behandlung von niedrigmalignen Gliomen im Kindesalter. Da diese Tumoren eine sehr gute Langzeitprognose besitzen, spielt das Risiko für Therapiefolgen eine besondere klinische Rolle und beeinflusst damit radiotherapeutische Behandlungsstrategien.Material und Methodik:Studien über die Anwendung von Radiotherapie bei niedrigmalignen Gliomen im Kindesalter wurden systematisch analysiert im Hinblick auf Daten bezüglich strahlentherapieinduzierter Spätfolgen im Hirnparenchym, endokriner Funktion, Wachstum und Entwicklung, neurokognitiver Funktion, Gefäßveränderungen und Zweittumoren.Ergebnisse:Literaturangaben über Späteffekte sind gering und heterogen. Zurückliegende Berichte schlossen nur retrospektive Serien der 30er Jahre bis heute ein, also eine Zeit, in der sich Behandlungsrichtlinien und Strahlentherapietechniken erheblich unterschieden und sich in jüngster Zeit deutlich änderten. Häufig bestand eine ausgeprägte Unsicherheit hinsichtlich des Gesundheitszustands vor Therapie und strahlentherapiebezogener Faktoren (wie Gesamtdosis, Einzeldosis, Bestrahlungsfelder). Trotz dieser Einschränkungen und häufig widersprüchlicher Beobachtungen scheint es, als wiesen insbesondere jüngere Kinder und Kinder mit Neurofibromatose (NF) ein besonderes Risiko für endokrinologische Störungen in Form von Wachstumsverzögerung und Entwicklungsstörungen ebenso wie für neurokognitive Dysfunktionen, ausgedrückt als Probleme in der psychosozialen Umgebung wie Erziehung, Ausbildung und Beruf, auf. Beide Beobachtungen können jedoch dem höheren Anteil von NF bei sehr jungen Kindern zugeschrieben werden, die häufig große Tumoren entlang der gesamten supratentoriellen Mittellinie entwickeln. Das Risiko für strahlentherapieinduzierte Störungen der Visusfunktion ist gering (kein Literaturbericht hierzu). Jüngere Kinder mit NF scheinen ein erhöhtes Risiko für Gefäßerkrankungen aufzuweisen. 33 Fälle von Moyamoya-Syndrom wurden gefunden (vorzugsweise bei sehr jungen Kindern), von denen 18 das klinische Bild einer NF boten. Andere zerebrovaskuläre Ereignisse (24 Fälle, davon 14 NF-positiv) und Zweittumoren (15 Fälle, von denen fünf innerhalb der Bestrahlungsfelder auftraten—vier waren hochmaligne Astrozytome) sind selten. Letztere sind nicht von späten Rückfällen mit Malignisierung zu unterscheiden. Moderne Bestrahlungstechniken scheinen das Risiko für strahlentherapiebedingte Spätfolgen zu senken.Schlussfolgerungen:Weitere prospektive Studien und eine klare Definition klinischer Endpunkte wie neurokognitives und endokrinologisches Behandlungsergebnis sind notwendig, um den Einfluss der Strahlentherapie auf das Risiko für Therapiefolgen abzuklären. Derzeit ist die Strategie, die Strahlentherapie bei jüngeren Kindern hinauszuzögern (besonders bei NF), gerechtfertigt, um das Risiko für Therapiefolgen zu reduzieren. Diese Informationen und der Beitrag von Tumor, Operation und Chemotherapie werden dazu dienen, die Rolle der Strahlentherapie in zukünftigen Behandlungsstrategien zu definieren, und klären helfen, ob die Anwendung hochpräziser und aufwendiger Bestrahlungstechniken gerechtfertigt ist. Die kürzlich initiierte prospektive Studie der APRO (Arbeitsgemeinschaft Pädiatrische Radioonkologie) zur Dokumentation von Dosisverschreibungen innerhalb von Risikoorganen und das Kompetenznetzwerk pädiatrische Onkologie der GPOH zur Untersuchung von Spätfolgen befassen sich ebenso wie die in Vorbereitung befindliche SIOP/GPOH- (International Society of Pediatric Oncology/Gesellschaft für Pädiatrische Onkologie und Hämatologie-)LGG-2003-Studie mit diesen Themen.

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.

Current and future strategies in radiotherapy of childhood low-grade glioma of the brain. Part II: Treatment-related late toxicity

Background:For more than 60 years, radiation therapy has been an integral part in the management of childhood low-grade glioma. As this tumor carries an excellent long-term prognosis, the risk of late effects is of particular clinical importance and impinges upon radiotherapeutic treatment strategies.Material and Methods:Studies on the use of radiation therapy in children with low-grade glioma were systematically reviewed for data on radiotherapy-induced side effects on brain parenchyma, endocrine dysfunction, growth retardation, neurocognitive dysfunction, vasculopathy, and secondary neoplasms.Results:Data on late effects are scarce and heterogeneous. Past reports included only retrospective series from the 1930s to present days, a time during which treatment policies and radiation techniques widely varied and considerably changed in recent years. Often, considerable uncertainty existed regarding pretreatment health status and radiotherapy-related factors (e. g., total dose, dose per fraction, treatment fields). In spite of these shortcomings and often conflicting observations, it appears that especially younger children and children with neurofibromatosis (NF) are at risk of endocrinopathies in terms of growth retardation and developmental abnormalities, as well as neurocognitive dysfunction expressed as problems in the psychosocial environment such as in education and occupation. However, both observations may be attributed to the higher proportion of NF in the very young who frequently develop large tumors spreading along the entire supratentorial midline. The risk of radiation-induced disturbances in visual function is low (no case reported). Young children with NF appear to have an increased risk of vasculopathies. 33 cases of moyamoya disease were found (preferably in the very young), 18 of whom were NF-positive. Other cerebrovascular accidents (24 cases, of whom 14 were NF-positive) and secondary neoplasms (15 cases, of whom only five occurred in field—four were high-grade astrocytomas) are a rare condition. The latter cannot be distinguished from late relapses with malignant transformation. Modern treatment techniques appear to reduce the risk of radiation-induced late effects.Conclusions:More studies and clear definitions of clinical endpoints such as neurocognitive and endocrinological outcome are needed in order to clarify the impact of radiation therapy on the risk of late sequelae. Presently, the strategy to postpone radiotherapy in the younger children, especially with NF, is justified to reduce the risk of late effects. These information and the contribution of tumor, surgery and chemotherapy will help to define the role of radiation therapy in the future management of childhood low-grade glioma and whether the use of highly sophisticated and expensive treatment techniques is justifiable. The recently initiated prospective study of the APRO (Pediatric Radiooncology Working Party) on documentation of dose prescription to organs at risk and the network of the GPOH to explore late effects as well as the forthcoming prospective SIOP/GPOH (International Society of Pediatric Oncology/German Society of Pediatric Oncology and Hematology) LGG 2003 trial are addressing these issues.Hintergrund:Seit mehr als 60 Jahren bildet die Bestrahlung einen integralen Therapiebestandteil bei der Behandlung von niedrigmalignen Gliomen im Kindesalter. Da diese Tumoren eine sehr gute Langzeitprognose besitzen, spielt das Risiko für Therapiefolgen eine besondere klinische Rolle und beeinflusst damit radiotherapeutische Behandlungsstrategien.Material und Methodik:Studien über die Anwendung von Radiotherapie bei niedrigmalignen Gliomen im Kindesalter wurden systematisch analysiert im Hinblick auf Daten bezüglich strahlentherapieinduzierter Spätfolgen im Hirnparenchym, endokriner Funktion, Wachstum und Entwicklung, neurokognitiver Funktion, Gefäßveränderungen und Zweittumoren.Ergebnisse:Literaturangaben über Späteffekte sind gering und heterogen. Zurückliegende Berichte schlossen nur retrospektive Serien der 30er Jahre bis heute ein, also eine Zeit, in der sich Behandlungsrichtlinien und Strahlentherapietechniken erheblich unterschieden und sich in jüngster Zeit deutlich änderten. Häufig bestand eine ausgeprägte Unsicherheit hinsichtlich des Gesundheitszustands vor Therapie und strahlentherapiebezogener Faktoren (wie Gesamtdosis, Einzeldosis, Bestrahlungsfelder). Trotz dieser Einschränkungen und häufig widersprüchlicher Beobachtungen scheint es, als wiesen insbesondere jüngere Kinder und Kinder mit Neurofibromatose (NF) ein besonderes Risiko für endokrinologische Störungen in Form von Wachstumsverzögerung und Entwicklungsstörungen ebenso wie für neurokognitive Dysfunktionen, ausgedrückt als Probleme in der psychosozialen Umgebung wie Erziehung, Ausbildung und Beruf, auf. Beide Beobachtungen können jedoch dem höheren Anteil von NF bei sehr jungen Kindern zugeschrieben werden, die häufig große Tumoren entlang der gesamten supratentoriellen Mittellinie entwickeln. Das Risiko für strahlentherapieinduzierte Störungen der Visusfunktion ist gering (kein Literaturbericht hierzu). Jüngere Kinder mit NF scheinen ein erhöhtes Risiko für Gefäßerkrankungen aufzuweisen. 33 Fälle von Moyamoya-Syndrom wurden gefunden (vorzugsweise bei sehr jungen Kindern), von denen 18 das klinische Bild einer NF boten. Andere zerebrovaskuläre Ereignisse (24 Fälle, davon 14 NF-positiv) und Zweittumoren (15 Fälle, von denen fünf innerhalb der Bestrahlungsfelder auftraten—vier waren hochmaligne Astrozytome) sind selten. Letztere sind nicht von späten Rückfällen mit Malignisierung zu unterscheiden. Moderne Bestrahlungstechniken scheinen das Risiko für strahlentherapiebedingte Spätfolgen zu senken.Schlussfolgerungen:Weitere prospektive Studien und eine klare Definition klinischer Endpunkte wie neurokognitives und endokrinologisches Behandlungsergebnis sind notwendig, um den Einfluss der Strahlentherapie auf das Risiko für Therapiefolgen abzuklären. Derzeit ist die Strategie, die Strahlentherapie bei jüngeren Kindern hinauszuzögern (besonders bei NF), gerechtfertigt, um das Risiko für Therapiefolgen zu reduzieren. Diese Informationen und der Beitrag von Tumor, Operation und Chemotherapie werden dazu dienen, die Rolle der Strahlentherapie in zukünftigen Behandlungsstrategien zu definieren, und klären helfen, ob die Anwendung hochpräziser und aufwendiger Bestrahlungstechniken gerechtfertigt ist. Die kürzlich initiierte prospektive Studie der APRO (Arbeitsgemeinschaft Pädiatrische Radioonkologie) zur Dokumentation von Dosisverschreibungen innerhalb von Risikoorganen und das Kompetenznetzwerk pädiatrische Onkologie der GPOH zur Untersuchung von Spätfolgen befassen sich ebenso wie die in Vorbereitung befindliche SIOP/GPOH- (International Society of Pediatric Oncology/Gesellschaft für Pädiatrische Onkologie und Hämatologie-)LGG-2003-Studie mit diesen Themen.

Second cancers in children treated with modern radiotherapy techniques

BACKGROUND AND PURPOSE The scattered radiation from the treatment volume might be more significant for children than for adults and, as a consequence, modern radiotherapy treatment techniques such as IMRT and passive proton therapy could potentially increase the number of secondary cancers. In this report, secondary cancer risk resulting from new treatment technologies was estimated for an adult prostate patient and a child. MATERIAL AND METHODS The organ equivalent dose (OED) concept with a linear-exponential, a plateau and a linear dose-response curve was applied to dose distributions of an adult prostate patient and a child with a rhabdomyosarcoma of the prostate. Conformal radiotherapy, IMRT with 6MV photons and proton therapy were planned. OED (cancer risk) was estimated for the whole body, the rectum and the bladder. In addition, relative cumulative risk was calculated. RESULTS Secondary cancer risk in the adult is not more than 15% it increased when IMRT or passive proton therapy was compared to conventional treatment planning. In the child, risk remains practically constant or was even reduced for proton therapy. The cumulative risk in the child relative to that in the adult can be as large as 10-15. CONCLUSIONS By a comparison between an adult patient and a child treated for a disease of the prostate, it was shown that modern radiotherapy techniques such as IMRT and proton therapy (active and passive) do not increase the risk for secondary cancers.

Spot-scanning-based proton therapy for extracranial chordoma.

PURPOSE To evaluate effectiveness and safety of spot-scanning-based proton-radiotherapy (PT) for extracranial chordomas (ECC). METHODS AND MATERIAL Between 1999-2006, 40 patients with chordoma of C-, T-, and L-spine and sacrum were treated at Paul Scherrer Institute (PSI) with PT using spot-scanning. Median patient age was 58 years (range, 10-81 years); 63% were male, and 36% were female. Nineteen patients (47%) had gross residual disease (mean 69 cc; range, 13-495 cc) before PT, and 21 patients (53%) had undergone prior titanium-based surgical stabilization (SS) and reconstruction of the axial skeleton. Proton doses were expressed as Gy(RBE). A conversion factor of 1.1 was used to account for higher relative biological effectiveness (RBE) of protons compared with photons. Mean total dose was 72.5 Gy(RBE) [range, 59.4-75.2 Gy(RBE)] delivered at 1.8-2.0 Gy(RBE) dose per fraction. Median follow-up time was 43 months. RESULTS In 19 patients without surgical stabilization, actuarial local control (LC) rate at 5 years was 100%. LC for patients with gross residual disease but without surgical stabilization was also 100% at 5 years. In contrast, 12 failures occurred in 21 patients with SS, yielding a significantly decreased 5-year LC rate of 30% (p = 0.0003). For the entire cohort, 5-year LC rates were 62%, disease-free survival rates were 57%, and overall survival rates were 80%. Rates were 100% for patients without SS. No other factor, including dosimetric parameters (V95, V80) were predictive for tumor control on univariate analysis. CONCLUSION Spot-scanning-based PT at PSI delivered subsequently to function-preserving surgery for tumor debulking, decompression of spinal cord, or biopsy only is safe and highly effective in patients with ECC without major surgical instrumentation even in view of large, unresectable disease.