Urs M. Lütolf

Genetic pathways to glioblastoma: a population-based study.

We conducted a population-based study on glioblastomas in the Canton of Zurich, Switzerland (population, 1.16 million) to determine the frequency of major genetic alterations and their effect on patient survival. Between 1980 and 1994, 715 glioblastomas were diagnosed. The incidence rate per 100,000 population/year, adjusted to the World Standard Population, was 3.32 in males and 2.24 in females. Observed survival rates were 42.4% at 6 months, 17.7% at 1 year, and 3.3% at 2 years. For all of the age groups, younger patients survived significantly longer, ranging from a median of 8.8 months (<50 years) to 1.6 months (>80 years). Loss of heterozygosity (LOH) 10q was the most frequent genetic alteration (69%), followed by EGFR amplification (34%), TP53 mutations (31%), p16INK4a deletion (31%), and PTEN mutations (24%). LOH 10q occurred in association with any of the other genetic alterations and was predictive of shorter survival. Primary (de novo) glioblastomas prevailed (95%), whereas secondary glioblastomas that progressed from low-grade or anaplastic gliomas were rare (5%). Secondary glioblastomas were characterized by frequent LOH 10q (63%) and TP53 mutations (65%). Of the TP53 mutations in secondary glioblastomas, 57% were in hotspot codons 248 and 273, whereas in primary glioblastomas, mutations were more equally distributed. G:C→A:T mutations at CpG sites were more frequent in secondary than primary glioblastomas (56% versus 30%; P = 0.0208). This suggests that the acquisition of TP53 mutations in these glioblastoma subtypes occurs through different mechanisms.

Radiation treatment planning with an integrated positron emission and computer tomography (PET/CT): A feasibility study

PURPOSE To investigate the usefulness of hardware coregistered PET/CT images for target volume definition. METHODS AND MATERIALS Thirty-nine patients presenting with various solid tumors were investigated. CT and a FDG-PET were obtained in treatment position in an integrated PET/CT scanner, and coregistered images were used for treatment planning. First, volume delineation was performed on the CT data. In a second step, the corresponding PET data were used as an overlay to the CT data to define the target volume. Delineation was done independently by two investigators. RESULTS Coregistered PET/CT showed good fusion accuracy. The GTV increased by 25% or more because of PET in 17% of cases with head-and-neck (2/12) and lung cancer (1/6), and in 33% (7/21) in cancer of the pelvis. The GTV was reduced > or =25% in 33% of patients with head-and-neck cancer (4/12), in 67% with lung cancer (4/6), and 19% with cancer of the pelvis (4/21). Overall, in 56% (22/39) of cases, GTV delineation was changed significantly if information from metabolic imaging was used in the planning process. The modification of the GTV translated into altered PTV changes exceeding >20% in 46% (18/39) of cases. With PET, volume delineation variability between two independent oncologists decreased from a mean volume difference of 25.7 cm(3) to 9.2 cm(3) associated with a reduction of the standard deviation from 38.3 cm(3) to 13.3 cm(3) (p = 0.02). In 16% of cases, PET/CT revealed distant metastasies, changing the treatment strategy from curative to palliative. CONCLUSION Integrated PET/CT for treatment planning for three-dimensional conformal radiation therapy improves the standardization of volume delineation compared with that of CT alone. PET/CT has the potential for reducing the risk for geographic misses, to minimize the dose of ionizing radiation applied to non-target organs, and to change the current practice to three-dimensional conformal radiation therapy planning by taking into account the metabolic and biologic features of cancer. The impact on treatment outcome remains to be demonstrated.

Osteoradionecrosis of the mandible: Minimized risk profile following intensity-modulated radiation therapy (IMRT)

Background and Purpose:Osteoradionecrosis (ON) of the mandible is a serious late complication of high-dose radiation therapy for tumors of the oropharynx and oral cavity. After doses between 60 and 72 Gy using standard fractionation, an incidence of ON between 5% and 15% is reported in a review from 1989, whereas in more recent publications using moderately accelerated or hyperfractionated irradiation and doses between 69 and 81 Gy, the incidence of ON is between < 1% and ~ 6%. Intensity-modulated radiation therapy (IMRT) is expected to translate into a further important reduction of ON. The aim of this descriptive study was to assess absolute and relative bone volumes exposed to high IMRT doses, related to observed bone tolerance.Patients and Methods:Between December 2001 and November 2004, 73 of 123 patients treated with IMRT were identified as subgroup “at risk” for ON (> 60 Gy for oropharyngeal or oral cavity cancer). 21/73 patients were treated in a postoperative setting, 52 patients underwent primary definitive irradiation. In 56 patients concomitant cisplatin-based chemotherapy was applied. Mean follow-up time was 22 months (12–46 months). Oral cavity including the mandible bone outside the planning target volume was contoured and dose-volume constraints were defined in order to spare bone tissue. Dose-volume histograms were obtained from contoured mandible in each patient and were analyzed and related to clinical mandible bone tolerance.Results:Using IMRT with doses between 60 and 75 Gy (mean 67 Gy), on average 7.8, 4.8, 0.9, and 0.3 cm3 were exposed to doses > 60, 65, 70, and 75 Gy, respectively. These values are substantially lower than when using three-dimensional conformal radiotherapy. The difference has been approximately quantified by comparison with a historic series. Additional ON risk factors of the patients were also analyzed. Only one grade 3 ON of the lingual horizontal branch, treated with lingual decortication, was observed.Conclusion:Using IMRT, only very small partial volumes of the mandibular bone are exposed to high radiation doses. This is expected to translate into a further reduction of ON and improved osseointegration of dental implants.Hintergrund und Ziel:Die Osteoradionekrose (ON) des Unterkiefers ist eine schwerwiegende Komplikation kurativer normofraktionierter Radiotherapie von Oropharynx- und Mundhöhlenkarzinomen. Nach Dosen zwischen 60 und 72 Gy besteht gemäß den Angaben einer Übersicht aus dem Jahr 1989 eine ON-Inzidenz von 5–15%, während laut neueren Arbeiten über leicht akzelerierte oder hyperfraktionierte Behandlungsschemata mit Dosen von 69–81 Gy die ON-Inzidenz zwischen < 1% und ca. 6% beträgt. Intensitätsmodulierte Radiotherapie (IMRT) dürfte die ON-Rate weiter reduzieren. Ziel dieser deskriptiven Arbeit war, absolute und relative Knochenvolumina mit hoher Dosisexposition zu evaluieren und in Beziehung zur beobachteten Knochentoleranz der eigenen Patienten nach IMRT-Behandlung zu setzen.Patienten und Methodik:Zwischen Dezember 2001 und November 2004 wurden an der eigenen Klinik 123 Patienten mit Tumoren der Kopf-Hals-Region mit IMRT behandelt; hiervon waren 73 einer Untergruppe von Patienten mit Risiko für ON zuzurechnen (Karzinome des Oropharynx oder der Mundhöhle und Herddosen > 60 Gy). 21 Patienten wurden postoperativ, 52 primär kurativ bestrahlt; 56 erhielten eine simultane cisplatinbasierte Chemotherapie. Die mittlere Beobachtungszeit betrug 22 Monate (12–46 Monate). Die Mundhöhle inkl. Kieferknochen außerhalb des Planungszielvolumens wurde konturiert, und Dosis-Volumen-Bedingungen zur Organschonung wurden festgelegt. Retrospektiv wurde für jeden Patienten das gesamte Kieferknochenvolumen konturiert, und die Dosis-Volumen-Histogramme wurden im Hinblick auf die klinische Knochentoleranz ausgewertet.Ergebnisse:Durch IMRT in Dosen zwischen 60 und 75 Gy (Mittelwert 67 Gy) wurden im Mittel 7,8, 4,8, 0,9 und 0,3 cm3 einer Dosis von > 60, 65, 70 und 75 Gy ausgesetzt (Tabelle 1 und Abbildung 1). Diese Werte sind deutlich kleiner als nach konventioneller Bestrahlung. Der Unterschied wurde im Vergleich mit einer historischen Serie näherungsweise quantifiziert (Abbildung 3). Zusätzliche Risikofaktoren der eigenen Patienten wurden analysiert (Abbildung 2). Nur ein ON-Ereignis (Grad 3) im Bereich des lingualen Horizontalasts der Mandibula wurde beobachtet und erfolgreich mit einer lingualen Dekortikation behandelt.Schlussfolgerung:Mittels IMRT werden nur sehr kleine Knochenvolumina hohen Bestrahlungsdosen ausgesetzt. Durch diese Knochenschonung werden eine weitere Reduktion des ON-Risikos und eine höhere Erfolgsrate rekonstruktiver Zahnimplantate (Tabelle 2) erwartet.

Cardiac lesions after mediastinal irradiation for Hodgkin's disease

We analysed the risk of myocardial infarctions in 339 patients with Hodgkins disease treated with radiotherapy (rt) with or without chemotherapy. A total of 112 patients underwent cardiac testing with echocardiography, rest and exercise electrocardiogram and myocardial scintigraphy. Nearly all patients have been treated with < 2.0 Gy per fraction to the anterior cardiac region. A significantly increased risk of myocardial infarctions or of sudden death has been observed (10 patients). No cardia events have been observed in 215 non-smokers without hypertension and without coronary artery disease (CAD) already present before rt. In the heart study group (112 patients), there were 6 patients with probable or proven CAD. Five of these 6 patients had known risk factors for CAD. Echocardiography showed sclerosis of the aortic and or the mitral valves in 34 patients. Of these patients, 2 had a slight and 1 a moderate aortic stenosis, 5 had a slight and 1 a moderate mitral regurgitation. Evidence for a disturbance of the diastolic function has not been observed. No patient had a clinically relevant pericardial lesion. In patients without risk factors for CAD, there is only a low risk of ischaemic cardiac events after modern mediastinal rt for Hodgkins disease. Patients should eliminate the known risk factors. There is a high incidence of sclerosis of the mitral and or the aortic valves developing into clinically important lesions in few patients. Decision on the treatment strategy and the rt technique should also involve consideration of the cardiac risk. For routine follow-up, we recommend inclusion of an echocardiography in intervals between 3 and 4 years.

Osteoradionecrosis of the Mandible

Background and Purpose:Osteoradionecrosis (ON) of the mandible is a serious late complication of high-dose radiation therapy for tumors of the oropharynx and oral cavity. After doses between 60 and 72 Gy using standard fractionation, an incidence of ON between 5% and 15% is reported in a review from 1989, whereas in more recent publications using moderately accelerated or hyperfractionated irradiation and doses between 69 and 81 Gy, the incidence of ON is between < 1% and ~ 6%. Intensity-modulated radiation therapy (IMRT) is expected to translate into a further important reduction of ON. The aim of this descriptive study was to assess absolute and relative bone volumes exposed to high IMRT doses, related to observed bone tolerance.Patients and Methods:Between December 2001 and November 2004, 73 of 123 patients treated with IMRT were identified as subgroup “at risk” for ON (> 60 Gy for oropharyngeal or oral cavity cancer). 21/73 patients were treated in a postoperative setting, 52 patients underwent primary definitive irradiation. In 56 patients concomitant cisplatin-based chemotherapy was applied. Mean follow-up time was 22 months (12–46 months). Oral cavity including the mandible bone outside the planning target volume was contoured and dose-volume constraints were defined in order to spare bone tissue. Dose-volume histograms were obtained from contoured mandible in each patient and were analyzed and related to clinical mandible bone tolerance.Results:Using IMRT with doses between 60 and 75 Gy (mean 67 Gy), on average 7.8, 4.8, 0.9, and 0.3 cm3 were exposed to doses > 60, 65, 70, and 75 Gy, respectively. These values are substantially lower than when using three-dimensional conformal radiotherapy. The difference has been approximately quantified by comparison with a historic series. Additional ON risk factors of the patients were also analyzed. Only one grade 3 ON of the lingual horizontal branch, treated with lingual decortication, was observed.Conclusion:Using IMRT, only very small partial volumes of the mandibular bone are exposed to high radiation doses. This is expected to translate into a further reduction of ON and improved osseointegration of dental implants.Hintergrund und Ziel:Die Osteoradionekrose (ON) des Unterkiefers ist eine schwerwiegende Komplikation kurativer normofraktionierter Radiotherapie von Oropharynx- und Mundhöhlenkarzinomen. Nach Dosen zwischen 60 und 72 Gy besteht gemäß den Angaben einer Übersicht aus dem Jahr 1989 eine ON-Inzidenz von 5–15%, während laut neueren Arbeiten über leicht akzelerierte oder hyperfraktionierte Behandlungsschemata mit Dosen von 69–81 Gy die ON-Inzidenz zwischen < 1% und ca. 6% beträgt. Intensitätsmodulierte Radiotherapie (IMRT) dürfte die ON-Rate weiter reduzieren. Ziel dieser deskriptiven Arbeit war, absolute und relative Knochenvolumina mit hoher Dosisexposition zu evaluieren und in Beziehung zur beobachteten Knochentoleranz der eigenen Patienten nach IMRT-Behandlung zu setzen.Patienten und Methodik:Zwischen Dezember 2001 und November 2004 wurden an der eigenen Klinik 123 Patienten mit Tumoren der Kopf-Hals-Region mit IMRT behandelt; hiervon waren 73 einer Untergruppe von Patienten mit Risiko für ON zuzurechnen (Karzinome des Oropharynx oder der Mundhöhle und Herddosen > 60 Gy). 21 Patienten wurden postoperativ, 52 primär kurativ bestrahlt; 56 erhielten eine simultane cisplatinbasierte Chemotherapie. Die mittlere Beobachtungszeit betrug 22 Monate (12–46 Monate). Die Mundhöhle inkl. Kieferknochen außerhalb des Planungszielvolumens wurde konturiert, und Dosis-Volumen-Bedingungen zur Organschonung wurden festgelegt. Retrospektiv wurde für jeden Patienten das gesamte Kieferknochenvolumen konturiert, und die Dosis-Volumen-Histogramme wurden im Hinblick auf die klinische Knochentoleranz ausgewertet.Ergebnisse:Durch IMRT in Dosen zwischen 60 und 75 Gy (Mittelwert 67 Gy) wurden im Mittel 7,8, 4,8, 0,9 und 0,3 cm3 einer Dosis von > 60, 65, 70 und 75 Gy ausgesetzt (Tabelle 1 und Abbildung 1). Diese Werte sind deutlich kleiner als nach konventioneller Bestrahlung. Der Unterschied wurde im Vergleich mit einer historischen Serie näherungsweise quantifiziert (Abbildung 3). Zusätzliche Risikofaktoren der eigenen Patienten wurden analysiert (Abbildung 2). Nur ein ON-Ereignis (Grad 3) im Bereich des lingualen Horizontalasts der Mandibula wurde beobachtet und erfolgreich mit einer lingualen Dekortikation behandelt.Schlussfolgerung:Mittels IMRT werden nur sehr kleine Knochenvolumina hohen Bestrahlungsdosen ausgesetzt. Durch diese Knochenschonung werden eine weitere Reduktion des ON-Risikos und eine höhere Erfolgsrate rekonstruktiver Zahnimplantate (Tabelle 2) erwartet.

Quality of life in patients cured from a carcinoma of the head and neck by radiotherapy : The importance of the target volume

PURPOSE To assess the health-related quality of life (QOL) of long-term survivors of carcinomas of different subsites of the head and neck following curative radiotherapy (RT). PATIENTS AND METHODS Patients continuously free from recurrence or second primary tumors treated 1988-1994 were contacted 5.1 to 5.9 years after RT and asked to fill in the EORTC QLQ-C30 core questionnaire and the H&N cancer module. RT had been restricted to the glottis (group A; carcinomas of the vocal cord T1-2 N0), or had included bilateral neck nodes and the primary tumor outside the nasopharynx (group B; AJC Stage II to IV) or within the nasopharynx, respectively (group C; Stage II to IV). Response rate was 97% (group A; n = 41), 69% (group B; n = 26) and 71% (group C; n = 12), respectively. The groups were different with respect to age (older in group A), alcohol consumption (absent in group C) and proportion of females (more in group C). RESULTS Patients with nasopharyngeal cancer reported the highest morbidity on the H&N module (dry mouth, sticky saliva, trismus, problems with teeth, trouble eating). However, these symptoms did not have a high impact on global QOL or function scores on the QLQ-C30 core questionnaire. Patients in group B reported a lower global QOL but less severe symptoms on the module. CONCLUSION The high morbidity of patients treated for a nasopharyngeal cancer may be explained by the location of the target volume which included the bilateral temporo-mandibular joints and the salivary glands. These patients require appropriate care during follow-up and will probably profit most from new RT techniques with sparing of normal tissues.

Age as a predictive factor in glioblastomas: population-based study

We evaluated 715 glioblastoma patients diagnosed during 1980–1994 in the Canton of Zurich, Switzerland, to provide information on how patients were treated at the population level. Despite a general policy during the study period of treatment by surgical intervention aimed at maximum tumor removal followed by radiotherapy, there was a marked tendency toward limited treatment with advancing patient age. Of those younger than 65 years, 82% were treated either with surgery followed by radiotherapy, surgery alone or radiotherapy alone, versus 47% of patients 65 years or older. Only 25% of patients older than 75 years underwent surgery and/or radiotherapy, while the remaining patients were given best supportive care (BSC). The mean ages of patients were 54.5 years for those treated with surgery and radiotherapy, 58.3 years for surgery alone, 62.2 years for radiotherapy alone and 69.2 years for BSC. Among patients who were treated with surgery plus radiotherapy and those treated with radiotherapy alone, younger patients (<60 years) had a significantly higher survival rate than older patients (≥60 years). In contrast, no significant difference in survival was observed between younger and older patients treated with surgery alone or receiving BSC, suggesting that lower survival rates in elderly patients with glioblastoma may be at least in part due to a lesser response to radiotherapy.

IMRT using simultaneously integrated boost (SIB) in head and neck cancer patients

BackgroundPreliminary very encouraging clinical results of intensity modulated radiation therapy (IMRT) in Head Neck Cancer (HNC) are available from several large centers. Tumor control rates seem to be kept at least at the level of conventional three-dimensional radiation therapy; the benefit of normal tissue preservation with IMRT is proven for salivary function. There is still only limited experience with IMRT using simultaneously integrated boost (SIB-IMRT) in the head and neck region in terms of normal tissue response.The aim of this work was (1) to establish tumor response in HNC patients treated with SIB-IMRT, and (2) to assess tissue tolerance following different SIB-IMRT schedules.ResultsBetween 1/2002 and 12/2004, 115 HNC patients have been curatively treated with IMRT. 70% received definitive IMRT (dIMRT), 30% were postoperatively irradiated. In 78% concomitant chemotherapy was given.SIB radiation schedules with 5–6 × 2 Gy/week to 60–70 Gy, 5 × 2.2 Gy/week to 66–68.2 Gy (according to the RTOG protocol H-0022), or 5 × 2.11 Gy/week to 69.6 Gy were used.After mean 18 months (10–44), 77% of patients were alive with no disease. Actuarial 2-year local, nodal, and distant disease free survival was 77%, 87%, and 78%, respectively. 10% were alive with disease, 10% died of disease. 20/21 locoregional failures occurred inside the high dose area. Mean tumor volume was significantly larger in locally failed (63 cc) vs controlled tumors (32 cc, p <0.01), and in definitive (43 cc) vs postoperative IMRT (25 cc, p <0.05); the locoregional failure rate was twofold higher in definitively irradiated patients.Acute reactions were mild to moderate and limited to the boost area, the persisting grade 3/4 late toxicity rate was low with 6%. The two grade 4 reactions (dysphagia, laryngeal fibrosis) were observed following the SIB schedule with 2.2 Gy per session.ConclusionSIB-IMRT in HNC using 2.0, 2.11 or 2.2 Gy per session is highly effective and safe with respect to tumor response and tolerance. SIB with 2.2 Gy is not recommended for large tumors involving laryngeal structures.

Volumetric staging (VS) is superior to TNM and AJCC staging in predicting outcome of head and neck cancer treated with IMRT

The UICC classification (TNM) represents the validated standard tool to describe tumor extent and includes prognostic information on the probability of disease control. The American Joint Committee on Cancer (AJCC) stage grouping is based on the evaluation of treatment and outcome. Gross tumor volume (GTV) might be more relevant than pure description (TNM) or stage grouping as prognostic factor for local control in head and neck cancer (HNC). Based on the observation of GTV-correlated outcome in our initial HNC patient cohort treated with IMRT, we tested the hypothesis that the GTV is the most reliable predictive tool in HNC outcome. A GTV based volumetric staging system (VS) was introduced, using two volumetric cut-off values (15 and 70 cm3). VS, TNM, and AJCC stages were assessed and correlated with outcome following primary radiation in 172 HNC patients. Analyses were based on Kaplan-Meier survival curves. VS proved to be superior to the TNM/AJCC in predicting outcome. In addition, VS enabled to stratify high- and low-risk patients in advanced TN stages. GTV represented the most important prognostic indicator in HNC treated with IMRT and is recommended to be considered for therapeutic decisions and estimation of outcome.

Effect of high dose per pulse flattening filter-free beams on cancer cell survival.

PURPOSE To investigate if there is a statistically significant difference in cancer cell survival using a high dose per pulse flattening filter-free (FFF) beam compared to a standard flattened beam. MATERIAL AND METHODS To validate the radiobiological effect of the flattened and FFF beam, two glioblastoma cell lines were treated with either 5 or 10 Gy using different dose rates. Dose verification was performed and colony formation assays were carried out. To compare the predictability of our data, radiobiological models were included. RESULTS The results presented here demonstrate that irradiation of glioblastoma cell lines using the FFF beam is more efficient in reducing clonogenic cell survival than the standard flattened beam, an effect which becomes more significant the higher the single dose. Interestingly, in our experimental setting, the radiobiological effect of the FFF beam is dependent on dose per pulse rather than on delivery time. The used radiobiological models are able to describe the observed dose rate dependency between 6 and 24 Gy/min. CONCLUSION The results presented here show that dose per pulse might become a crucial factor which influences cancer cell survival. Using high dose rates, currently used radiobiological models as well as molecular mechanisms involved urgently need to be re-examined.