Temporal Lobe Reactions After Radiotherapy With Carbon Ions: Incidence and Estimation of the Relative Biological Effectiveness by the Local Effect Model

Int. J. Radiation Oncology Biol. Phys., Vol. 80, No. 3, pp. 815–823, 2011 Copyright Ó 2011 Elsevier Inc. Printed in the USA. All rights reserved 0360-3016/$–see front matter

doi:10.1016/j.ijrobp.2010.03.001

CLINICAL INVESTIGATION

Brain

TEMPORAL LOBE REACTIONS AFTER RADIOTHERAPY WITH CARBON IONS: INCIDENCE AND ESTIMATION OF THE RELATIVE BIOLOGICAL EFFECTIVENESS BY THE LOCAL EFFECT MODEL INGMAR SCHLAMPP,* CHRISTIAN P. KARGER, PH.D.,y OLIVER JA¨KEL, PH.D.,yx MICHAEL SCHOLZ, PH.D.,z BERND DIDINGER, M.D.,* ANNA NIKOGHOSYAN, M.D.,* ANGELIKA HOESS, M.SC.,* MICHAEL KRA¨MER, PH.D.,z LUTZ EDLER, PH.D.,** JU¨RGEN DEBUS, M.D., PH.D.,* { AND DANIELA SCHULZ-ERTNER, M.D.* *Department of Radiation Oncology, University of Heidelberg, Germany; yDepartment of Medical Physics in Radiation Oncology, German Cancer Research Center (DKFZ) Heidelberg, Germany; zDepartment of Biophysics, GSI, Darmstadt, Germany; {Radiological Institute (Medical Care Unit), Markus Hospital, Frankfurt/Main, Germany; xHeidelberg Ion Beam Therapy Centre of the University Hospital Heidelberg, Germany; and **Department of Biostatistics, German Cancer Research Center (DKFZ), Heidelberg, Germany Purpose: To identify predictors for the development of temporal lobe reactions (TLR) after carbon ion radiation therapy (RT) for radiation-resistant tumors in the central nervous system and to evaluate the predictions of the local effect model (LEM) used for calculation of the biologically effective dose. Methods and Materials: This retrospective study reports the TLR rates in patients with skull base chordomas and chondrosarcomas irradiated with carbon ions at GSI, Darmstadt, Germany, in the years 2002 and 2003. Calculation of the relative biological effectiveness and dose optimization of treatment plans were performed on the basis of the LEM. Clinical examinations and magnetic resonance imaging (MRI) were performed at 3, 6, and 12 months after RT and annually thereafter. Local contrast medium enhancement in temporal lobes, as detected on MRI, was regarded as radiation-induced TLR. Dose-volume histograms of 118 temporal lobes in 59 patients were analyzed, and 16 therapy-associated and 2 patient-associated factors were statistically evaluated for their predictive value for the occurrence of TLR. Results: Median follow-up was 2.5 years (range, 0.3–6.6 years). Age and maximum dose applied to at least 1 cm3 of the temporal lobe (Dmax,V  1 cm3, maximum dose in the remaining temporal lobe volume, excluding the volume 1 cm3 with the highest dose) were found to be the most important predictors for TLR. Dose response curves of Dmax,V  1 cm3 were calculated. The biologically equivalent tolerance doses for the 5% and 50% probabilities to develop TLR were 68.8 ± 3.3 Gy equivalents (GyE) and 87.3 ± 2.8 GyE, respectively. Conclusions: Dmax,V  1 cm3 is predictive for radiation-induced TLR. The tolerance doses obtained seem to be consistent with published data for highly conformal photon and proton irradiations. We could not detect any clinically relevant deviations between clinical findings and expectations based on predictions of the LEM. Ó 2011 Elsevier Inc. Carbon ion radiation therapy, Toxicity, Local effect model (LEM), Chordoma, Chondrosarcoma.

Therapy for radiation-resistant tumors occurring close to the central nervous system has improved since the introduction of new radiation techniques, allowing for a more conformal irradiation of target volumes and simultaneous sparing of adjacent healthy tissue by a steeper dose gradient. For treatment of chordomas and chondrosarcomas, this improvement has been achieved especially by radiotherapy (RT) with particle beams (1–3).

Particle beams using protons and carbon ions provide an inverted depth dose profile and a finite range of the radiation in tissue. Along the path of the particles, the dose increases up to a maximum, the so-called Bragg peak, which is located at a given depth that depends on the beam’s energy. This radiation modality has the capacity to escalate the dose within tumors while sparing organs at risk (1, 2). Protons and carbon ions share certain physical properties, however; carbon ions are distinct such that they offer

Reprint requests to: Daniela Schulz-Ertner, M.D., Radiologisches Institut (MVZ) am Markus Krankenhaus, Wilhelm-Epstein-Straße 4, 60431 Frankfurt am Main, Germany. Tel: (+49) (0)69-95332240; Fax: (+49) (0)69-9533-2554; E-mail: Daniela.Ertner@fkd. info

Presented at the 50th Annual Meeting of American Society for Radiation Oncology, Boston, MA, September 21 - 24, 2008. Conflict of interest: none. Received April 6, 2009, and in revised form March 5, 2010. Accepted for publication March 17, 2010.

INTRODUCTION

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a variable relative biological effectiveness (RBE) that increases from the entrance region toward the Bragg peak (4,5). At the Gesellschaft fu¨r Schwerionenforschung (GSI, Darmstadt, Germany), the RBE is calculated at each voxel within the treatment field by using the local effect model (LEM) (6–9). The model has been tested in animal experiments, but further clinical validation of the model is still needed (5). In order to examine the LEM in terms of clinical doseeffect probabilities, we correlated toxicity data retrospectively for 59 patients treated with carbon ions for skull base chordoma and chondrosarcoma to their respective temporal lobe dose-volume histograms (DVH). The purpose of this study was to identify factors predictive for TLR, to analyze them through dose- and volume-effect models, and to validate the LEM by comparing the results with photon and proton treatment data from the literature. METHODS AND MATERIALS Patient characteristics This retrospective analysis includes all evaluable 59 patients (27 females and 32 males) treated with carbon ion RT for chordomas (40 patients) and low-grade chondrosarcomas (19 patients) of the skull base at GSI within a clinical phase I/II trial from March 2002 to November 2003. All patients were required to receive at least one follow-up examination 3 months after RT, to be included in the analysis. In the same time period, 2 patients were treated at GSI within the clinical phase I/II trial, who were not included in our analysis. One of the nonevaluable patients presented for radiation therapy in a bad general condition. Stabilization could not be obtained during RT, and the patient died before the first follow-up examination scheduled at 3 months. The second patient moved abroad directly after completion of radiation therapy and refused follow-up examinations. Median patient age was 49 years (range, 16–79 years). All patients had macroscopic tumor residuals before RT and had undergone at least one surgical procedure. The responsible ethics committee approved the clinical phase I/II study. All patients gave their written informed consent that the clinical data might be further evaluated later on.

Treatment planning Patients were immobilized by individual head masks, and stereotactic localization of the target point was performed. Slice thickness of planning computed tomography (CT) and magnetic resonance imaging (MRI) scans was 3 mm, and pixel size was 1 mm. After coregistration of MR and CT images, two planning target volumes (PTV) were defined. PTVs were delineated on T1-weighted postgadolinium and T2-weighted fat-saturated MRI sequences. PTV1 included the gross tumor volume, a clinical tumor volume margin that encompassed suspected subclinical disease, based on clinical risk estimation, taking into account surgical and histological reports, MRI findings, anatomic boundaries, and a 1- to 2-mm margin to account for intra- and interfractional motion. PTV2 included a 1- to 2-mm margin beyond the gross tumor volume in order to account for uncertainties in the delivery of the treatment. Temporal lobes and other organs at risk were defined using stereotactically coregistered CT and MR scans. The temporal lobes

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Table 1. RTOG/EORTC late radiation morbidity scoring scheme for the brain Grade 0 1 2 3 4 5

Clinical symptoms None Mild headache, slight lethargy Moderate headache, great lethargy Severe headaches, severe central nervous system dysfunction (partial loss of power or dyskinesia) Seizures or paralysis, coma Death directly related to radiation late effects

were contoured up to their natural anatomical boundaries such as frontal and parietal lobes. Details of treatment planning and irradiation have been described previously (10–12). Treatment planning included a biological plan optimization using TReatment plannIng for Particles (TRIP) software (13–15). Local RBE values were calculated for each voxel, and from there, biologically effective doses (BED) were derived using the LEM introduced by Scholz et al. (6–8, 15). For visualization of the dose distribution, VIRTUal radiOtherapy Simulator (Virtuos) software was used (16,17). Treatment planning aimed at covering the planning target volumes by the 90% isodose line. Dose was delivered over 20 consecutive days, including weekends, using the intensity-controlled raster scan technique (18). After 15 fractions, the target volume was reduced from PTV1 to PTV2. Three different fractionation schedules were accomplished, as follows: (i) 20 x 3.0 Gy equivalents (GyE) (49 patients), (ii) 20 x 3.3 GyE (2 patients), and (iii) 20 x 3.5 GyE (8 patients). Hence, the total doses to PTV2 were 60, 66, and 70 GyE, respectively. Using an a/b value of 2 Gy, these doses corresponded to biologically equivalent doses for a treatment of 2 Gy per fraction of 75 GyE, 87.5 GyE, and 96.2 GyE, respectively. The optic nerves, chiasm, and brain stem were constrained to 54 GyE, corresponding to a biologically equivalent dose of 63 GyE. The position of the patient was verified daily by comparison of orthogonal X-rays and digitally reconstructed radiographs calculated from the planning CT (19).

Follow-up All patients had follow-up examinations with MRI at 3 months after RT, 54 (92%) patients had follow-up examinations with MRI at 6 months and 48 (81%) patients at 12 months. More than half the patients (n = 36 [61%]) had follow-up at 2 years, and 27 (46%) patients received follow-up after 3 years. Follow-up included clinical examination and MRI scans of the head and neck region. Control MRI parameters were kept identical to the MRI parameters used for treatment planning. Patients who developed radiationinduced toxicity were scored according to Common Terminology Criteria for Adverse Events version 3.0 and European Organization for Research and Treatment of Cancer(EORTC)/Radiation Therapy Oncology Group (RTOG) toxicity scoring system (Table 1) (20). Diagnosis of tumor progression, radiation necrosis, and scoring of radiation damage was performed jointly by a radiologist and a radiation oncologist.

Assessment of radiation-induced TLR For the 59 patients included in this study, the T1-weighted postgadolinium MR images of all available follow-up examinations were reevaluated retrospectively by two examiners (I.S. and D.S.). TLR was defined as visible contrast medium (CM) enhancement

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on T1-weighted post-gadolinium MRI within the volume affected by high doses on at least one of the predefined examinations, at least 3 months after RT. To rule out the possibility that the MRI changes were caused by other reasons, such as recurrence of the tumor, careful differential diagnostics were applied. This was achieved by considering complementary MRI sequences and topographic relationships to the brain surface. If a TLR was found, the MRI scan was coregistered with the treatment planning CT, and CM enhancements were delineated to determine the volume and dose distribution within this area in order to describe the characteristics of CM enhancements further. The incidence of the development of TLR after carbon ion RT was determined as the temporal lobe reaction rate (number of postCM-enhanced MR images, based on n = 59 patients) over the individual observation period, as well as at the scheduled time points: 3, 6, and 12 months and annually thereafter. Time to first TLR after RT was evaluated as temporal lobe reaction-free survival time, using the Kaplan-Meier method for censored failure time data. A patient was identified as censored at the time of the last follow-up when he or she was TLR-free at that time.

DVH analysis For analysis of DVHs, it was assumed that the temporal lobes of each patient responded completely independent from each other. DVH analysis was based on the BED distribution within each individual’s entire temporal lobe (n = 118). To obtain comparability within this study, as well as with data from the literature, DVHs were rescaled for a treatment schedule with 2 Gy per fraction, using the linear-quadratic model and an a/b value of 2 Gy for the biological endpoint late toxicity to normal brain tissue (21): D2 ¼ Dx

a=b þ dx a=b þ d2

Here, Dx is the total dose applied with the dose per fraction x, denoted as dx ,and D2 is the isoeffective total dose applied with 2 GyE per fraction. The value of 2 Gy for a/b was selected to obtain consistency with the calculation of the BED by the LEM, which uses the same a/b value. When Dx and dx were set to the prescribed doses, the prescribed doses for a treatment with 2 Gy per fraction resulted in prescribed doses of 75, 87.5 and 96.2 GyE, respectively. Calculation of the biologically equivalent doses did not account for reduced treatment time by including the weekends in the fractionation pattern of carbon ion RT at GSI. Fifteen DVH-based variables were determined for the temporal lobe, including median and mean doses. The dose variables Dmax,V x characterize the maximum dose in the temporal lobe, which was applied to at least a volume of x of the temporal lobe. There were dose variables for the volume x values of 0, 1, 2, 5, and 10 cm3. The variable Dmax,V x characterizes the maximum dose in the remaining volume, excluding the volume x value of 0, 1, 2, 5, or 10 cm3 with the highest doses, respectively. VD > y indicates the volume receiving more than the minimal dose, y, of 50, 60, 70, 75, 80, 85, 90, and 95 GyE, respectively. In the absence of information for weighing the influence of the different DVH parameters, it was decided to use all 15 variables for the predictive analysis, although a high correlation had to be postulated between them. Additionally, the therapy-associated variable-prescribed dose and the patient-related variables age and gender were tested. These three variables were referred to as clinical variables.

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Multivariable analysis for the prediction of TLR A predictive model for TLR was established using the unconditional logistic regression of the TLR rate with a predictive set chosen from the set of 15 DVH-based and three clinical variables. In a preprocessing step, we investigated their correlation structures for 118 temporal lobes for significance of pairwise correlations, using the Spearman rank correlation coefficient; next, we investigated all 15 DVH variables by principal component analysis (PCA) in order to identify clusters of variables of common information. In case of high pairwise correlations of the variables, it was possible to select variables within each group of the PCA from the clinical perspective to achieve a selection of a few variables that were inserted into multivariate analyses. Multivariate analyses were arranged by a final step-down selection procedure in a logistic regression model to determine significant predictive factors. Statistical analysis was performed using SAS/STAT software (22).

Dose response analysis Dose and volume variables, determined as the most predictive for TLR by multivariate analysis, were analyzed in terms of dose and volume response curves. The response variable was defined by classifying each temporal lobe depending on whether changes on T1weighted post-gadolinium MRI occurred or not. Dose and volume response curves were calculated using the nonlinear regression module of Statistica software (23) using the logistic dose response model PðxÞ ¼

eb0 þb1 ,x ; 1 þ eb0 þb1 ,x

where x is the independent dose or volume variable, respectively. The model parameters b0 and b1 are determined by a maximum likelihood-fitting procedure. The values obtained for b0 and b1 were then used to calculate tolerance doses (TD) at different effect probabilities with their respective standard errors obtained from the maximum likelihood estimation. For visualization, the fitted curve and the superior and inferior standard error bounds were plotted together with the empirical incidence rates, x/n (reactions exhibited by x of n temporal lobes), calculated for discretized dose intervals of equal widths of 10 GyE. The dose and volume response curves, however, were calculated based on the individual doses for each patient.

RESULTS Clinical and radiological findings Median follow-up time was 2.5 years (range, 0.3–6.6 years). Eleven patients had follow-up periods of less than 12 months, mostly due to tumor progression or death. Ten of 59 patients developed TLR on MRI. Instances of bilateral TLR were found in 5 of 10 patients. Median latency time until appearance of the first TLR was 1.2 years (0.2–1.9 years) from RT among patients with TLR. The TLR-free survival rate is shown by a Kaplan-Meier estimation (Fig. 1). The actuarial temporal lobe reaction rates were 10.2 % and 28.1 % at 1 and 2 years, respectively. Neurological symptoms related to late radiation damage of the temporal lobe, classified as grade 2 and grade 3 reactions using the EORTC/RTOG scale, were observed only in 2 patients. One of the these patients was a 66-year-old man whose treatment planning MRI showed CM enhancement, which was considered to be related to surgery. Repeated MRI revealed increasing bilateral CM enhancement, expanding

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Fig. 1. Probability for the temporal lobe reaction-free survival (n = 59) is shown. Each censored observation is indicated by a cross.

within several months. The patient was treated with dexamethasone for cerebral edema. The enlargement of the lesion, starting 3 months after RT and enduring for several months, was classified as TLR. Symptoms and signs for this patient were scored as grade 3 reaction on the EORTC/RTOG scale. Another patient, a 33-year-old patient, developed symptoms related to CM enhancement that measured 6.6 cm3. The clinical symptoms were less distinct and therefore were classified as EORTC/RTOG grade 2 reaction. Symptoms improved after symptomatic therapy, and the patient was included in the follow-up. The volumes of CM-enhancing areas were in the range of <1 cm3 (four lobes), 1 to 2 cm3 (four lobes), 2 to 3 cm3 (three lobes), and >3 cm3 (four lobes), respectively. The median size of detected CM enhancements was 2.1 cm3 (range, 0.2–16.0 cm3).

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In general, CM enhancements appeared in areas of the temporal lobe that were directly adjacent to high-dose areas and at least partially included in PTV2, as planning target volumes also contained a small amount of normal tissue due to the inclusion of a safety margin of 1 to 2 mm in the PTV. In all cases, CM enhancement was separated from the hyperintense tumor residuals by a thin fringe marking the dura (Fig. 2). TLR could be observed over a longer period of time. CM enhancements typically started in the white matter. Involvement of the grey matter was seen in more pronounced reactions. At the latest, 1 year after their appearance, all CM enhancements showed no further increase in volume. Six CM enhancements diminished in size after reaching a maximum volume. Six of 10 patients who received a prescribed dose of 87.5 or 96.2 GyE developed TLR. Both of the patients who developed symptomatic lesions belonged to this group. Four of 49 patients receiving 75 GyE developed TLR. Predictive factors Maximum, minimum, and mean values of DVH-based variables are given in Table 2 for volume variables and in Table 3 for maximum dose variables. For the maximum dose to the temporal lobes, the median for all patients was 75 GyE. The median value for all individual median temporal lobe doses was 3.3 GyE (range, 0.3–43.5 GyE). TLR occurred in 6 male and 4 female patients. The median age of these patients was 59 years (range, 30–79 years) and therefore was higher than that of the group of patients without TLR (median, 48 years; range, 16–48 years). In univariate analysis using the Spearman rank correlation coefficient, volume variables (VD>y) and maximum-dose variables (Dmax,V  x) revealed statistically significant pairwise correlation, with correlation coefficients usually larger than

Fig. 2. CM enhancements appear within the temporal lobes (arrow) of a 62-year-old patient on axial (a) and coronal (b) MRI views.

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Table 2. Characteristics of volume variable VD>y Variable value for patients without CM enhancement Volume with dose (GyE)

Variable value for patients with CM enhancement

Median (cm3)

Minimum (cm3)

Maximum (cm3)

Median (cm3)

Minimum (cm3)

Maximum (cm3)

0.0 0.0 0.0 0.0 0.0 0.3 2.0 4.6

0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0

6.2 9.3 12.7 17.2 18.8 19.8 21.6 27.7

0.5 1.5 2.3 3.1 4.0 5.0 7.8 9.7

0.0 0.0 0.0 0.0 0.2 1.4 3.0 5.0

6.2 9.3 12.7 17.2 18.8 19.8 21.6 23.3

> 95 > 90 > 85 > 80 > 75 > 70 > 60 > 50

0.6. Median and mean doses did not show a uniform behavior in pairwise correlation with the other variables. Age was univariately correlated with five of the DVH-based variables. Gender was independent of all other variables. All DVHbased variables, except for the mean dose, were significantly correlated with the appearance of TLR. PCA revealed that a maximum of three clusters of variables (cluster 1, desired dose, all Dmax,V  x , and the two lowest VD>y; cluster 2, VD>y above 70 Gy; and cluster 3, age median and mean doses) explain more than 77.7% of the variation and that these clusters would be only moderately correlated (values for intercluster correlation values were between 0.03 and 0.67). One variable was selected from each class to investigate correlation with the appearance of TLR in a multivariate regression. Since variables were highly correlated within one cluster, variables were selected using clinical considerations. Dmax,V  x qualifies small areas of high dose and was therefore selected to account for steep dose gradients. VD>85 was selected as the volume-effect curve for TLR of VD>85 was expected to meet the axis of the ordinate close to the clinically relevant 5% probability and was chosen to represent dose distributions in highly irradiated temporal lobes, and VD>85 had a high loading (0.893 for and 0.985 for VD>85) within their clusters. Age was preferred in the third cluster to median and mean doses. The variable-prescribed dose was added to the multivariate analysis because of its clinical relevance. As a result, the variables Dmax,V  1 cm3 (cluster 1) and VD>85 GyE (cluster 2), the prescribed dose (cluster 1), and age (cluster 3) were used in a final step-down multivariate logistic regression analysis. The prescribed dose and VD>85 GyE variable were not significant. After omitting them, Dmax,V  1 cm3 (p = 0.001;

OR, 1.066–1.181) and age (p = 0.026; OR 1.006-1.096) were obtained as the best parsimonious predictors of TLR. Dose- and volume-effect model Dose- and volume-effect curves were generated for Dmax,V  1 cm3 and VD>85 GyE. Figure 3a shows the adjusted curve for the variable Dmax,V  1 cm3. The curve shows an increasing effect probability with increasing dose. The tolerance doses TD5 and TD50 were 68.3  3.3 GyE and 87.3  2.8 GyE, respectively. Further tolerance doses for several probability levels are provided in Table 4. The influence of age can be seen by fitting the curves for subgroups, separated by age (Fig. 3b). Comparison of the dose-effect curves for older patients and younger patients revealed a higher radiosensitivity in older patients. For the volume VD>85 GyE, an increasing volume response curve was found (Fig. 4). Only 21 of the investigated temporal lobes included areas that received more than 85 GyE. In 10 of these 21 temporal lobes, TLR were detected. Ninetyseven temporal lobes, among them five with TLR, received doses of less than 85 GyE. As a consequence, the volume -effect curve does not run through the origin of the coordinate system, indicating a 5% probability for the induction of TLR in patients receiving less than 85 GyE. DISCUSSION Radiotherapy with carbon ions gave promising results in cases of patients with chordomas and chondrosarcomas of the skull base, recently. Treatment effectiveness for patients included in the clinical phase I/II study at GSI was published previously (2,3,24). Total doses applied to the patients in this study are comparable to those of previously published proton

Table 3. Characteristics of maximum dose variable Dmax,V  x Variable value for patients without CM enhancement

Variable value for patients with CM enhancement

Variable

Median (GyE)

Minimum (GyE)

Maximum (GyE)

Median (GyE)

Minimum (GyE)

Maximum (GyE)

Dmax;V0cm3 Dmax;V1cm3 Dmax;V2cm3 Dmax;V5cm3 Dmax;V10cm3

75.0 65.1 60.2 48.9 38.1

9.5 5.0 3.5 1.1 0.3

122.2 99.7 98.7 96.8 88.9

98.5 92.9 87.0 69.8 48.1

77.0 72.3 65.7 50.0 36.8

122.2 99.7 98.7 96.8 88.9

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Fig. 3. Dose effect curves for all patients (a) and for two subgroups of patients differing by age (b). Dashed lines indicate the single standard error of the tolerance dose at a given effect probability level. To visualize the underlying data, incident rates were calculated for intervals of 10 GyE and are displayed numerically (number responding/number of irradiated temporal lobes), as well as graphically (circles). Data points are assigned to the mean dose of each 10-GyE interval.

therapy studies, if the doses are recalculated to the same dose per fraction (2). According to Schultheiss et al. (25), late radiation damage to the central nervous system is regarded to be irreversible and progressive. CM enhancement on T1-weighted MRI can also be found in reversible radiation-induced late reactions to the brain. A radiation-induced breakdown of the blood–brain barrier is thought to be responsible for the observed CM enhancements (26). Perifocal edema and demyelination are seen as hyperintense areas on T2-weighted MR images (27). These injured areas are regarded as precursors of radiation necroses (28). Actually, some of the observed lesions continue to develop into brain necroses, while others do not. Therefore, our chosen endpoint is not equivalent to irreversible brain necrosis but also contains transient disruptions of the blood–brain barrier after irradiation. Reversible late radiation damage after heavy ion therapy has most recently been reported by Kishimoto et al. (29). In 6 patients, diminution and complete restitution of CM enhancing areas were observed in our analysis during follow-up. The remaining four lesions observed in our series continued to develop into brain necroses, showing a uniform configuration with CM-enhancing borders and inhomogene-

ously reduced CM enhancement in the center, corresponding to reduced perfusion (28). Latency periods and follow-up The latency period until appearance of late radiation injury is frequently defined as at least 3 months, but periods of several years also have been reported (25). High dose per fraction and an increased LET (linear energy transfer) within the Bragg peak seems to reduce the latency time (5). The median follow-up period of only 2.5 years is regarded as the limiting factor for the power of our study, as this period is probably too short to ensure that all radiation injuries were detected. The incidence of TLR might therefore be

Table 4. Tolerance doses for several effect probability levels for all patients and for two subgroups of patients differing by age Tolerance doses for Dmax;V1cm3 (GyE) Tolerance dose

All patients

Age, <50 years

Age, $50 years

TD5 TD10 TD30 TD50 TD80 TD90 TD95

68.8  3.3 73.5  2.8 82.0  2.4 87.3  2.8 96.0  4.1 101.4  5.0 105.8  5.9

78.1  5.5 81.4  4.6 87.4  3.6 91.2  3.8 97.4  5.0 101.0  6.1 104.3  7.2

64.5  4.7 69.6  3.7 78.7  3.1 84.5  3.6 93.9  5.5 99.4  6.8 104.5  8.1

Fig. 4. Volume-effect curve for the variable VD>85 GyE. Dashed lines indicate the single standard error of the tolerance volume at a given effect probability. To visualize the underlying data, incident rates were calculated for intervals of 0.5 cm3 and are displayed numerically (number responding/number of irradiated temporal lobes) as well as graphically (circles). Data points are assigned to the mean volume of each 0.5-cm3 interval. Temporal lobe reactions after radiotherapy with carbon ions: incidence and estimation of the relative biological effectiveness (RBE) by the local effect model (LEM)

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Table 5. Incidence rates for late radiation injury of the brain relative to the fractionation schedule Prescribed dose Study (ref.)

Fractionation (Gy)

No. of patients

Lee et al. 1998 (31)

12 x 3.8 Gy 14 x 3.8 Gy 12 x 4.2 Gy 24 x 2.5 Gy 33 x 2.0 Gy 24 x 2.5 Gy 24 x 2.5 Gy 17 x 3.5 Gy 20 x 2.0 + 9x 2.5 Gy 20 x 2.0 + 9x 2.5 Gy 16 x 2.5 + 6x 3.5 Gy 8 x 2.5 + 32x 1.6 Gy 37 x1.8 GyE 40 x1.8 GyE 15x3.0 +5 x3.0 GyE 15x3.3 +5 x3.3 GyE 15x3.5 +5 x3.5 GyE

56 11 621 320 141 126 89 53 218 109 212 48 44 52 49 2 8

Lee et al. 2002 (32)

Santoni et al. (33) This study

Total dose (Gy) 45.6 Gy 53.2 Gy 50.4 Gy 60.0 Gy 66.0 Gy 60.0 Gy 60.0 Gy 59.5 Gy 62.5 Gy 62.5 Gy 61.0 Gy 71.2 Gy 66.6 GyE 72.0 GyE 60.0 GyE 66.0 GyE 70.0 GyE

LQED2*

Incidence (%) of radiation injury

66.1 77.1 78.1 67.5 66.0 67.5 67.5 81.8 65.3 65.3 87.0 68.6 63.3 68.4 75.0 87.5 96.2

4.8 9.1 10.1 2.8 0.0 3.2 11.2 24.4 1.4 0.9 1.9 33.3 7.0 13.0 8.1 50.0 62.5

* LQED2 (linear quadratic equivalent dose at 2 Gy per fraction) was calculated assuming an a/b ratio of 2 Gy.

underestimated. However, closer examination showed that the observed TLRs were not related to prolonged follow-up periods. The number of TLRs is therefore regarded to be representative for the study population. The last TLR to appear in our study was observed in a 62-year-old woman after 2.1 years. Influence of patient-associated factors on the development of radiation-induced TLR Age appears to be a significant factor for the development of radiation-induced TLR in our study. Literature data concerning age of patients with respect to effect probability after radiation reveals contradicting results as the age of patients was usually not regarded as a predictive factor for radiation-induced reactions (30-33). The age-associated diseases diabetes and arterial hypertension are believed to be associated with increased sensitivity to radiation therapy (34). These factors were not included in our analysis but might be a possible reason for increased radiation sensitivity of the elderly in our series. Influence of therapy associated factors on the development of TLR In our analysis, a strong correlation between the prescribed dose and the dose to the temporal lobe was seen only for temporal lobes with TLR and not for temporal lobes without TLR. This is mainly because carbon ion RT is a highly conformal RT modality, delivering high doses to tumors, while temporal lobes can be spared in most of the patients. Nevertheless, the factor of prescribed dose was used in several clinical studies investigating radiation sensitivity of normal tissue (31-33). Table 5 summarizes the incidence rates of TLR found in literature for different fractionation schemes. These data demonstrate that similar prescribed doses do not necessarily imply similar effect probabilities.

In the literature, there is only little information available for the correlation of DVH-based parameters with radiation injury to the brain. Debus et al. (34) investigated DVHbased parameters in 365 patients with skull base chordoma and chordosarcoma treated with combined photon and proton RT. They identified the volumes receiving more than 50, 55, or 60 GyE as predictive factors for brainstem toxicity, besides diabetes mellitus and the number of surgical procedures (34). Miyawaki et al. (35) assessed the incidence of radiation injury after proton and carbon ion therapy for head-and-neck tumors in 59 patients. The actuarial rates for the occurrence of radiation-induced brain tissue changes were found to be 20% after 2 years and 39% after 3 years. DVH analysis revealed a significant volume -effect after high-dose RT exposure in this study (35). In the univariate analyses of our study, the importance of volume variables for TLR was also seen, although the variable Dmax,V  1 cm3 was found to be a better predictor in the multivariate analysis. For carbon ion RT at GSI, the largest uncertainty in the specification of the BED to the temporal lobe is related to the uncertainty of the involved RBE model, i.e., the LEM. A reliable calculation of the RBE for the variable Dmax,V  1 cm3 and the endpoint used in this study would require the knowledge of the dose -effect curve for lowLET radiation. Such data, however, are not available in the published literature. Nevertheless, the biologically effective tolerance doses derived from this study can be compared with estimated tolerance doses from the literature. Based on a single patient and using a normal tissue complication probability model, Tatsuzsaki et al. (36) published DVHs for the temporal lobe for photon and proton treatment plans, which have a normal tissue complication probability of less than 5%. The aim of this treatment planning study was to evaluate the impact of setup uncertainty and beam modality

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on target volume coverage. Assuming that the setup uncertainty of 3 mm and the resulting DVH are most comparable to the clinical situation of carbon RT, the value for Dmax,V  1 cm3 could be found to be 70 GyE in case of photons and 72 GyE in case of protons. Both values are close to the calculated TD5 of 68.3  3.3 GyE for the 5% effect probability, based on the DVH factor Dmax,V  1 cm3 (group of all patients, Table 4) found in our analysis. Due to different radiation sensitivities of normal brain tissue and spinal cord, tolerance doses are assumed to be comparable only after applying a correction factor, which may be derived by the quotient of the respective tolerance doses from literature. Tolerance doses were specified by Emami et al. (37) for portions of the spinal cord and for the brain. For irradiation of one-third of the brain, the TD5 was estimated to be 60 Gy. The corresponding TD5 for the spinal cord was found to be 50 Gy. This suggests that the sensitivity of the spinal cord is increased by a factor of 1.2 relative to that of the brain. This factor is also consistent with the ratio of dose constraints we use for treatment planning, which are 54 Gy for the brain and 45 Gy for the spinal cord, respectively. Schultheiss (38) calculated a dose -effect curve for the spinal cord by using clinical data from several publications. That study reported TD5 and TD50 values of 59.3 Gy and 69.4 Gy, respectively. Scaling these doses by the factor of 1.2 for the transition from spinal cord to the brain yields 71.2 Gy as TD5 and 83.3 Gy as TD50, respectively. These values are also in good agreement with the tolerance doses determined in our study (group of all patients [Table 4]), which where 68.8  3.3 GyE for TD5 and 87.3  2.8 GyE for TD50, respectively (agreement within 1 standard error [SE] for TD5 and within 2 SE for TD50). It can therefore be concluded

Volume 80, Number 3, 2011

that the tolerance doses we determined on the basis of the BED are consistent with available data for the brain and scaled data for the spinal cord. Relevance of the LEM The LEM used for biological plan optimization for carbon ion RT at GSI was developed on the basis of cell experiments and was evaluated later on for the brain and the spinal cord in animal experiments with rats (5,39,40). The accuracy of the LEM in predicting the RBE was considered to be clinically acceptable, although the spinal cord experiment with rats suggested an overestimation of the calculated RBE values in the entrance region and an underestimation in the peak region. In contrast to the underestimation in the peak region found in the spinal cord experiment, analysis of the clinical data presented in this study suggests that there is no clinically significant discrepancy between the estimated and observed tolerance doses. Hence, the underlying RBE calculation used for carbon ion RT appears to be suitable to estimate clinical endpoints. It must be noted, however, that this conclusion is based on additional assumptions used for the estimation of the tolerance doses for low-LET irradiation, where no dose -effect curves are available. These estimations include the use of biological models (36) and published tolerance doses for conventional rather than conformal RT (37). Therefore, significant uncertainties may be involved in these estimates. Nevertheless, this analysis increases the confidence that the LEM estimates the RBE values with a clinically acceptable accuracy for the brain and skull base region. The data of this analysis can serve to optimize tumor control and avoid side effects in challenging skull base tumors.

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