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Dose–Volume Relationships Associated With Temporal Lobe Radiation Necrosis After Skull Base Proton Beam Therapy
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International Journal of
Radiation Oncology biology
physics
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Clinical Investigation
DoseeVolume Relationships Associated With Temporal Lobe Radiation Necrosis After Skull Base Proton Beam Therapy Mark W. McDonald, MD,*,y Okechukwu R. Linton, MD, MBA,* and Cynthia S.J. Calley, MAz *Department of Radiation Oncology and zDepartment of Biostatistics, Indiana University School of Medicine, Indianapolis, Indiana; and yIndiana University Health Proton Therapy Center, Bloomington, Indiana Received Apr 18, 2014, and in revised form Sep 29, 2014. Accepted for publication Oct 6, 2014.
Summary Analysis of 66 patients treated with proton therapy for skull base tumors identified doseevolume parameters as the only factor correlated with risk of developing temporal lobe radiation necrosis. After 3 years, a 15% risk of anygrade temporal lobe radiation necrosis can be expected when the absolute volume of a temporal lobe receiving 60 Gy (relative biological effectiveness) (aV60) exceeds > 5.5 cm3, or aV70 > 1.7 cm3.
Purpose: We evaluated patient and treatment parameters correlated with development of temporal lobe radiation necrosis. Methods and Materials: This was a retrospective analysis of a cohort of 66 patients treated for skull base chordoma, chondrosarcoma, adenoid cystic carcinoma, or sinonasal malignancies between 2005 and 2012, who had at least 6 months of clinical and radiographic follow-up. The median radiation dose was 75.6 Gy (relative biological effectiveness [RBE]). Analyzed factors included gender, age, hypertension, diabetes, smoking status, use of chemotherapy, and the absolute dose:volume data for both the right and left temporal lobes, considered separately. A generalized estimating equation (GEE) regression analysis evaluated potential predictors of radiation necrosis, and the median effective concentration (EC50) model estimated doseevolume parameters associated with radiation necrosis. Results: Median follow-up time was 31 months (range 6-96 months) and was 34 months in patients who were alive. The Kaplan-Meier estimate of overall survival at 3 years was 84.9%. The 3-year estimate of any grade temporal lobe radiation necrosis was 12.4%, and for grade 2 or higher radiation necrosis was 5.7%. On multivariate GEE, only doseevolume relationships were associated with the risk of radiation necrosis. In the EC50 model, all dose levels from 10 to 70 Gy (RBE) were highly correlated with radiation necrosis, with a 15% 3-year risk of any-grade temporal lobe radiation necrosis when the absolute volume of a temporal lobe receiving 60 Gy (RBE) (aV60) exceeded 5.5 cm3, or aV70 > 1.7 cm3. Conclusions: Doseevolume parameters are highly correlated with the risk of developing temporal lobe radiation necrosis. In this study the risk of radiation necrosis
Reprint requests to: Mark W. McDonald, MD, Indiana University Health Proton Therapy Center, 2425 N Milo B Sampson Lane, Bloomington, IN 47408-1398. Tel: (812) 349-5074; E-mail: [email protected] NotedAn online CME test for this article can be taken at http:// astro.org/MOC. Int J Radiation Oncol Biol Phys, Vol. 91, No. 2, pp. 261e267, 2015 0360-3016/$ - see front matter Ó 2015 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.ijrobp.2014.10.011
Conflict of interest: none. Supported in part by the Jesse N. Jones, III, Memorial Fund for Head and Neck Cancer Research at the Indiana University Melvin and Bren Simon Cancer Center.
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increased sharply when the temporal lobe aV60 exceeded 5.5 cm3 or aV70 > 1.7 cm3. Treatment planning goals should include constraints on the volume of temporal lobes receiving higher dose. The EC50 model provides suggested doseevolume temporal lobe constraints for conventionally fractionated high-dose skull base radiation therapy. Ó 2015 Elsevier Inc.
Introduction Temporal lobe radiation necrosis is a well-recognized and potentially lethal complication of skull base and central nervous systemedirected radiation therapy (1). Total radiation dose, fraction size, and treatment volume are recognized factors associated with the development of radiation necrosis (2). The incidence of brain radiation necrosis appears to increase as doses exceed 54 Gy in conventional fractionation (3). Many skull base tumors require higherdose radiation therapy for optimal local control, resulting in at least a portion of the temporal lobes necessarily exposed to high doses of radiation. We sought to analyze the doseevolume relationships in relation to development of temporal lobe radiation necrosis in a series of patients receiving proton therapy for skull base malignancies.
Methods and Materials Institutional review board approval was obtained for this retrospective analysis. Inclusion criteria were patients treated with proton therapy for base-of-skull chordoma, chondrosarcoma, adenoid cystic carcinoma, or nasopharyngeal or sinonasal malignancy between 2004 and 2012 at the now closed Indiana University Health Proton Therapy Center, with a minimum of 6 months of clinical and radiographic follow-up after completion of radiation. Patients treated with palliative intent and patients who had received prior radiation therapy were excluded. Patient factors analyzed were gender, age, hypertension, diabetes mellitus, smoking status, and clival-based tumors versus noneclival tumor locations. Treatment variables analyzed were whether the temporal lobes were contoured prospectively at the time of treatment planning or retrospectively, the use of concurrent chemotherapy, total prescribed radiation dose, dose per fraction, number of treatment fields, number of fields treated per day, and absolute and percentage of dose delivered via through and patch beam arrangements. Doseevolume histogram (DVH) data were exported from the treatment planning system for each patient for both the right and left temporal lobes using the absolute volume of each temporal lobe and the absolute volume (aV) of temporal lobe receiving 10 to 70 Gy (relative biological effectivess [RBE]) in 10 Gy (RBE) increments (ie aV10, aV20, etc). Patients had been treated with 3-dimensional conformal proton radiation therapy using uniform scanning beam delivery, which delivers a uniform spread-out Bragg peak across each field (4). Brass apertures and Lucite range
compensators were used. Treatment optimization involved multiple iterative adjustments in individual field shape and design to achieve the desired target coverage and normal tissue sparing. Details of our proton beam delivery system have been previously published (5). Patient immobilization included an alpha-cradle and thermoplastic mask. Treatment delivery was image guided with orthogonal x-rays and a robotic patient positioner with 6 of freedom (6). Proton dose is expressed in Gy (RBE) with an RBE of 1.1 compared to megavoltage x-ray therapy. Since 2010, both temporal lobes are routinely contoured in patients treated for skull base tumors, although no hard constraints were placed on these structures. Those not contoured at original planning were retrospectively contoured, and all patients’ temporal lobes were contoured by the same physician (MM). Temporal lobe contours were guided by coregistered T1 weighted post-contrast magnetic resonance imaging (MRI). The anatomy of the temporal lobe is well described (7). The medial border of the temporal lobe contour specifically excluded the cavernous sinus. The cranial border is defined by the lateral fissure, the localization of which was augmented by coronal MRI. Because the posterior border with the occipital lobe is more subjective, we recorded the absolute volume of temporal lobe in cubic centimeters (cm3) rather than relative percentage of structure volume. Patient follow-up included MRI of the brain every 6 months. Follow-up time was measured from the completion date of radiation treatment until the date of last patient evaluation. The diagnosis of temporal lobe radiation necrosis was made by the development of new radiographic changes of T1 enhancement on MRI with surrounding T2 edema, with or without accompanying clinical symptoms, and graded according to the Common Terminology Criteria for Adverse Events (version 4.0) from the National Cancer Institute. MRI diffusion, perfusion, or spectroscopy studies were often used to characterize the abnormalities (8), and only 1 patient had pathologic confirmation of radiation necrosis. The date of the MRI showing these changes was used as the date of onset of radiation necrosis and the Kaplan-Meier method was used to estimate the incidence of temporal lobe radiation necrosis. The first MRI demonstrating radiation necrosis was coregistered to the treatment plan and the volume of enhancing abnormality contoured. An independent-samples t test was used to compare the mean values of the aV40-70 for patients with and without radiation necrosis and to compare the volume of radiation necrosis and the minimum, maximum, mean, and epicenter dose between those with asymptomatic grade 1 radiation necrosis and those with grade 2 or higher radiation necrosis.
Volume 91 Number 2 2015 Table 1
Doseevolume relationship for temporal lobe necrosis
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Patient characteristics No radiation necrosis (nZ54)
Radiation necrosis (nZ12)
P value
53.5 15-78 29/54 (53.7%) 25/54 (46.3%) 16/54 (29.6%) 8/54 (14.8%) 8/54 (14.8%) 18/54 (33.3%) 7/54 (13.0%) 16/54 (29.6%) 75.6 Gy (RBE) 62-79.2 Gy (RBE)
48.5 31-68 4/12 (33.3) 8/12 (66.7%) 1/12 (8.3%) 0/12 (0%) 1/12 (8.3%) 6/12 (50%) 0/12 (0%) 3/12 (25%) 73.8 Gy (RBE) 70.2-79.2 Gy (RBE)
.74
50 4 10 5-19 2 1-6 21.8 Gy (RBE) 0-75.6 Gy (RBE) 29.6%
10 2 11 4-15 2 2-5 13.5 Gy (RBE) 0-79.2 Gy (RBE) 17.5%
Median age, y Age range, y Male Female Hypertension Diabetes Smoking Clival-based tumor Concurrent chemotherapy Temporal lobes prospectively contoured Median total prescribed dose Prescribed dose range Dose per fraction 1.8 Gy (RBE) 2 Gy (RBE) Median no. of treatment fields Total no. of treatment fields Median no. of fields treated per day No. of fields treated per day Median dose delivered by through-patch techniques Range of dose delivered by through-patch techniques Median percentage of total dose delivered by through-patch techniques Percentage of patients with >50% of total dose delivered by through-patch techniques Mean aV40 Mean aV50 Mean aV60 Mean aV70
24.1% (13/54) 10.3 cm3 6.8 cm3 3.9 cm3 1.6 cm3
16.7% (2/12) 20.4 cm3 14.8 cm3 9.4 cm3 4.7 cm3
.20 .16 .33 >.99 .33 .33 >.99 .64
.30 .68 .40 .61 0.59 .72 <.001 <.001 <.001 <.001
Abbreviations: aV Z absolute volume of temporal lobes exposed to dose in Gy (RBE); RBE Z relative biological effectiveness.
Generalized estimating equation (GEE) models were used to test for associations between each variable and the development of radiation necrosis. GEE adjusts for the within-subject correlation due to repeated measures (right and left temporal lobes) on the same subject. A multivariable GEE model was fit that included the variables of patient age, gender, hypertension, clival versus nonclival tumors, prospective or retrospective contouring of the temporal lobe, and dose variables. The median effective concentration (EC50) dosee response model (9) was used to analyze the DVH data for the temporal lobes: YZTOP 1 þ 10^ ½ðlogEC50 XÞ)Hillslope where Y is the actual risk of temporal lobe radiation necrosis, expressed as a percentage of the maximal risk; TOP is the maximal risk (the minimal risk is 0); Hillslope is the steepness of the curve; and logEC50 represents the irradiated temporal lobe volume in which 50% of the maximal risk is observed. The model was applied to the temporal lobe aV10, aV20, aV30, aV40, aV50, aV60, and aV70. The Spearman rank correlation coefficient was used to assess for correlation between lower-dose (aV30 and aV40) and higher-dose volumes (aV70).
Results A total of 66 patients and 131 temporal lobes were included in the analysis. One patient treated for an orbital tumor received radiation only to the ipsilateral underlying temporal lobe. Patient characteristics are listed in Table 1. The median prescribed dose was 75.6 Gy (RBE) (range, 62 -79.2 Gy [RBE], interquartile range 72-77.4 Gy [RBE]). The median follow-up time for all patients was 31 months (range, 6-96 months) and 34 months in those patients who were alive at last follow-up (range, 7-96 months). The Kaplan-Meier estimate of overall survival at 3 years was 84.9% (95% confidence interval [CI] Z 74.9%-94.9%). The estimate of the incidence of any grade temporal lobe radiation necrosis at 3 years was 12.4% (95% CI Z 6.1%-18.7%). The estimate of grade 2 (symptomatic) or higher radiation necrosis at 3 years was 5.7% (95% CI Z 1.2%-10.2%). Radiation necrosis developed in 16 temporal lobes in 12 patients, with 4 patients developing bitemporal radiation necrosis. The median time from completion of radiation therapy until development of radiation necrosis was 21 months (range, 8-51 months). The median follow-up time after diagnosis of radiation necrosis in these 12 patients was an additional 12.5 months (range, 5-35 months).
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Fig. 1. An example of radiation necrosis in a patient treated for a clival chordoma. The left panel shows the presenting magnetic resonance imaging (MRI) with a clival and suprasellar T2 hyperintense tumor with bilateral cavernous sinus involvement and significant brainstem compression. The middle 2 panels show an axial and coronal image of the foci of asymptomatic radiation necrosis that developed in the left temporal lobe. MRI perfusion and spectroscopy were supportive of a diagnosis of radiation necrosis. Encephalomacia is noted in the right temporal lobe from prior surgery. The right panel shows the prior radiation dose superimposed on the MRI demonstrating radiation necrosis, which is transected by the prior 95% isodose line of therapy. Of note, based on its location at the time of treatment planning MRI, the maximum surface dose to the brainstem was 63 Gy (relative biological effectiveness). The patient remains without evidence of recurrent disease 3 years after radiation therapy. After initiation of pentoxifylline and Vitamin E, the area resolved on follow-up MRI. Seven patients developed asymptomatic radiographic changes in 8 temporal lobes (grade 1 radiation necrosis). One patient had unilateral radiation necrosis with symptoms requiring transient steroid use (grade 2). Three patients with symptomatic radiation necrosis in 5 temporal lobes required medical intervention with hyperbaric oxygen therapy, seizure medication, or bevacizumab (grade 3). One patient had symptomatic bitemporal radiation necrosis requiring transient hospitalization and protracted medical management (grade 4). An example of a patient developing radiation necrosis is shown in Figure 1. There were no statistically significant differences in analyzed patient, medical, social or treatment factors between those patients who developed radiation necrosis and those who did not (Table 1). On GEE multivariate analysis, temporal lobe maximum dose and all aV dose levels were statistically significantly associated with the development of radiation necrosis. A comparison of the mean DVH of temporal lobes with and without subsequent radiation necrosis is shown in Figure 2. Table 2 outlines radiation dose details in the patients who developed radiation necrosis. Table 3 compares necrosis volume and dose parameters between those patients with asymptomatic versus symptomatic radiation necrosis. In the EC50 model, all dose levels from 10 to 70 Gy (RBE) were highly correlated with development of radiation necrosis, although the model could not fit a curve at the 20-Gy (RBE) dose level. The EC50 model estimates a 15% 3-year risk of any-grade temporal lobe radiation necrosis when the temporal lobe aV40 > 16.5 cm3, aV50 > 9.6 cm3, aV60 > 5.5 cm3, or aV70 > 1.7 cm3 (Table 4, Figs. 3 and 4). The Spearman rank-order correlation showed a positive correlation between aV70 and both aV30 and aV40, which was statistically significant (rs Z 0.77 for
aV30, 0.82 for aV40, both P<.01). Figure 5 illustrates the relationship between aV40 and aV70 in patients with and without subsequent radiation necrosis. There were no cases of radiation necrosis noted in temporal lobes where the aV70 was <0.1 cm3.
Discussion Many of the data on radiation necrosis come from series of patients treated with older techniques in which relatively
Fig. 2. Mean doseevolume histogram for temporal lobes with and without radiation necrosis (any grade). The 95% confidence intervals for the mean of each curve are shown by the dashed lines.
Volume 91 Number 2 2015 Table 2
Doseevolume relationship for temporal lobe necrosis
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Doseevolume information to area of radiation necrosis in patients who developed radiation necrosis
Case
Temporal lobe Volume of radiation necrosis (cm3) Minimum dose
1 2 3 4 5 6 7 8 9 9 10 10 11 11 12 12
Left Right Right Left Right Left Left Right Left Right Left Right Left Right Left Right
0.4 0.58 1 1.2 4.4 6 10.2 15.2 0.05 0.15 0.42 0.16 0.43 0.53 0.40 3.83
Maximum dose
55.2 58.7 53.6 57.6 44.4 44.3 28.5 22.2 57.4 70.3 63.6 66.4 63.3 54.7 49.5 47.8
72.1 73.5 82.4 86.5 85.9 73.9 79 78.7 73.1 71.7 85.6 82.1 75.8 73.8 80.9 80.9
Mean dose Epicenter dose 66.0 70.8 68.2 77.6 70.4 67.8 68.8 66.1 65.0 71.3 77.1 76.7 72.3 66.9 71.9 71.3
63 72.1 73.1 82.3 74.5 72.8 72.2 74.0 72.8 71.7 79.7 77.7 73.3 66.9 76.3 72.2
Grade 1 1 1 3 3 1 1 2 1 1 4 4 1 1 3 3
Dose is given in Gy (relative biological effectiveness).
large volumes of brain were uniformly treated. Fewer data are available regarding the incidence of temporal lobe radiation necrosis in patients treated with complex dose distributions such as are achieved with intensity-modulated radiation therapy and particle therapy, or in patients treated to doses >60 Gy in conventional fractionation. The Quantitative Analysis of Normal Tissue Effects in the Clinic review suggests that partial brain irradiation to 72 Gy in standard fractionation is associated with a 5% risk of symptomatic radiation necrosis, but provides no specific guidance on doseevolume parameters (2). Santoni et al reported a 5-year estimated 13.2% risk of temporal lobe radiation necrosis (90% symptomatic) from a series of 96 patients receiving 64.8-72 Gy (RBE) of combined photoneproton radiation for skull base tumors, but identified no treatment parameters associated with radiation necrosis (10). Pehlivan et al reported an analysis of temporal lobe toxicity after spot scanning proton therapy in 62 patients treated for skull base tumors. A planning constraint of 74 Gy to 2 cm3 was suggested (11), which fits well with our model in which the risk of radiation necrosis appears to rise sharply with an increasing volume exposed to 70 Gy. Su et al reported an analysis of dosimetric factors associated with development of temporal lobe necrosis in a
series of 259 patients with nasopharyngeal cancer treated to 68 Gy with IMRT. Temporal lobe radiation necrosis was observed at a crude incidence of 15.4% at 5 years, and multivariate analysis showed a strong correlation between the absolute volume of temporal lobe receiving 40 Gy and the development of radiation necrosis (12). Their data suggest a 15% crude rate of temporal lobe radiation necrosis when the temporal lobe aV40 exceeds 10 cm3, similar to our own data set in which aV40 > 16.5 cm3 was associated with a 15% estimated risk of radiation necrosis. There is an association between lower dose levels such as aV40 and high dose levels such that an increasing volume receiving a higher dose necessarily means that an increasing volume is also exposed to a lower dose. This conundrum of multicollinearity among dose levels has been discussed in detail elsewhere and confounds identification of what independent volume effect may arise from the lower-dose regions (13, 14). However, given the increasingly complex dose distributions that may be achieved with current and improving radiation treatment modalities, low and high dose levels to organs at risk are not necessarily highly correlated in every case. Barring more conclusive
Table 4 Doseevolume levels associated with 3-year risk of any-grade temporal lobe radiation necrosis Table 3 Mean doseevolume information to area of radiation necrosis by grade of radiation necrosis Grade 1/asymptomatic Grade 2 or higher P value Volume, cm3 Minimum dose Maximum dose Mean dose Epicenter dose
2.15 54.0 75.0 68.6 70.9
3.66 50.2 82.9 73.0 76.7
Dose is given in Gy (relative biological effectiveness).
.51 .58 <.01 .02 <.01
Risk level
aV40
aV50
aV60
aV70
10% 15% 20% 30% 40% 50%
16.5 16.5 16.6 16.7 16.7 16.8
9.0 9.6 10.1 10.8 11.4 12.2
5.1 5.5 5.8 6.3 6.8 7.2
1.2 1.7 2.0 2.5 3.1 3.9
Abbreviations: aV Z absolute volume of temporal lobes exposed to dose in Gy (RBE); RBE Z relative biological effectiveness. Volume is expressed in cubic centimeters (cm3).
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Fig. 3. Median effective concentration volume risk analysis for temporal lobe radiation necrosis (any grade). Each curve is labeled for the absolute volume of temporal lobe exposed to a dose level in Gy (relative biological effectiveness). data, it seems prudent to incorporate doseevolume optimization goals at more than 1 dose level in an effort to bend the overall shape of the organ-at-risk DVH curve rather than merely constrain its intersection at a single-point dose. Animal data for the partoid gland (15) and spinal cord (16) have suggested that exposing larger volumes of adjacent organ to a lower-dose “bath” of radiation lowers the
Fig. 4. Absolute doseeabsolute volume histogram curve predicted to have a 15% risk of any grade temporal lobe radiation necrosis.
International Journal of Radiation Oncology Biology Physics
Fig. 5. Semilog graph of the correlation between the absolute volume (aV) of temporal lobe receiving 40 Gy (y axis) and 70 Gy (x axis) for temporal lobes with and without subsequent development of any-grade radiation necrosis. Spearman rank-order correlation coefficient between aV40 and aV70 was 0.82, P<.01. threshold for toxicity when a small subvolume is exposed to a higher dose. The mechanism of this effect is uncertain, but it has been proposed that the recovery of portions of an organ exposed to higher doses of radiation may be delayed or stymied by depletion of progenitor cells in adjacent tissues exposed to lower-dose radiation. Potentially, an increasing volume of surrounding parenchyma exposed to low and moderate doses of radiation may have an effect on microvasculature and cellular environment that could enhance the likelihood of developing necrosis in the portion of the brain exposed to higher dose. Our data suggest a dose relationship in the development of symptomatic radiation necrosis, also suggested by others (11). It may be that higher doses were associated with symptoms due to greater edema or eventual progression to a larger area of radiation necrosis, but these potential associations could not be explored in this analysis. Because our patients were followed up relatively frequently with MRI, asymptomatic parenchymal brain changes consistent with radiation necrosis were detected that would otherwise be subclinical. This should be kept in mind when comparing the rate of radiation necrosis with older series in which MRI was not a routine component of surveillance or used only when concerning clinical symptoms developed. Although half of the patients in our series who developed radiation necrosis had asymptomatic grade 1 radiation necrosis, we believe these cases are still clinically relevant. In our experience, the development of even
Volume 91 Number 2 2015
asymptomatic MRI changes can prompt diagnostic confusion with those unfamiliar with this potential sequela of skull base radiation therapy, patient anxiety, and sometimes therapeutic intervention because of concern for potential symptoms with potential future progression. Only 10.6% of the patients in this series received concurrent chemotherapy, which may reduce the ability to detect a potential sensitizing effect of concurrent chemotherapy on the development of radiation necrosis. There was no apparent correlation between other patient factors and development of radiation necrosis. Other factors that are not evaluated here include how the range uncertainties in particle therapy may affect volume assessments and to what extent the higher relative biological effect at the terminal range of a proton beam may influence the risk of radiation necrosis. Our findings have not yet been tested in an independent data set to assess their validity or to test their generalizability to other treatment modalities or practices. In our series, pathologic confirmation of radiation necrosis was obtained in only 1 patient. However, the radiographic picture, which normally included MRI diffusion, perfusion, or spectroscopy, was highly suggestive of radiation necrosis (17), and the foci of necrosis correlated well with the radiation dose distribution. Substantial follow-up was available in these patients after diagnosis of radiation necrosis to confirm that the clinical and radiographic course was consistent with radiation necrosis rather than parenchymal brain metastases, infection, or a secondary glioma. The median follow-up time for patients remaining alive is more than a year longer than the median time interval to development of radiation necrosis in this cohort; however, delayed radiation necrosis is well described, and with longer follow-up time a higher incidence of radiation necrosis may be seen. Although these data suggest doseevolume constraints for treatment planning, the importance of adequate target coverage must be kept in mind. Terahara et al have shown a correlation between local control of skull base chordomas and both the minimum target dose and a lower dose to the coolest 5 cm3 of the target (18). Given the critical importance of target coverage in disease control for these patients, we believe that tumor coverage should not be compromised in an effort to meet temporal lobe constraints in the same way as it may be to meet dose constraints to the brainstem and optic apparatus, but rather that these proposed temporal lobe dose constraints should represent a secondary goal of plan optimization achieved through iterative plan design rather than compromises to tumor coverage.
Conclusions Doseevolume parameters are highly correlated with the risk of developing temporal lobe radiation necrosis. The risk of radiation necrosis increased sharply when the temporal lobe aV60 exceeded 5.5 cm3 or aV70 > 1.7 cm3.
Doseevolume relationship for temporal lobe necrosis
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Treatment planning goals should include constraints on the volume of temporal lobes receiving higher dose. The EC50 model provides suggested doseevolume temporal lobe constraints for conventionally fractionated high-dose skull base radiation therapy.
References 1. Dropcho EJ. Neurotoxicity of radiation therapy. Neurol Clin 2010;28: 217-234. 2. Lawrence YR, Li XA, el Naqa I, et al. Radiation dose-volume effects in the brain. Int J Radiat Oncol Biol Phys 2010;76(3 Suppl): S20-S27. 3. Marks JE, Baglan RJ, Prassad SC, et al. Cerebral radionecrosis: Incidence and risk in relation to dose, time, fractionation and volume. Int J Radiat Oncol Biol Phys 1981;7:243-252. 4. Anferov VA. Scan pattern optimization for uniform proton beam scanning. Med Phys 2009;36:3560-3567. 5. Farr JB, Mascia AE, Hsi WC, et al. Clinical characterization of a proton beam continuous uniform scanning system with dose layer stacking. Med Phys 2008;35:4945-4954. 6. Allgower CE, Schreuder AN, Farr JB, et al. Experiences with an application of industrial robotics for accurate patient positioning in proton radiotherapy. Int J Med Robotics Comput Assist Surg 2007;3: 72-81. 7. Kiernan JA. Anatomy of the temporal lobe. Epilepsy Res Treat 2012; 176157. http://dx.doi.org/10.1155/2012/176157. 8. Verma N, Cowperthwaite MC, Burnett MG, et al. Differentiating tumor recurrence from treatment necrosis: A review of neurooncologic imaging strategies. Neuro Oncol 2013;15:515-534. 9. Andolino DL, Forquer JA, Henderson MA, et al. Chest wall toxicity after stereotactic body radiotherapy for malignant lesions of the lung and liver. Int J Radiat Oncol Biol Phys 2011;80:692-697. 10. Santoni R, Liebsch N, Finkelstein DM, et al. Temporal lobe (TL) damage following surgery and high-dose photon and proton irradiation in 96 patients affected by chordomas and chondrosarcomas of the base of the skull. Int J Radiat Oncol Biol Phys 1998;41:59-68. 11. Pehlivan B, Ares C, Lomax AJ, et al. Temporal lobe toxicity analysis after proton radiation therapy for skull base tumors. Int J Radiat Oncol Biol Phys 2012;83:1432-1440. 12. Su SF, Huang SM, Han F, et al. Analysis of dosimetric factors associated with temporal lobe necrosis (TLN) in patients with nasopharyngeal carcinoma (NPC) after intensity modulated radiotherapy. Radiat Oncol 2013;8:17. 13. Michalski JM, Gay H, Jackson A, et al. Radiation dose-volume effects in radiation-induced rectal injury. Int J Radiat Oncol Biol Phys 2010; 76(3 Suppl):S123-S129. 14. Bentzen SM, Constine LS, Deasy JO, et al. Quantitative Analyses of Normal Tissue Effects in the Clinic (QUANTEC): An introduction to the scientific issues. Int J Radiat Oncol Biol Phys 2010;76(3 Suppl): S3-S9. 15. Van Luijk P, Faber H, Schippers JM, et al. Bath and shower effects in the rat parotid gland explain increased relative risk of parotid gland dysfunction after intensity-modulated radiotherapy. Int J Radiat Oncol Biol Phys 2009;74:1002-1005. 16. Bijl HP, van Luijk P, Coppes RP, et al. Influence of adjacent low-dose fields on tolerance to high doses of protons in rat cervical spinal cord. Int J Radiat Oncol Biol Phys 2006;64:1204-1210. 17. Shah R, Vattoth S, Jacob R, et al. Radiation necrosis in the brain: Imaging features and differentiation from tumor recurrence. Radiographics 2012;32:1343-1359. 18. Terahara A, Niemierko A, Goitein M, et al. Analysis of the relationship between tumor dose inhomogeneity and local control in patients with skull base chordoma. Int J Radiat Oncol Biol Phys 1999;45:351-358.
International Journal of
Radiation Oncology biology
physics
www.redjournal.org
Clinical Investigation
DoseeVolume Relationships Associated With Temporal Lobe Radiation Necrosis After Skull Base Proton Beam Therapy Mark W. McDonald, MD,*,y Okechukwu R. Linton, MD, MBA,* and Cynthia S.J. Calley, MAz *Department of Radiation Oncology and zDepartment of Biostatistics, Indiana University School of Medicine, Indianapolis, Indiana; and yIndiana University Health Proton Therapy Center, Bloomington, Indiana Received Apr 18, 2014, and in revised form Sep 29, 2014. Accepted for publication Oct 6, 2014.
Summary Analysis of 66 patients treated with proton therapy for skull base tumors identified doseevolume parameters as the only factor correlated with risk of developing temporal lobe radiation necrosis. After 3 years, a 15% risk of anygrade temporal lobe radiation necrosis can be expected when the absolute volume of a temporal lobe receiving 60 Gy (relative biological effectiveness) (aV60) exceeds > 5.5 cm3, or aV70 > 1.7 cm3.
Purpose: We evaluated patient and treatment parameters correlated with development of temporal lobe radiation necrosis. Methods and Materials: This was a retrospective analysis of a cohort of 66 patients treated for skull base chordoma, chondrosarcoma, adenoid cystic carcinoma, or sinonasal malignancies between 2005 and 2012, who had at least 6 months of clinical and radiographic follow-up. The median radiation dose was 75.6 Gy (relative biological effectiveness [RBE]). Analyzed factors included gender, age, hypertension, diabetes, smoking status, use of chemotherapy, and the absolute dose:volume data for both the right and left temporal lobes, considered separately. A generalized estimating equation (GEE) regression analysis evaluated potential predictors of radiation necrosis, and the median effective concentration (EC50) model estimated doseevolume parameters associated with radiation necrosis. Results: Median follow-up time was 31 months (range 6-96 months) and was 34 months in patients who were alive. The Kaplan-Meier estimate of overall survival at 3 years was 84.9%. The 3-year estimate of any grade temporal lobe radiation necrosis was 12.4%, and for grade 2 or higher radiation necrosis was 5.7%. On multivariate GEE, only doseevolume relationships were associated with the risk of radiation necrosis. In the EC50 model, all dose levels from 10 to 70 Gy (RBE) were highly correlated with radiation necrosis, with a 15% 3-year risk of any-grade temporal lobe radiation necrosis when the absolute volume of a temporal lobe receiving 60 Gy (RBE) (aV60) exceeded 5.5 cm3, or aV70 > 1.7 cm3. Conclusions: Doseevolume parameters are highly correlated with the risk of developing temporal lobe radiation necrosis. In this study the risk of radiation necrosis
Reprint requests to: Mark W. McDonald, MD, Indiana University Health Proton Therapy Center, 2425 N Milo B Sampson Lane, Bloomington, IN 47408-1398. Tel: (812) 349-5074; E-mail: [email protected] NotedAn online CME test for this article can be taken at http:// astro.org/MOC. Int J Radiation Oncol Biol Phys, Vol. 91, No. 2, pp. 261e267, 2015 0360-3016/$ - see front matter Ó 2015 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.ijrobp.2014.10.011
Conflict of interest: none. Supported in part by the Jesse N. Jones, III, Memorial Fund for Head and Neck Cancer Research at the Indiana University Melvin and Bren Simon Cancer Center.
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increased sharply when the temporal lobe aV60 exceeded 5.5 cm3 or aV70 > 1.7 cm3. Treatment planning goals should include constraints on the volume of temporal lobes receiving higher dose. The EC50 model provides suggested doseevolume temporal lobe constraints for conventionally fractionated high-dose skull base radiation therapy. Ó 2015 Elsevier Inc.
Introduction Temporal lobe radiation necrosis is a well-recognized and potentially lethal complication of skull base and central nervous systemedirected radiation therapy (1). Total radiation dose, fraction size, and treatment volume are recognized factors associated with the development of radiation necrosis (2). The incidence of brain radiation necrosis appears to increase as doses exceed 54 Gy in conventional fractionation (3). Many skull base tumors require higherdose radiation therapy for optimal local control, resulting in at least a portion of the temporal lobes necessarily exposed to high doses of radiation. We sought to analyze the doseevolume relationships in relation to development of temporal lobe radiation necrosis in a series of patients receiving proton therapy for skull base malignancies.
Methods and Materials Institutional review board approval was obtained for this retrospective analysis. Inclusion criteria were patients treated with proton therapy for base-of-skull chordoma, chondrosarcoma, adenoid cystic carcinoma, or nasopharyngeal or sinonasal malignancy between 2004 and 2012 at the now closed Indiana University Health Proton Therapy Center, with a minimum of 6 months of clinical and radiographic follow-up after completion of radiation. Patients treated with palliative intent and patients who had received prior radiation therapy were excluded. Patient factors analyzed were gender, age, hypertension, diabetes mellitus, smoking status, and clival-based tumors versus noneclival tumor locations. Treatment variables analyzed were whether the temporal lobes were contoured prospectively at the time of treatment planning or retrospectively, the use of concurrent chemotherapy, total prescribed radiation dose, dose per fraction, number of treatment fields, number of fields treated per day, and absolute and percentage of dose delivered via through and patch beam arrangements. Doseevolume histogram (DVH) data were exported from the treatment planning system for each patient for both the right and left temporal lobes using the absolute volume of each temporal lobe and the absolute volume (aV) of temporal lobe receiving 10 to 70 Gy (relative biological effectivess [RBE]) in 10 Gy (RBE) increments (ie aV10, aV20, etc). Patients had been treated with 3-dimensional conformal proton radiation therapy using uniform scanning beam delivery, which delivers a uniform spread-out Bragg peak across each field (4). Brass apertures and Lucite range
compensators were used. Treatment optimization involved multiple iterative adjustments in individual field shape and design to achieve the desired target coverage and normal tissue sparing. Details of our proton beam delivery system have been previously published (5). Patient immobilization included an alpha-cradle and thermoplastic mask. Treatment delivery was image guided with orthogonal x-rays and a robotic patient positioner with 6 of freedom (6). Proton dose is expressed in Gy (RBE) with an RBE of 1.1 compared to megavoltage x-ray therapy. Since 2010, both temporal lobes are routinely contoured in patients treated for skull base tumors, although no hard constraints were placed on these structures. Those not contoured at original planning were retrospectively contoured, and all patients’ temporal lobes were contoured by the same physician (MM). Temporal lobe contours were guided by coregistered T1 weighted post-contrast magnetic resonance imaging (MRI). The anatomy of the temporal lobe is well described (7). The medial border of the temporal lobe contour specifically excluded the cavernous sinus. The cranial border is defined by the lateral fissure, the localization of which was augmented by coronal MRI. Because the posterior border with the occipital lobe is more subjective, we recorded the absolute volume of temporal lobe in cubic centimeters (cm3) rather than relative percentage of structure volume. Patient follow-up included MRI of the brain every 6 months. Follow-up time was measured from the completion date of radiation treatment until the date of last patient evaluation. The diagnosis of temporal lobe radiation necrosis was made by the development of new radiographic changes of T1 enhancement on MRI with surrounding T2 edema, with or without accompanying clinical symptoms, and graded according to the Common Terminology Criteria for Adverse Events (version 4.0) from the National Cancer Institute. MRI diffusion, perfusion, or spectroscopy studies were often used to characterize the abnormalities (8), and only 1 patient had pathologic confirmation of radiation necrosis. The date of the MRI showing these changes was used as the date of onset of radiation necrosis and the Kaplan-Meier method was used to estimate the incidence of temporal lobe radiation necrosis. The first MRI demonstrating radiation necrosis was coregistered to the treatment plan and the volume of enhancing abnormality contoured. An independent-samples t test was used to compare the mean values of the aV40-70 for patients with and without radiation necrosis and to compare the volume of radiation necrosis and the minimum, maximum, mean, and epicenter dose between those with asymptomatic grade 1 radiation necrosis and those with grade 2 or higher radiation necrosis.
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Doseevolume relationship for temporal lobe necrosis
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Patient characteristics No radiation necrosis (nZ54)
Radiation necrosis (nZ12)
P value
53.5 15-78 29/54 (53.7%) 25/54 (46.3%) 16/54 (29.6%) 8/54 (14.8%) 8/54 (14.8%) 18/54 (33.3%) 7/54 (13.0%) 16/54 (29.6%) 75.6 Gy (RBE) 62-79.2 Gy (RBE)
48.5 31-68 4/12 (33.3) 8/12 (66.7%) 1/12 (8.3%) 0/12 (0%) 1/12 (8.3%) 6/12 (50%) 0/12 (0%) 3/12 (25%) 73.8 Gy (RBE) 70.2-79.2 Gy (RBE)
.74
50 4 10 5-19 2 1-6 21.8 Gy (RBE) 0-75.6 Gy (RBE) 29.6%
10 2 11 4-15 2 2-5 13.5 Gy (RBE) 0-79.2 Gy (RBE) 17.5%
Median age, y Age range, y Male Female Hypertension Diabetes Smoking Clival-based tumor Concurrent chemotherapy Temporal lobes prospectively contoured Median total prescribed dose Prescribed dose range Dose per fraction 1.8 Gy (RBE) 2 Gy (RBE) Median no. of treatment fields Total no. of treatment fields Median no. of fields treated per day No. of fields treated per day Median dose delivered by through-patch techniques Range of dose delivered by through-patch techniques Median percentage of total dose delivered by through-patch techniques Percentage of patients with >50% of total dose delivered by through-patch techniques Mean aV40 Mean aV50 Mean aV60 Mean aV70
24.1% (13/54) 10.3 cm3 6.8 cm3 3.9 cm3 1.6 cm3
16.7% (2/12) 20.4 cm3 14.8 cm3 9.4 cm3 4.7 cm3
.20 .16 .33 >.99 .33 .33 >.99 .64
.30 .68 .40 .61 0.59 .72 <.001 <.001 <.001 <.001
Abbreviations: aV Z absolute volume of temporal lobes exposed to dose in Gy (RBE); RBE Z relative biological effectiveness.
Generalized estimating equation (GEE) models were used to test for associations between each variable and the development of radiation necrosis. GEE adjusts for the within-subject correlation due to repeated measures (right and left temporal lobes) on the same subject. A multivariable GEE model was fit that included the variables of patient age, gender, hypertension, clival versus nonclival tumors, prospective or retrospective contouring of the temporal lobe, and dose variables. The median effective concentration (EC50) dosee response model (9) was used to analyze the DVH data for the temporal lobes: YZTOP 1 þ 10^ ½ðlogEC50 XÞ)Hillslope where Y is the actual risk of temporal lobe radiation necrosis, expressed as a percentage of the maximal risk; TOP is the maximal risk (the minimal risk is 0); Hillslope is the steepness of the curve; and logEC50 represents the irradiated temporal lobe volume in which 50% of the maximal risk is observed. The model was applied to the temporal lobe aV10, aV20, aV30, aV40, aV50, aV60, and aV70. The Spearman rank correlation coefficient was used to assess for correlation between lower-dose (aV30 and aV40) and higher-dose volumes (aV70).
Results A total of 66 patients and 131 temporal lobes were included in the analysis. One patient treated for an orbital tumor received radiation only to the ipsilateral underlying temporal lobe. Patient characteristics are listed in Table 1. The median prescribed dose was 75.6 Gy (RBE) (range, 62 -79.2 Gy [RBE], interquartile range 72-77.4 Gy [RBE]). The median follow-up time for all patients was 31 months (range, 6-96 months) and 34 months in those patients who were alive at last follow-up (range, 7-96 months). The Kaplan-Meier estimate of overall survival at 3 years was 84.9% (95% confidence interval [CI] Z 74.9%-94.9%). The estimate of the incidence of any grade temporal lobe radiation necrosis at 3 years was 12.4% (95% CI Z 6.1%-18.7%). The estimate of grade 2 (symptomatic) or higher radiation necrosis at 3 years was 5.7% (95% CI Z 1.2%-10.2%). Radiation necrosis developed in 16 temporal lobes in 12 patients, with 4 patients developing bitemporal radiation necrosis. The median time from completion of radiation therapy until development of radiation necrosis was 21 months (range, 8-51 months). The median follow-up time after diagnosis of radiation necrosis in these 12 patients was an additional 12.5 months (range, 5-35 months).
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Fig. 1. An example of radiation necrosis in a patient treated for a clival chordoma. The left panel shows the presenting magnetic resonance imaging (MRI) with a clival and suprasellar T2 hyperintense tumor with bilateral cavernous sinus involvement and significant brainstem compression. The middle 2 panels show an axial and coronal image of the foci of asymptomatic radiation necrosis that developed in the left temporal lobe. MRI perfusion and spectroscopy were supportive of a diagnosis of radiation necrosis. Encephalomacia is noted in the right temporal lobe from prior surgery. The right panel shows the prior radiation dose superimposed on the MRI demonstrating radiation necrosis, which is transected by the prior 95% isodose line of therapy. Of note, based on its location at the time of treatment planning MRI, the maximum surface dose to the brainstem was 63 Gy (relative biological effectiveness). The patient remains without evidence of recurrent disease 3 years after radiation therapy. After initiation of pentoxifylline and Vitamin E, the area resolved on follow-up MRI. Seven patients developed asymptomatic radiographic changes in 8 temporal lobes (grade 1 radiation necrosis). One patient had unilateral radiation necrosis with symptoms requiring transient steroid use (grade 2). Three patients with symptomatic radiation necrosis in 5 temporal lobes required medical intervention with hyperbaric oxygen therapy, seizure medication, or bevacizumab (grade 3). One patient had symptomatic bitemporal radiation necrosis requiring transient hospitalization and protracted medical management (grade 4). An example of a patient developing radiation necrosis is shown in Figure 1. There were no statistically significant differences in analyzed patient, medical, social or treatment factors between those patients who developed radiation necrosis and those who did not (Table 1). On GEE multivariate analysis, temporal lobe maximum dose and all aV dose levels were statistically significantly associated with the development of radiation necrosis. A comparison of the mean DVH of temporal lobes with and without subsequent radiation necrosis is shown in Figure 2. Table 2 outlines radiation dose details in the patients who developed radiation necrosis. Table 3 compares necrosis volume and dose parameters between those patients with asymptomatic versus symptomatic radiation necrosis. In the EC50 model, all dose levels from 10 to 70 Gy (RBE) were highly correlated with development of radiation necrosis, although the model could not fit a curve at the 20-Gy (RBE) dose level. The EC50 model estimates a 15% 3-year risk of any-grade temporal lobe radiation necrosis when the temporal lobe aV40 > 16.5 cm3, aV50 > 9.6 cm3, aV60 > 5.5 cm3, or aV70 > 1.7 cm3 (Table 4, Figs. 3 and 4). The Spearman rank-order correlation showed a positive correlation between aV70 and both aV30 and aV40, which was statistically significant (rs Z 0.77 for
aV30, 0.82 for aV40, both P<.01). Figure 5 illustrates the relationship between aV40 and aV70 in patients with and without subsequent radiation necrosis. There were no cases of radiation necrosis noted in temporal lobes where the aV70 was <0.1 cm3.
Discussion Many of the data on radiation necrosis come from series of patients treated with older techniques in which relatively
Fig. 2. Mean doseevolume histogram for temporal lobes with and without radiation necrosis (any grade). The 95% confidence intervals for the mean of each curve are shown by the dashed lines.
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Doseevolume relationship for temporal lobe necrosis
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Doseevolume information to area of radiation necrosis in patients who developed radiation necrosis
Case
Temporal lobe Volume of radiation necrosis (cm3) Minimum dose
1 2 3 4 5 6 7 8 9 9 10 10 11 11 12 12
Left Right Right Left Right Left Left Right Left Right Left Right Left Right Left Right
0.4 0.58 1 1.2 4.4 6 10.2 15.2 0.05 0.15 0.42 0.16 0.43 0.53 0.40 3.83
Maximum dose
55.2 58.7 53.6 57.6 44.4 44.3 28.5 22.2 57.4 70.3 63.6 66.4 63.3 54.7 49.5 47.8
72.1 73.5 82.4 86.5 85.9 73.9 79 78.7 73.1 71.7 85.6 82.1 75.8 73.8 80.9 80.9
Mean dose Epicenter dose 66.0 70.8 68.2 77.6 70.4 67.8 68.8 66.1 65.0 71.3 77.1 76.7 72.3 66.9 71.9 71.3
63 72.1 73.1 82.3 74.5 72.8 72.2 74.0 72.8 71.7 79.7 77.7 73.3 66.9 76.3 72.2
Grade 1 1 1 3 3 1 1 2 1 1 4 4 1 1 3 3
Dose is given in Gy (relative biological effectiveness).
large volumes of brain were uniformly treated. Fewer data are available regarding the incidence of temporal lobe radiation necrosis in patients treated with complex dose distributions such as are achieved with intensity-modulated radiation therapy and particle therapy, or in patients treated to doses >60 Gy in conventional fractionation. The Quantitative Analysis of Normal Tissue Effects in the Clinic review suggests that partial brain irradiation to 72 Gy in standard fractionation is associated with a 5% risk of symptomatic radiation necrosis, but provides no specific guidance on doseevolume parameters (2). Santoni et al reported a 5-year estimated 13.2% risk of temporal lobe radiation necrosis (90% symptomatic) from a series of 96 patients receiving 64.8-72 Gy (RBE) of combined photoneproton radiation for skull base tumors, but identified no treatment parameters associated with radiation necrosis (10). Pehlivan et al reported an analysis of temporal lobe toxicity after spot scanning proton therapy in 62 patients treated for skull base tumors. A planning constraint of 74 Gy to 2 cm3 was suggested (11), which fits well with our model in which the risk of radiation necrosis appears to rise sharply with an increasing volume exposed to 70 Gy. Su et al reported an analysis of dosimetric factors associated with development of temporal lobe necrosis in a
series of 259 patients with nasopharyngeal cancer treated to 68 Gy with IMRT. Temporal lobe radiation necrosis was observed at a crude incidence of 15.4% at 5 years, and multivariate analysis showed a strong correlation between the absolute volume of temporal lobe receiving 40 Gy and the development of radiation necrosis (12). Their data suggest a 15% crude rate of temporal lobe radiation necrosis when the temporal lobe aV40 exceeds 10 cm3, similar to our own data set in which aV40 > 16.5 cm3 was associated with a 15% estimated risk of radiation necrosis. There is an association between lower dose levels such as aV40 and high dose levels such that an increasing volume receiving a higher dose necessarily means that an increasing volume is also exposed to a lower dose. This conundrum of multicollinearity among dose levels has been discussed in detail elsewhere and confounds identification of what independent volume effect may arise from the lower-dose regions (13, 14). However, given the increasingly complex dose distributions that may be achieved with current and improving radiation treatment modalities, low and high dose levels to organs at risk are not necessarily highly correlated in every case. Barring more conclusive
Table 4 Doseevolume levels associated with 3-year risk of any-grade temporal lobe radiation necrosis Table 3 Mean doseevolume information to area of radiation necrosis by grade of radiation necrosis Grade 1/asymptomatic Grade 2 or higher P value Volume, cm3 Minimum dose Maximum dose Mean dose Epicenter dose
2.15 54.0 75.0 68.6 70.9
3.66 50.2 82.9 73.0 76.7
Dose is given in Gy (relative biological effectiveness).
.51 .58 <.01 .02 <.01
Risk level
aV40
aV50
aV60
aV70
10% 15% 20% 30% 40% 50%
16.5 16.5 16.6 16.7 16.7 16.8
9.0 9.6 10.1 10.8 11.4 12.2
5.1 5.5 5.8 6.3 6.8 7.2
1.2 1.7 2.0 2.5 3.1 3.9
Abbreviations: aV Z absolute volume of temporal lobes exposed to dose in Gy (RBE); RBE Z relative biological effectiveness. Volume is expressed in cubic centimeters (cm3).
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Fig. 3. Median effective concentration volume risk analysis for temporal lobe radiation necrosis (any grade). Each curve is labeled for the absolute volume of temporal lobe exposed to a dose level in Gy (relative biological effectiveness). data, it seems prudent to incorporate doseevolume optimization goals at more than 1 dose level in an effort to bend the overall shape of the organ-at-risk DVH curve rather than merely constrain its intersection at a single-point dose. Animal data for the partoid gland (15) and spinal cord (16) have suggested that exposing larger volumes of adjacent organ to a lower-dose “bath” of radiation lowers the
Fig. 4. Absolute doseeabsolute volume histogram curve predicted to have a 15% risk of any grade temporal lobe radiation necrosis.
International Journal of Radiation Oncology Biology Physics
Fig. 5. Semilog graph of the correlation between the absolute volume (aV) of temporal lobe receiving 40 Gy (y axis) and 70 Gy (x axis) for temporal lobes with and without subsequent development of any-grade radiation necrosis. Spearman rank-order correlation coefficient between aV40 and aV70 was 0.82, P<.01. threshold for toxicity when a small subvolume is exposed to a higher dose. The mechanism of this effect is uncertain, but it has been proposed that the recovery of portions of an organ exposed to higher doses of radiation may be delayed or stymied by depletion of progenitor cells in adjacent tissues exposed to lower-dose radiation. Potentially, an increasing volume of surrounding parenchyma exposed to low and moderate doses of radiation may have an effect on microvasculature and cellular environment that could enhance the likelihood of developing necrosis in the portion of the brain exposed to higher dose. Our data suggest a dose relationship in the development of symptomatic radiation necrosis, also suggested by others (11). It may be that higher doses were associated with symptoms due to greater edema or eventual progression to a larger area of radiation necrosis, but these potential associations could not be explored in this analysis. Because our patients were followed up relatively frequently with MRI, asymptomatic parenchymal brain changes consistent with radiation necrosis were detected that would otherwise be subclinical. This should be kept in mind when comparing the rate of radiation necrosis with older series in which MRI was not a routine component of surveillance or used only when concerning clinical symptoms developed. Although half of the patients in our series who developed radiation necrosis had asymptomatic grade 1 radiation necrosis, we believe these cases are still clinically relevant. In our experience, the development of even
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asymptomatic MRI changes can prompt diagnostic confusion with those unfamiliar with this potential sequela of skull base radiation therapy, patient anxiety, and sometimes therapeutic intervention because of concern for potential symptoms with potential future progression. Only 10.6% of the patients in this series received concurrent chemotherapy, which may reduce the ability to detect a potential sensitizing effect of concurrent chemotherapy on the development of radiation necrosis. There was no apparent correlation between other patient factors and development of radiation necrosis. Other factors that are not evaluated here include how the range uncertainties in particle therapy may affect volume assessments and to what extent the higher relative biological effect at the terminal range of a proton beam may influence the risk of radiation necrosis. Our findings have not yet been tested in an independent data set to assess their validity or to test their generalizability to other treatment modalities or practices. In our series, pathologic confirmation of radiation necrosis was obtained in only 1 patient. However, the radiographic picture, which normally included MRI diffusion, perfusion, or spectroscopy, was highly suggestive of radiation necrosis (17), and the foci of necrosis correlated well with the radiation dose distribution. Substantial follow-up was available in these patients after diagnosis of radiation necrosis to confirm that the clinical and radiographic course was consistent with radiation necrosis rather than parenchymal brain metastases, infection, or a secondary glioma. The median follow-up time for patients remaining alive is more than a year longer than the median time interval to development of radiation necrosis in this cohort; however, delayed radiation necrosis is well described, and with longer follow-up time a higher incidence of radiation necrosis may be seen. Although these data suggest doseevolume constraints for treatment planning, the importance of adequate target coverage must be kept in mind. Terahara et al have shown a correlation between local control of skull base chordomas and both the minimum target dose and a lower dose to the coolest 5 cm3 of the target (18). Given the critical importance of target coverage in disease control for these patients, we believe that tumor coverage should not be compromised in an effort to meet temporal lobe constraints in the same way as it may be to meet dose constraints to the brainstem and optic apparatus, but rather that these proposed temporal lobe dose constraints should represent a secondary goal of plan optimization achieved through iterative plan design rather than compromises to tumor coverage.
Conclusions Doseevolume parameters are highly correlated with the risk of developing temporal lobe radiation necrosis. The risk of radiation necrosis increased sharply when the temporal lobe aV60 exceeded 5.5 cm3 or aV70 > 1.7 cm3.
Doseevolume relationship for temporal lobe necrosis
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Treatment planning goals should include constraints on the volume of temporal lobes receiving higher dose. The EC50 model provides suggested doseevolume temporal lobe constraints for conventionally fractionated high-dose skull base radiation therapy.
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