CME
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.
262
International Journal of Radiation Oncology Biology Physics
McDonald et al.
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
263
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 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 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
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.
262
International Journal of Radiation Oncology Biology Physics
McDonald et al.
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
263
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 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 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
