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Whole-brain Irradiation Field Design: A Comparison of Parotid Dose
ARTICLE IN PRESS Medical Dosimetry ■■ (2017) ■■–■■
Medical Dosimetry j o u r n a l h o m e p a g e : w w w. m e d d o s . o r g
Clinical Radiation Oncology Contribution:
Whole-brain Irradiation Field Design: A Comparison of Parotid Dose Cheng-Chia Wu, M.D., Ph.D.,* Yen-Ruh Wuu, B.S.,* Ashish Jani, M.D.,* Anurag Saraf, B.A.,* Cheng-Hung Tai, B.A.,* Matthew E. Lapa, B.S.,* Jacquelyn I.S. Andrew, B.A.,* Akhil Tiwari, B.S.,* Heva J. Saadatmand, M.P.H.,* Steven R. Isaacson, M.D.,*,† Simon K. Cheng, M.D., Ph.D.,*,‡ and Tony J. C. Wang, M.D.*,‡ *Department of Radiation Oncology, Columbia University Medical Center, 622 West 168th Street, BNH B-11, New York, NY 10032; †Department of Neurological Surgery, Columbia University Medical Center, New York, NY 10032; and ‡Herbert Irving Comprehensive Cancer Center, Columbia University Medical Center, New York, NY 10032
A R T I C L E
I N F O
Article history: Received 10 November 2016 Accepted 27 February 2017 Keywords: Whole-brain radiation WBRT Parotid Xerostomia
A B S T R A C T
Whole-brain radiation therapy (WBRT) plays an important role in patients with diffusely metastatic intracranial disease. Whether the extent of the radiation field design to C1 or C2 affects parotid dose and risk for developing xerostomia is unknown. The goal of this study is to examine the parotid dose based off of the inferior extent of WBRT field to either C1 or C2. Patients treated with WBRT with either 30 Gy or 37.5 Gy from 2011 to 2014 at a single institution were examined. Parotid dose constraints were compared with Radiation Therapy Oncology Group (RTOG) 0615 nasopharyngeal carcinoma for a 33fraction treatment: mean <26 Gy, volume constraint at 20 Gy (V20) < 20 cc, and dose at 50% of the parotid volume (D50) < 30 Gy. Biologically effective dose (BED) conversions with an α/β of 3 for normal parotid were performed to compare with 10-fraction and 15-fraction treatments of WBRT. The constraints are as follows: mean < BED 32.83 Gy, V15.76 (for 10-fraction WBRT) or V17.35 (for 15-fraction WBRT) < 20 cc, and D50 < BED 39.09 Gy. Nineteen patients treated to C1 and 26 patients treated to C2 were analyzed. Comparing WBRT to C1 with WBRT to C2, the mean left, right, and both parotids’ doses were lower when treated to C1. Converting mean dose to BED3, the parotid doses were lower than BED3 constraint of 32.83 Gy: left (30.12 Gy), right (30.69 Gy), and both parotids (30.32 Gy). V20 to combined parotids was lower in patients treated to C1. When accounting for fractionation of WBRT received, the mean corrected V20 volume was less than 20 cc when treating to C1. D50 for C1 was lower than C2 for the left parotid, right parotid, and both parotids. BED3 conversion for the mean D50 of the left, right, and both parotids was less than 39.09 Gy. In conclusion, WBRT to C1 limits parotid dose, and parotid dose constraints are achievable compared with inferior border at C2. A possible mean parotid dose constraint with BED3 should be less than 32.83 Gy. © 2017 American Association of Medical Dosimetrists.
Introduction Historically, radiation therapy plays a main role in the treatment of brain metastasis. The use of palliative whole-brain radiation therapy (WBRT) in treating patients with multiple brain metastases has historically shown to improve neurologic symptoms and
Cheng-Chia Wu and Yen-Ruh Wuu contributed equally to this work. Reprint requests to Simon K. Cheng, M.D., Ph.D., Department of Radiation Oncology, Columbia University Medical Center, 622 West 168th Street, BNH B-11, New York, NY 10032. E-mail: [email protected] Reprint requests to Tony J.C. Wang, M.D., Department of Radiation Oncology, Columbia University Medical Center, 622 West 168th Street, BNH B-11, New York, NY 10032. E-mail: [email protected] http://dx.doi.org/10.1016/j.meddos.2017.02.006 0958-3947/Copyright © 2017 American Association of Medical Dosimetrists
median overall survival from approximately 1 to 2 months to 3 to 6 months.1 With the advancement of stereotactic radiosurgery, patients with good prognosis and limited disease in the brain are often treated with stereotactic radiosurgery. However, WBRT still plays a significant role in patients with high numbers of brain metastasis or poorer prognosis.1,2 The dose for WBRT ranges from 2000 cGy to 4000 cGy.3,4 The conventional dose fractionation for WBRT is 3000 cGy in 10 fractions, but with recent publications examining the neuroprotective role of memantine, patients are also often treated with 3750 cGy in 15 fractions.3-6 Side effects related to this treatment are often neglected given the unfavorable prognosis of metastatic disease. Given the improved systemic treatment options, surgical options, radiation treatment modalities, as well as a better understanding of the different histologic and molecular marker characteristics of brain metastasis, various prognostic indices have stratified patients with
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cated by p = 0.936 (Table 1). For patients treated with 3000 cGy in 10 fractions, treating to C2 increased the mean parotid dose by approximately 8 Gy (Table 2). Similarly, in patients treated with 3750 cGy in 15 fractions to C2, the mean parotid dose increased by approximately 5 Gy (Table 3). Comparing WBRT to C1 with WBRT to C2, the combined mean left parotid dose (19.53 Gy vs 26.35 Gy, p < 0.001), right parotid dose (19.67 Gy vs 25.07 Gy, p = 0.003), and both parotids’ dose (19.63 Gy vs 25.71 Gy, p < 0.001) were lower when treated to C1 vs C2, respectively (Table 4). Given that some patients received 3000 cGy in 10 fractions or 3750 cGy in 15 fractions, mean dose was converted to BED with an α/β of 3 for normal parotid. Converting mean dose to BED3, the doses were as follows: left parotid (30.12 Gy vs 45.40 Gy, p < 0.001), right parotid (30.69 Gy vs 42.47 Gy, p = 0.002), and both parotids (30.32 Gy vs 43.85 Gy, p < 0.001). Using the RTOG 0615 dose constraint for parotid dose of mean dose less than 26 Gy over 33 fractions, BED3 was calculated with a mean parotid dose constraint of BED3 less than 32.83 Gy. The mean BED3 dose to the left, right, or both parotids in patients treated to C1 was less than 32.83 Gy (Table 4). In addition to a mean dose constraint, the V20 to the combined parotids was examined. V20 to the combined parotids was lower in patients treated to C1 than in patients treated to C2 (17.50 cc vs 26.82 cc, p = 0.002). When accounting for fractionation of WBRT received, the corrected V20 volumes were determined at equivalent dose at 10 fractions (V15.76 at 15.76 Gy) and at 15 fractions (V17.35 at 17.35 Gy). The average volumes for the corrected V20 of the combined parotids were 18.95 cc to C1 vs 28.22 cc to C2 (p = 0.003) (Table 5). Lastly, the D50 for C1 was lower than C2 for the left parotid (21.46 Gy vs 30.16 Gy, p = 0.006), right parotid (21.73 Gy vs 28.30 Gy, p = 0.002), and both parotids (21.05 Gy vs 29.60 Gy, p = 0.011). BED3 conversions for the left parotid, right parotid, and both parotids were 35.12 Gy vs 55.22 Gy (p = 0.007), 36.47 Gy vs 50.60 Gy (p = 0.005), and 34.40 Gy vs 53.78 Gy (p = 0.016), respectively. As compared with the RTOG constraint of D50 < 30 Gy (BED3 conversion to 39.09 Gy), the mean D50 dose to the left, right, and both parotids was less than 39.09 Gy when treated to C1 (Table 6).
brain metastasis with a median overall survival ranging from approximately 3 months to 1 year.1 With improved survival, there is a need to better understand the potential side effects related to WBRT. Efforts have been made to examine neurocognitive effects of WBRT as well as potential interventions to mitigate these toxicities, including N-methyl-Daspartate receptor blockers used in Alzheimer disease and hippocampal-sparing field design.5-7 Very little is known about the effects of WBRT on xerostomia and parotid dose. Furthermore, parotid glands are not routinely delineated as organs at risk (OARs) for treatment planning. Treatment field design for WBRT involves 2 opposed lateral beams, with the inferior field border ending at the inferior border of the cervical spine C1 or C2. It is unclear as to how the difference in the inferior beam edge will affect parotid dose. This study examines and compares the parotid dose when planning WBRT to C1 vs WBRT to C2, as well as radiation dose of 3000 cGy in 10 fractions vs 3750 cGy in 15 fractions. Methods and Materials Patients treated with WBRT from 2011 to 2014 were retrospectively examined. Patients with a medical history of leptomeningeal disease were selected to screen for WBRT with treatment field ending at C2. All WBRT radiation treatment plans were established with 3-dimensional-computed tomography (3D-CT) planning with a multileaflet collimator (MLC) block. Radiation treatment plans were limited to patients who received 3000 cGy in 10 fractions or 3750 cGy in 15 fractions. No prior parotid contours were delineated. Patients who had radiation treatment fields that ended in the middle of the vertebral body, typically C2, were excluded. Bilateral parotid volumes were contoured, and a dose-volume histogram was used to evaluate parotid dose. Parotid dose constraints were compared with that of the Radiation Therapy Oncology Group (RTOG) 0615 study of nasopharyngeal carcinoma for a 33fraction treatment: mean parotid dose less than 26 Gy, volume constraint at 20 Gy (V20) less than 20 cc, and dose at 50% of the parotid volume (D50) less than 30 Gy. Biologically effective dose (BED) conversion of the dose constraints was performed using an α/β of 3 for normal parotid to compare with 10-fraction and 15-fraction treatments of WBRT.8 Mean dose less than 32.83 Gy was assessed (BED3 of 26 Gy). A corrected V20 was determined based on fractionation of WBRT received (10 fractions vs 15 fractions). V15.76 (total dose of BED3 conversion of 20 Gy assuming 10 fractions) less than 20 cc or V17.35 (total dose of BED3 conversion of 20 Gy assuming 15 fractions) less than 20 cc was assessed depending on the WBRT dose received (3000 cGy/10 fractions or 3750 cGy/15 fractions, respectively). D50 less than 39.09 Gy was assessed (BED3 of 30 Gy). Statistical analysis was performed using χ2 test and Student t-test.
Results
Discussion
Forty-five patients were analyzed, with 19 patients receiving WBRT to C1 and 26 patients receiving WBRT to C2. Twenty-four patients received 3750 cGy in 15 fractions and 21 patients received 3000 cGy in 10 fractions. There were no differences in patients who received WBRT to C1 or C2 receiving 3000 cGy or 3750 cGy, indi-
WBRT remains the standard of care for patients with a large number of brain metastases. The treatment of WBRT is associated with multiple toxicities including neurocognitive deficits such as memory loss, fatigue and somnolence, nausea, vomiting, alopecia, and dermatitis.9 Very little is known about the risk to the parotid gland in the setting of WBRT. Radiation-induced xerostomia is well documented in patients receiving higher fractionation treatments in the setting of head and neck cancers.10,11 Although limited information is known about xerostomia in the setting of WBRT, in which patients are treated with 10 to 15 fractions, there is sufficient evidence that low-dose radiation delivered to major salivary glands over a course of low fractionation can lower saliva production. Radiotherapy to the salivary glands is clinically used in the setting of sialorrhea in patients with Parkinson disease or amyo-
Table 1 Patient demographic
C1 spine C2 spine Total
3750 cGy
3000 cGy
Total
10 14 24
9 12 21
19 26 45
Table 2 Unadjusted mean parotid dose for patients treated with 30 Gy in 10 fractions
Mean left parotid (3000 cGy) Mean right parotid (3000 cGy) Mean both parotids (3000 cGy)
C1 C2 C1 C2 C1 C2
N
Mean
Std. deviation
Std. error mean
p
9 12 9 12 9 12
15.77 24.60 16.12 23.22 15.99 23.89
5.05 3.53 5.72 4.96 5.00 4.09
1.68 1.02 1.91 1.43 1.67 1.18
< 0.001 0.007 0.001
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Table 3 Unadjusted mean parotid dose for patients treated with 37.5 Gy in 15 fractions
Mean left parotid (3750 cGy)
C1 C2 C1 C2 C1 C2
Mean right parotid (3750 cGy) Mean both parotids (3750 cGy)
N
Mean (Gy)
Std. deviation
Std. error mean
p
10 14 10 14 10 14
22.91 27.86 22.86 26.65 22.90 27.27
3.99 4.98 5.78 4.90 4.05 4.56
1.26 1.33 1.83 1.31 1.28 1.22
0.016 0.097 0.024
Table 4 Unadjusted and BED3 converted mean parotid dose of the entire cohort
Combined mean left parotid
C1 C2 C1 C2 C1 C2 C1 C2 C1 C2 C1 C2
Combined mean right parotid Combined mean both parotids Combined mean left parotid BED Combined mean right parotid BED Combined mean both parotids’ BED
N
Mean (Gy)
Std. dev
Std. error mean
p
19 26 19 26 19 26 19 26 19 26 19 26
19.53 26.35 19.67 25.07 19.63 25.71 30.12 45.40 30.69 42.47 30.32 43.85
5.72 4.60 6.57 5.13 5.64 4.59 10.08 9.84 12.16 11.37 10.08 9.95
1.31 0.90 1.51 1.01 1.29 0.90 2.31 1.93 2.79 2.23 2.31 1.95
< 0.001
trophic lateral sclerosis.12 In a meta-analysis of 216 patients treated with radiation treatment, approximately 80% of the patients had a response to radiotherapy. Treatment regimen ranged from singlefraction treatment to 16 fractions, and the median follow-up was 9 months (3 to 39 months).12 Similarly, response to radiation was also observed in patients treated between 10 and 14 fractions. Borg and Hirst examined 34 patients treated with radiation treatment for sialorrhea. A wide range of fractionation schemes were used; however, in patients who received 30 Gy in 10 fractions, 60% had either a complete or a partial response. Two patients received 10 Gy in 12 fractions and both had a complete response.13 Anecdotally, patients have reported evidence of xerostomia after WBRT. Furthermore, acute parotiditis has been reported as well.14 Given
0.003 < 0.001 < 0.001 0.002 < 0.001
the lack of information related to parotid toxicity in relationship to WBRT, currently, there is a prospective trial evaluation of patientreported xerostomia after whole-brain radiation (ClinicalTrials.gov Identifier: NCT02682199). Historically, for the treatment field of WBRT, the inferior field edge ends at the inferior border of C1 or C2. Oftentimes, C2 coverage, as opposed to C1, is included when treating patients with leptomeningeal disease. Very little is known about the parotid dose when WBRT to C2 is used. Few published studies in the past have examined parotid dose of radiation in relationship to WBRT. Initial studies by Noh and colleagues examined 32 patients who received WBRT using CT-based simulation with bilateral 2-field arrangement.15 Patients examined were treated with 30 Gy in 10
Table 5 Unadjusted and corrected volume constraint to the combined parotids
V20 both parotids
C1 C2 C1 C2
Corrected V20 both parotids*
N
Mean (cc)
Std. dev
Std. error mean
p
19 26 19 26
17.50 26.82 18.95 28.22
8.83 9.47 9.36 9.81
2.02 1.86 2.15 1.92
0.002 0.003
* A corrected V20 was calculated depending on WBRT 10 fraction treatment vs 15 fraction.
Table 6 Unadjusted and BED3 converted dose at 50% volume
D50 left parotid D50 right parotid D50 both parotids D50 left parotid BED D50 right parotid BED D50 both parotids’ BED
C1 C2 C1 C2 C1 C2 C1 C2 C1 C2 C1 C2
N
Mean (cGy)
Std. dev
Std. error mean
p
19 26 19 26 19 26 19 26 19 26 19 26
21.46 30.16 21.73 28.30 21.05 29.60 35.12 55.22 36.47 50.60 34.40 53.78
9.07 5.96 10.36 6.62 9.03 6.11 17.60 12.27 20.43 14.05 17.65 12.67
2.08 1.17 2.38 1.30 2.07 1.20 4.04 2.41 4.69 2.76 4.05 2.49
0.006 0.002 0.011 0.007 0.005 0.016
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fractions. The mean parotid dose was 17.6 ± 3.8, 17.4 ± 4.7, and 17.5 ± 3.9 Gy for the right gland, left gland, and both glands combined, respectively. The V20 for the parotid glands was 46.6 ± 14.4% for both glands combined.15 These values were similar to those that were obtained in our study for patients who received 30 Gy in 10 fractions covering to C1. Given the doses of radiation received by the parotids from WBRT, the importance of considering the parotid gland as an OAR was proposed in the setting of WBRT.15 Multiple groups examined treatment planning techniques to limit the parotid dose in the setting of WBRT. Prior studies examined the dose of radiation to the parotids for patients receiving WBRT with 2-dimensional (2D) treatment planning. Seven patients who required WBRT with 30 Gy in 10 fractions underwent 2D treatment planning. The field designs from the 2D planning were replicated with 3D planning to calculate dose-volume statistics for the parotid glands. Dose-volume histogram analysis showed that 2 of 7 patients (28%) had an excessive dose to the parotids, with a mean dose greater than 20 Gy.16 Loos and colleagues further examined the differences in parotid dose using rotation of the collimator to avoid lens dose vs the usage of MLC blocks. The usage of MLC blocks significantly decreased the parotid dose with a mean parotid dose of 9.63 Gy vs 12.32 Gy with field rotation, when treating with 30 Gy in 10 fractions.17 Similarly, low parotid doses were achieved with 3D-CT planning using 2 fields (gantry angles 90° to 270°) with an approximate 70° collimator angle with MLC block.18 With evidence suggesting better parotid sparing with 3D planning technique, the question remains whether the parotid dose can be further spared by modifying the lower field margin using 3D-CT–based determination of the extent of the brain vs using the conventional method of using the bottom of C1. Eighty-five patients were analyzed, in which 2 WBRT plans were generated, both using the lower extent of C1 as well as a modified field design. The modified field was generated using a clinical target volume (CTV) of the contoured brain with a planning target volume (PTV) expansion of 1 cm, with the exception of 5 mm in the area of the parotid as well as 5 mm from the caudal margin. Significantly lower doses were seen with the modified field design with a parotid gland V20 of 48.4% vs 18.2% (conventional vs modified) and a mean parotid dose of 17.4 vs 8.7 Gy (conventional vs modified).19 In the setting of WBRT treatment planning to C1 or C2, very little is known in terms of the parotid dose and risk for xerostomia. Preliminary results were presented by Orton and colleagues at the American Radium Society 2015, which examined the changes in parotid dose when treating to C1 vs C2. Fifteen patients underwent CT simulation of the brain and 2 treatment plans were produced with the extent of the inferior edge ending at C1 or C2. Results from their study showed that when treating to 3000 cGy, the parotid dose increased from 14.3 Gy to 18.3 Gy when comparing C1 with C2 (p < 0.01). Similarly, with 3750 cGy, WBRT fields to C2 increased the parotid dose from 18.5 Gy to 23.4 Gy (p < 0.01).20 Given that this study was performed by designing 2 treatment plans per patient, there may be confounding factors in which the treatment plan may affect the measured parotid dose. Furthermore, given that the fractionation and dose per fraction for WBRT is different from the standard radiation dose for the typical head and neck parotid dose constraint, we wanted to compare the parotid dose with known dose constraints by adjusting with BED. In our study, we examined 45 patients: 19 patients received WBRT to C1 and 26 patients received WBRT to C2. There was no statistical difference in terms of patients receiving either 3000 cGy or 3750 cGy in either C1- or C2-treated plans. Similar to prior reports, WBRT treatment plans to C2 significantly increased the parotid dose as compared with C1. Interestingly, when converting to BED3 to compare the parotid dose with RTOG dose constraint for parotids, patients treated with WBRT to C1 had a mean BED3
parotid dose less than the BED3 dose constraint. Similarly, when adjusting for the different whole-brain fractionation, the mean corrected V20 of both parotids was less than 20 cc when treating to C1 vs when treating to C2. These findings were consistent with the D50 parotid BED3 doses in which the D50 left parotid BED3, D50 right parotid BED3, and D50 both parotids’ BED3 were less than BED3 of 30 Gy (39.09 Gy). These results suggest that when treating patients with WBRT, the parotid glands should be considered as OARs. With treatment to C1, the adjusted parotid constraints may be readily achievable with standard field design. With treatment to C2 when clinically indicated, further planning techniques such as MLC blocking may be needed to achieve the adjusted parotid constraints. Currently, the standard field design for WBRT include bilateral opposed fields; however, given the neurotoxicity of WBRT in relationship to cognitive deficits, current trials are examining the role of intensity-modulated radiation therapy for hippocampal sparing. In the clinical trial NRG-CC001 that studies the role of hippocampal sparing with intensity-modulated radiation therapy–based WBRT, listed OARs include optic structures, the lens, and the hippocampus. Further studies of parotid dose and its associated risk for xerostomia are necessary. Conclusion WBRT to C2 increases radiation dose to the parotids. When treating patients with WBRT to C1, parotid dose constraint is achievable and it may be reasonable to consider the parotid glands as OAR using a mean parotid dose constraint with BED3 of less than 32.83 Gy. Further studies are needed to see whether this will limit risk for xerostomia. Conflict of Interest There are no potential conflicts of interest from all coauthors. References 1. Lin, X.; DeAngelis, L.M. Treatment of brain metastases. J. Clin. Oncol. 33:3475–84; 2015. 2. Tsao, M.N.; Rades, D.; Wirth, A.; et al. Radiotherapeutic and surgical management for newly diagnosed brain metastasis(es): an American Society for Radiation Oncology evidence-based guideline. Pract. Radiat. Oncol. 2:210–25; 2012. 3. Tsao, M.N.; Lloyd, N.; Wong, R.K.; et al. Whole brain radiotherapy for the treatment of newly diagnosed multiple brain metastases. Cochrane Database Syst. Rev. (4):CD003869; 2012. 4. Gunderson, L.L.; Tepper, J.E.; Bogart, J.A. Clinical Radiation Oncology. 3rd ed. Philadelphia, PA: Elsevier Saunders; 2012. 5. Brown, P.D.; Pugh, S.; Laack, N.N.; et al. Memantine for the prevention of cognitive dysfunction in patients receiving whole-brain radiotherapy: a randomized, double-blind, placebo-controlled trial. Neuro Oncol. 15:1429–37; 2013. 6. Rapp, S.R.; Case, L.D.; Peiffer, A.; et al. Donepezil for irradiated brain tumor survivors: a phase III randomized placebo-controlled clinical trial. J. Clin. Oncol. 33:1653–9; 2015. 7. Gondi, V.; Tolakanahalli, R.; Mehta, M.P.; et al. Hippocampal-sparing whole-brain radiotherapy: a “how-to” technique using helical tomotherapy and linear accelerator-based intensity-modulated radiotherapy. Int. J. Radiat. Oncol. Biol. Phys. 78:1244–52; 2010. 8. Scrimger, R.A.; Stavrev, P.; Parliament, M.B.; et al. Phenomenologic model describing flow reduction for parotid gland irradiation with intensity-modulated radiotherapy: evidence of significant recovery effect. Int. J. Radiat. Oncol. Biol. Phys. 60:178–85; 2004. 9. McTyre, E.; Scott, J.; Chinnaiyan, P. Whole brain radiotherapy for brain metastasis. Surg. Neurol. Int. 4:S236–44; 2013. 10. Pinna, R.; Campus, G.; Cumbo, E.; et al. Xerostomia induced by radiotherapy: an overview of the physiopathology, clinical evidence, and management of the oral damage. Ther. Clin. Risk Manag. 11:171–88; 2015. 11. Lee, S.W.; Kang, K.W.; Wu, H.G. Prospective investigation and literature review of tolerance dose on salivary glands using quantitative salivary gland scintigraphy in the intensity-modulated radiotherapy era. Head Neck 38(suppl. 1):E1746–55; 2016. 12. Hawkey, N.M.; Zaorsky, N.G.; Galloway, T.J. The role of radiation therapy in the management of sialorrhea: a systematic review. Laryngoscope 126:80–5; 2016.
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13. Borg, M.; Hirst, F. The role of radiation therapy in the management of sialorrhea. Int. J. Radiat. Oncol. Biol. Phys. 41:1113–9; 1998. 14. Cairncross, J.G.; Salmon, J.; Kim, J.H.; et al. Acute parotitis and hyperamylasemia following whole-brain radiation therapy. Ann. Neurol. 7:385–7; 1980. 15. Noh, O.K.; Chun, M.; Nam, S.S.; et al. Parotid gland as a risk organ in whole brain radiotherapy. Radiother. Oncol. 98:223–6; 2011. 16. Trignani, M.; Genovesi, D.; Vinciguerra, A.; et al. Parotid glands in whole-brain radiotherapy: 2D versus 3D technique for no sparing or sparing. Radiol. Med. (Torino) 120:324–8; 2015.
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17. Loos, G.; Paulon, R.; Verrelle, P.; et al. Whole brain radiotherapy for brain metastases: the technique of irradiation influences the dose to parotid glands. Cancer Radiother. 16:136–9; 2012. 18. Fiorentino, A.; Caivano, R.; Chiumento, C.; et al. Technique of whole brain radiotherapy: conformity index and parotid glands. Clin. Oncol. 24:e140–1; 2012. 19. Cho, O.; Chun, M.; Park, S.H.; et al. Parotid gland sparing effect by computed tomography-based modified lower field margin in whole brain radiotherapy. Radiat. Oncol. J. 31:12–7; 2013. 20. Orton, A.; Gordon, J.; Vigh, T.; et al. (p138) dosimetric evaluation of parotid dose in whole-brain radiation plans covering C1 vs C2. Oncology 29:2015.
Medical Dosimetry j o u r n a l h o m e p a g e : w w w. m e d d o s . o r g
Clinical Radiation Oncology Contribution:
Whole-brain Irradiation Field Design: A Comparison of Parotid Dose Cheng-Chia Wu, M.D., Ph.D.,* Yen-Ruh Wuu, B.S.,* Ashish Jani, M.D.,* Anurag Saraf, B.A.,* Cheng-Hung Tai, B.A.,* Matthew E. Lapa, B.S.,* Jacquelyn I.S. Andrew, B.A.,* Akhil Tiwari, B.S.,* Heva J. Saadatmand, M.P.H.,* Steven R. Isaacson, M.D.,*,† Simon K. Cheng, M.D., Ph.D.,*,‡ and Tony J. C. Wang, M.D.*,‡ *Department of Radiation Oncology, Columbia University Medical Center, 622 West 168th Street, BNH B-11, New York, NY 10032; †Department of Neurological Surgery, Columbia University Medical Center, New York, NY 10032; and ‡Herbert Irving Comprehensive Cancer Center, Columbia University Medical Center, New York, NY 10032
A R T I C L E
I N F O
Article history: Received 10 November 2016 Accepted 27 February 2017 Keywords: Whole-brain radiation WBRT Parotid Xerostomia
A B S T R A C T
Whole-brain radiation therapy (WBRT) plays an important role in patients with diffusely metastatic intracranial disease. Whether the extent of the radiation field design to C1 or C2 affects parotid dose and risk for developing xerostomia is unknown. The goal of this study is to examine the parotid dose based off of the inferior extent of WBRT field to either C1 or C2. Patients treated with WBRT with either 30 Gy or 37.5 Gy from 2011 to 2014 at a single institution were examined. Parotid dose constraints were compared with Radiation Therapy Oncology Group (RTOG) 0615 nasopharyngeal carcinoma for a 33fraction treatment: mean <26 Gy, volume constraint at 20 Gy (V20) < 20 cc, and dose at 50% of the parotid volume (D50) < 30 Gy. Biologically effective dose (BED) conversions with an α/β of 3 for normal parotid were performed to compare with 10-fraction and 15-fraction treatments of WBRT. The constraints are as follows: mean < BED 32.83 Gy, V15.76 (for 10-fraction WBRT) or V17.35 (for 15-fraction WBRT) < 20 cc, and D50 < BED 39.09 Gy. Nineteen patients treated to C1 and 26 patients treated to C2 were analyzed. Comparing WBRT to C1 with WBRT to C2, the mean left, right, and both parotids’ doses were lower when treated to C1. Converting mean dose to BED3, the parotid doses were lower than BED3 constraint of 32.83 Gy: left (30.12 Gy), right (30.69 Gy), and both parotids (30.32 Gy). V20 to combined parotids was lower in patients treated to C1. When accounting for fractionation of WBRT received, the mean corrected V20 volume was less than 20 cc when treating to C1. D50 for C1 was lower than C2 for the left parotid, right parotid, and both parotids. BED3 conversion for the mean D50 of the left, right, and both parotids was less than 39.09 Gy. In conclusion, WBRT to C1 limits parotid dose, and parotid dose constraints are achievable compared with inferior border at C2. A possible mean parotid dose constraint with BED3 should be less than 32.83 Gy. © 2017 American Association of Medical Dosimetrists.
Introduction Historically, radiation therapy plays a main role in the treatment of brain metastasis. The use of palliative whole-brain radiation therapy (WBRT) in treating patients with multiple brain metastases has historically shown to improve neurologic symptoms and
Cheng-Chia Wu and Yen-Ruh Wuu contributed equally to this work. Reprint requests to Simon K. Cheng, M.D., Ph.D., Department of Radiation Oncology, Columbia University Medical Center, 622 West 168th Street, BNH B-11, New York, NY 10032. E-mail: [email protected] Reprint requests to Tony J.C. Wang, M.D., Department of Radiation Oncology, Columbia University Medical Center, 622 West 168th Street, BNH B-11, New York, NY 10032. E-mail: [email protected] http://dx.doi.org/10.1016/j.meddos.2017.02.006 0958-3947/Copyright © 2017 American Association of Medical Dosimetrists
median overall survival from approximately 1 to 2 months to 3 to 6 months.1 With the advancement of stereotactic radiosurgery, patients with good prognosis and limited disease in the brain are often treated with stereotactic radiosurgery. However, WBRT still plays a significant role in patients with high numbers of brain metastasis or poorer prognosis.1,2 The dose for WBRT ranges from 2000 cGy to 4000 cGy.3,4 The conventional dose fractionation for WBRT is 3000 cGy in 10 fractions, but with recent publications examining the neuroprotective role of memantine, patients are also often treated with 3750 cGy in 15 fractions.3-6 Side effects related to this treatment are often neglected given the unfavorable prognosis of metastatic disease. Given the improved systemic treatment options, surgical options, radiation treatment modalities, as well as a better understanding of the different histologic and molecular marker characteristics of brain metastasis, various prognostic indices have stratified patients with
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cated by p = 0.936 (Table 1). For patients treated with 3000 cGy in 10 fractions, treating to C2 increased the mean parotid dose by approximately 8 Gy (Table 2). Similarly, in patients treated with 3750 cGy in 15 fractions to C2, the mean parotid dose increased by approximately 5 Gy (Table 3). Comparing WBRT to C1 with WBRT to C2, the combined mean left parotid dose (19.53 Gy vs 26.35 Gy, p < 0.001), right parotid dose (19.67 Gy vs 25.07 Gy, p = 0.003), and both parotids’ dose (19.63 Gy vs 25.71 Gy, p < 0.001) were lower when treated to C1 vs C2, respectively (Table 4). Given that some patients received 3000 cGy in 10 fractions or 3750 cGy in 15 fractions, mean dose was converted to BED with an α/β of 3 for normal parotid. Converting mean dose to BED3, the doses were as follows: left parotid (30.12 Gy vs 45.40 Gy, p < 0.001), right parotid (30.69 Gy vs 42.47 Gy, p = 0.002), and both parotids (30.32 Gy vs 43.85 Gy, p < 0.001). Using the RTOG 0615 dose constraint for parotid dose of mean dose less than 26 Gy over 33 fractions, BED3 was calculated with a mean parotid dose constraint of BED3 less than 32.83 Gy. The mean BED3 dose to the left, right, or both parotids in patients treated to C1 was less than 32.83 Gy (Table 4). In addition to a mean dose constraint, the V20 to the combined parotids was examined. V20 to the combined parotids was lower in patients treated to C1 than in patients treated to C2 (17.50 cc vs 26.82 cc, p = 0.002). When accounting for fractionation of WBRT received, the corrected V20 volumes were determined at equivalent dose at 10 fractions (V15.76 at 15.76 Gy) and at 15 fractions (V17.35 at 17.35 Gy). The average volumes for the corrected V20 of the combined parotids were 18.95 cc to C1 vs 28.22 cc to C2 (p = 0.003) (Table 5). Lastly, the D50 for C1 was lower than C2 for the left parotid (21.46 Gy vs 30.16 Gy, p = 0.006), right parotid (21.73 Gy vs 28.30 Gy, p = 0.002), and both parotids (21.05 Gy vs 29.60 Gy, p = 0.011). BED3 conversions for the left parotid, right parotid, and both parotids were 35.12 Gy vs 55.22 Gy (p = 0.007), 36.47 Gy vs 50.60 Gy (p = 0.005), and 34.40 Gy vs 53.78 Gy (p = 0.016), respectively. As compared with the RTOG constraint of D50 < 30 Gy (BED3 conversion to 39.09 Gy), the mean D50 dose to the left, right, and both parotids was less than 39.09 Gy when treated to C1 (Table 6).
brain metastasis with a median overall survival ranging from approximately 3 months to 1 year.1 With improved survival, there is a need to better understand the potential side effects related to WBRT. Efforts have been made to examine neurocognitive effects of WBRT as well as potential interventions to mitigate these toxicities, including N-methyl-Daspartate receptor blockers used in Alzheimer disease and hippocampal-sparing field design.5-7 Very little is known about the effects of WBRT on xerostomia and parotid dose. Furthermore, parotid glands are not routinely delineated as organs at risk (OARs) for treatment planning. Treatment field design for WBRT involves 2 opposed lateral beams, with the inferior field border ending at the inferior border of the cervical spine C1 or C2. It is unclear as to how the difference in the inferior beam edge will affect parotid dose. This study examines and compares the parotid dose when planning WBRT to C1 vs WBRT to C2, as well as radiation dose of 3000 cGy in 10 fractions vs 3750 cGy in 15 fractions. Methods and Materials Patients treated with WBRT from 2011 to 2014 were retrospectively examined. Patients with a medical history of leptomeningeal disease were selected to screen for WBRT with treatment field ending at C2. All WBRT radiation treatment plans were established with 3-dimensional-computed tomography (3D-CT) planning with a multileaflet collimator (MLC) block. Radiation treatment plans were limited to patients who received 3000 cGy in 10 fractions or 3750 cGy in 15 fractions. No prior parotid contours were delineated. Patients who had radiation treatment fields that ended in the middle of the vertebral body, typically C2, were excluded. Bilateral parotid volumes were contoured, and a dose-volume histogram was used to evaluate parotid dose. Parotid dose constraints were compared with that of the Radiation Therapy Oncology Group (RTOG) 0615 study of nasopharyngeal carcinoma for a 33fraction treatment: mean parotid dose less than 26 Gy, volume constraint at 20 Gy (V20) less than 20 cc, and dose at 50% of the parotid volume (D50) less than 30 Gy. Biologically effective dose (BED) conversion of the dose constraints was performed using an α/β of 3 for normal parotid to compare with 10-fraction and 15-fraction treatments of WBRT.8 Mean dose less than 32.83 Gy was assessed (BED3 of 26 Gy). A corrected V20 was determined based on fractionation of WBRT received (10 fractions vs 15 fractions). V15.76 (total dose of BED3 conversion of 20 Gy assuming 10 fractions) less than 20 cc or V17.35 (total dose of BED3 conversion of 20 Gy assuming 15 fractions) less than 20 cc was assessed depending on the WBRT dose received (3000 cGy/10 fractions or 3750 cGy/15 fractions, respectively). D50 less than 39.09 Gy was assessed (BED3 of 30 Gy). Statistical analysis was performed using χ2 test and Student t-test.
Results
Discussion
Forty-five patients were analyzed, with 19 patients receiving WBRT to C1 and 26 patients receiving WBRT to C2. Twenty-four patients received 3750 cGy in 15 fractions and 21 patients received 3000 cGy in 10 fractions. There were no differences in patients who received WBRT to C1 or C2 receiving 3000 cGy or 3750 cGy, indi-
WBRT remains the standard of care for patients with a large number of brain metastases. The treatment of WBRT is associated with multiple toxicities including neurocognitive deficits such as memory loss, fatigue and somnolence, nausea, vomiting, alopecia, and dermatitis.9 Very little is known about the risk to the parotid gland in the setting of WBRT. Radiation-induced xerostomia is well documented in patients receiving higher fractionation treatments in the setting of head and neck cancers.10,11 Although limited information is known about xerostomia in the setting of WBRT, in which patients are treated with 10 to 15 fractions, there is sufficient evidence that low-dose radiation delivered to major salivary glands over a course of low fractionation can lower saliva production. Radiotherapy to the salivary glands is clinically used in the setting of sialorrhea in patients with Parkinson disease or amyo-
Table 1 Patient demographic
C1 spine C2 spine Total
3750 cGy
3000 cGy
Total
10 14 24
9 12 21
19 26 45
Table 2 Unadjusted mean parotid dose for patients treated with 30 Gy in 10 fractions
Mean left parotid (3000 cGy) Mean right parotid (3000 cGy) Mean both parotids (3000 cGy)
C1 C2 C1 C2 C1 C2
N
Mean
Std. deviation
Std. error mean
p
9 12 9 12 9 12
15.77 24.60 16.12 23.22 15.99 23.89
5.05 3.53 5.72 4.96 5.00 4.09
1.68 1.02 1.91 1.43 1.67 1.18
< 0.001 0.007 0.001
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Table 3 Unadjusted mean parotid dose for patients treated with 37.5 Gy in 15 fractions
Mean left parotid (3750 cGy)
C1 C2 C1 C2 C1 C2
Mean right parotid (3750 cGy) Mean both parotids (3750 cGy)
N
Mean (Gy)
Std. deviation
Std. error mean
p
10 14 10 14 10 14
22.91 27.86 22.86 26.65 22.90 27.27
3.99 4.98 5.78 4.90 4.05 4.56
1.26 1.33 1.83 1.31 1.28 1.22
0.016 0.097 0.024
Table 4 Unadjusted and BED3 converted mean parotid dose of the entire cohort
Combined mean left parotid
C1 C2 C1 C2 C1 C2 C1 C2 C1 C2 C1 C2
Combined mean right parotid Combined mean both parotids Combined mean left parotid BED Combined mean right parotid BED Combined mean both parotids’ BED
N
Mean (Gy)
Std. dev
Std. error mean
p
19 26 19 26 19 26 19 26 19 26 19 26
19.53 26.35 19.67 25.07 19.63 25.71 30.12 45.40 30.69 42.47 30.32 43.85
5.72 4.60 6.57 5.13 5.64 4.59 10.08 9.84 12.16 11.37 10.08 9.95
1.31 0.90 1.51 1.01 1.29 0.90 2.31 1.93 2.79 2.23 2.31 1.95
< 0.001
trophic lateral sclerosis.12 In a meta-analysis of 216 patients treated with radiation treatment, approximately 80% of the patients had a response to radiotherapy. Treatment regimen ranged from singlefraction treatment to 16 fractions, and the median follow-up was 9 months (3 to 39 months).12 Similarly, response to radiation was also observed in patients treated between 10 and 14 fractions. Borg and Hirst examined 34 patients treated with radiation treatment for sialorrhea. A wide range of fractionation schemes were used; however, in patients who received 30 Gy in 10 fractions, 60% had either a complete or a partial response. Two patients received 10 Gy in 12 fractions and both had a complete response.13 Anecdotally, patients have reported evidence of xerostomia after WBRT. Furthermore, acute parotiditis has been reported as well.14 Given
0.003 < 0.001 < 0.001 0.002 < 0.001
the lack of information related to parotid toxicity in relationship to WBRT, currently, there is a prospective trial evaluation of patientreported xerostomia after whole-brain radiation (ClinicalTrials.gov Identifier: NCT02682199). Historically, for the treatment field of WBRT, the inferior field edge ends at the inferior border of C1 or C2. Oftentimes, C2 coverage, as opposed to C1, is included when treating patients with leptomeningeal disease. Very little is known about the parotid dose when WBRT to C2 is used. Few published studies in the past have examined parotid dose of radiation in relationship to WBRT. Initial studies by Noh and colleagues examined 32 patients who received WBRT using CT-based simulation with bilateral 2-field arrangement.15 Patients examined were treated with 30 Gy in 10
Table 5 Unadjusted and corrected volume constraint to the combined parotids
V20 both parotids
C1 C2 C1 C2
Corrected V20 both parotids*
N
Mean (cc)
Std. dev
Std. error mean
p
19 26 19 26
17.50 26.82 18.95 28.22
8.83 9.47 9.36 9.81
2.02 1.86 2.15 1.92
0.002 0.003
* A corrected V20 was calculated depending on WBRT 10 fraction treatment vs 15 fraction.
Table 6 Unadjusted and BED3 converted dose at 50% volume
D50 left parotid D50 right parotid D50 both parotids D50 left parotid BED D50 right parotid BED D50 both parotids’ BED
C1 C2 C1 C2 C1 C2 C1 C2 C1 C2 C1 C2
N
Mean (cGy)
Std. dev
Std. error mean
p
19 26 19 26 19 26 19 26 19 26 19 26
21.46 30.16 21.73 28.30 21.05 29.60 35.12 55.22 36.47 50.60 34.40 53.78
9.07 5.96 10.36 6.62 9.03 6.11 17.60 12.27 20.43 14.05 17.65 12.67
2.08 1.17 2.38 1.30 2.07 1.20 4.04 2.41 4.69 2.76 4.05 2.49
0.006 0.002 0.011 0.007 0.005 0.016
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fractions. The mean parotid dose was 17.6 ± 3.8, 17.4 ± 4.7, and 17.5 ± 3.9 Gy for the right gland, left gland, and both glands combined, respectively. The V20 for the parotid glands was 46.6 ± 14.4% for both glands combined.15 These values were similar to those that were obtained in our study for patients who received 30 Gy in 10 fractions covering to C1. Given the doses of radiation received by the parotids from WBRT, the importance of considering the parotid gland as an OAR was proposed in the setting of WBRT.15 Multiple groups examined treatment planning techniques to limit the parotid dose in the setting of WBRT. Prior studies examined the dose of radiation to the parotids for patients receiving WBRT with 2-dimensional (2D) treatment planning. Seven patients who required WBRT with 30 Gy in 10 fractions underwent 2D treatment planning. The field designs from the 2D planning were replicated with 3D planning to calculate dose-volume statistics for the parotid glands. Dose-volume histogram analysis showed that 2 of 7 patients (28%) had an excessive dose to the parotids, with a mean dose greater than 20 Gy.16 Loos and colleagues further examined the differences in parotid dose using rotation of the collimator to avoid lens dose vs the usage of MLC blocks. The usage of MLC blocks significantly decreased the parotid dose with a mean parotid dose of 9.63 Gy vs 12.32 Gy with field rotation, when treating with 30 Gy in 10 fractions.17 Similarly, low parotid doses were achieved with 3D-CT planning using 2 fields (gantry angles 90° to 270°) with an approximate 70° collimator angle with MLC block.18 With evidence suggesting better parotid sparing with 3D planning technique, the question remains whether the parotid dose can be further spared by modifying the lower field margin using 3D-CT–based determination of the extent of the brain vs using the conventional method of using the bottom of C1. Eighty-five patients were analyzed, in which 2 WBRT plans were generated, both using the lower extent of C1 as well as a modified field design. The modified field was generated using a clinical target volume (CTV) of the contoured brain with a planning target volume (PTV) expansion of 1 cm, with the exception of 5 mm in the area of the parotid as well as 5 mm from the caudal margin. Significantly lower doses were seen with the modified field design with a parotid gland V20 of 48.4% vs 18.2% (conventional vs modified) and a mean parotid dose of 17.4 vs 8.7 Gy (conventional vs modified).19 In the setting of WBRT treatment planning to C1 or C2, very little is known in terms of the parotid dose and risk for xerostomia. Preliminary results were presented by Orton and colleagues at the American Radium Society 2015, which examined the changes in parotid dose when treating to C1 vs C2. Fifteen patients underwent CT simulation of the brain and 2 treatment plans were produced with the extent of the inferior edge ending at C1 or C2. Results from their study showed that when treating to 3000 cGy, the parotid dose increased from 14.3 Gy to 18.3 Gy when comparing C1 with C2 (p < 0.01). Similarly, with 3750 cGy, WBRT fields to C2 increased the parotid dose from 18.5 Gy to 23.4 Gy (p < 0.01).20 Given that this study was performed by designing 2 treatment plans per patient, there may be confounding factors in which the treatment plan may affect the measured parotid dose. Furthermore, given that the fractionation and dose per fraction for WBRT is different from the standard radiation dose for the typical head and neck parotid dose constraint, we wanted to compare the parotid dose with known dose constraints by adjusting with BED. In our study, we examined 45 patients: 19 patients received WBRT to C1 and 26 patients received WBRT to C2. There was no statistical difference in terms of patients receiving either 3000 cGy or 3750 cGy in either C1- or C2-treated plans. Similar to prior reports, WBRT treatment plans to C2 significantly increased the parotid dose as compared with C1. Interestingly, when converting to BED3 to compare the parotid dose with RTOG dose constraint for parotids, patients treated with WBRT to C1 had a mean BED3
parotid dose less than the BED3 dose constraint. Similarly, when adjusting for the different whole-brain fractionation, the mean corrected V20 of both parotids was less than 20 cc when treating to C1 vs when treating to C2. These findings were consistent with the D50 parotid BED3 doses in which the D50 left parotid BED3, D50 right parotid BED3, and D50 both parotids’ BED3 were less than BED3 of 30 Gy (39.09 Gy). These results suggest that when treating patients with WBRT, the parotid glands should be considered as OARs. With treatment to C1, the adjusted parotid constraints may be readily achievable with standard field design. With treatment to C2 when clinically indicated, further planning techniques such as MLC blocking may be needed to achieve the adjusted parotid constraints. Currently, the standard field design for WBRT include bilateral opposed fields; however, given the neurotoxicity of WBRT in relationship to cognitive deficits, current trials are examining the role of intensity-modulated radiation therapy for hippocampal sparing. In the clinical trial NRG-CC001 that studies the role of hippocampal sparing with intensity-modulated radiation therapy–based WBRT, listed OARs include optic structures, the lens, and the hippocampus. Further studies of parotid dose and its associated risk for xerostomia are necessary. Conclusion WBRT to C2 increases radiation dose to the parotids. When treating patients with WBRT to C1, parotid dose constraint is achievable and it may be reasonable to consider the parotid glands as OAR using a mean parotid dose constraint with BED3 of less than 32.83 Gy. Further studies are needed to see whether this will limit risk for xerostomia. Conflict of Interest There are no potential conflicts of interest from all coauthors. References 1. Lin, X.; DeAngelis, L.M. Treatment of brain metastases. J. Clin. Oncol. 33:3475–84; 2015. 2. Tsao, M.N.; Rades, D.; Wirth, A.; et al. Radiotherapeutic and surgical management for newly diagnosed brain metastasis(es): an American Society for Radiation Oncology evidence-based guideline. Pract. Radiat. Oncol. 2:210–25; 2012. 3. Tsao, M.N.; Lloyd, N.; Wong, R.K.; et al. Whole brain radiotherapy for the treatment of newly diagnosed multiple brain metastases. Cochrane Database Syst. Rev. (4):CD003869; 2012. 4. Gunderson, L.L.; Tepper, J.E.; Bogart, J.A. Clinical Radiation Oncology. 3rd ed. Philadelphia, PA: Elsevier Saunders; 2012. 5. Brown, P.D.; Pugh, S.; Laack, N.N.; et al. Memantine for the prevention of cognitive dysfunction in patients receiving whole-brain radiotherapy: a randomized, double-blind, placebo-controlled trial. Neuro Oncol. 15:1429–37; 2013. 6. Rapp, S.R.; Case, L.D.; Peiffer, A.; et al. Donepezil for irradiated brain tumor survivors: a phase III randomized placebo-controlled clinical trial. J. Clin. Oncol. 33:1653–9; 2015. 7. Gondi, V.; Tolakanahalli, R.; Mehta, M.P.; et al. Hippocampal-sparing whole-brain radiotherapy: a “how-to” technique using helical tomotherapy and linear accelerator-based intensity-modulated radiotherapy. Int. J. Radiat. Oncol. Biol. Phys. 78:1244–52; 2010. 8. Scrimger, R.A.; Stavrev, P.; Parliament, M.B.; et al. Phenomenologic model describing flow reduction for parotid gland irradiation with intensity-modulated radiotherapy: evidence of significant recovery effect. Int. J. Radiat. Oncol. Biol. Phys. 60:178–85; 2004. 9. McTyre, E.; Scott, J.; Chinnaiyan, P. Whole brain radiotherapy for brain metastasis. Surg. Neurol. Int. 4:S236–44; 2013. 10. Pinna, R.; Campus, G.; Cumbo, E.; et al. Xerostomia induced by radiotherapy: an overview of the physiopathology, clinical evidence, and management of the oral damage. Ther. Clin. Risk Manag. 11:171–88; 2015. 11. Lee, S.W.; Kang, K.W.; Wu, H.G. Prospective investigation and literature review of tolerance dose on salivary glands using quantitative salivary gland scintigraphy in the intensity-modulated radiotherapy era. Head Neck 38(suppl. 1):E1746–55; 2016. 12. Hawkey, N.M.; Zaorsky, N.G.; Galloway, T.J. The role of radiation therapy in the management of sialorrhea: a systematic review. Laryngoscope 126:80–5; 2016.
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17. Loos, G.; Paulon, R.; Verrelle, P.; et al. Whole brain radiotherapy for brain metastases: the technique of irradiation influences the dose to parotid glands. Cancer Radiother. 16:136–9; 2012. 18. Fiorentino, A.; Caivano, R.; Chiumento, C.; et al. Technique of whole brain radiotherapy: conformity index and parotid glands. Clin. Oncol. 24:e140–1; 2012. 19. Cho, O.; Chun, M.; Park, S.H.; et al. Parotid gland sparing effect by computed tomography-based modified lower field margin in whole brain radiotherapy. Radiat. Oncol. J. 31:12–7; 2013. 20. Orton, A.; Gordon, J.; Vigh, T.; et al. (p138) dosimetric evaluation of parotid dose in whole-brain radiation plans covering C1 vs C2. Oncology 29:2015.