Abstract

Purpose

Periorbital tumor location presents a significant challenge with 3-dimensional conformal radiation therapy or intensity modulated radiation therapy due to high tumor dose needed in the setting of close proximity to orbital structures with lower tolerance. Proton beam therapy (PBT) is felt to be an effective modality in such cases due to its sharp dose gradient.

Materials and Methods

We reviewed our institutional PBT registry and identified 17 patients with tumor epicenters within 2 cm of the eye and optic apparatus treated with passive scatter PBT with comparison volumetric arc therapy plans available. Maximum and mean doses to organs at risk of interest, including optic nerves, optic chiasm, lens, eye ball, pituitary, cochlea, lacrimal gland, and surrounding brain, were compared using the paired Wilcoxon signed rank test. Overall survival was determined using the Kaplan-Meier method.

Results

Median age was 67. Median follow-up was 19.7 months. Fourteen patients underwent upfront resection and received postoperative radiation and 3 received definitive radiation. One patient received elective neck radiation, 2 underwent reirradiation, and 3 had concurrent chemotherapy. There was a statistically significant reduction in mean dose to the optic nerves and chiasm, brain, pituitary gland, lacrimal glands, and cochlea as well as in the maximum dose to the optic nerves and chiasm, pituitary gland, lacrimal glands, and cochlea with PBT. The 18-month cumulative incidence of local failure was 19.1% and 1-year overall survival was 80.9%.

Conclusion

Proton beam therapy resulted in significant dose reductions to several periorbital and optic structures compared with volumetric arc therapy. Proton beam therapy appears to be the optimal radiation modality in such cases to minimize risk of toxicity to periorbital organs at risk.

Introduction

Periorbital tumors refer to lesions arising in proximity to the optic structures, including the nasal cavity, nasopharynx, paranasal sinus, adjacent dura, and skin. These tumors can be of varying histologic types, including squamous cell, basal cell, melanoma, adenoid cystic, adenocarcinoma, lymphoma, or sarcoma. Surgery when possible is considered the standard of care treatment in this region, especially for cutaneous lesions [1]. Adjuvant radiation therapy (RT) is often indicated when there are other high-risk features for recurrence, such as close or positive margins, bone invasion, perineural invasion, or history of recurrence(s). Radiation therapy can also be delivered in the definitive setting as an alternative to surgical intervention. This is typically performed when surgical resection cannot be accomplished without significant morbidity or if the patient is felt to be medically unfit for surgery.

The role of photon or X-ray and electron radiation in the treatment of orbital and periorbital lesions is well established [24]. Unlike photons, protons are charged particles. While considered biologically similar to conventional, photon radiation, they differ physically with a defined range depending on energy. Specifically, protons deposit most of their energy toward the end of their path, as defined by the Bragg peak, which allows for sparing of distal structures. Consequently, the primary advantage of PBT is decreased collateral damage due to a lower integral dose to the surrounding normal tissues, reported to be as high as 60% [5]. In the orbital location protons have been used in the management of ocular melanomas [6, 7], choroidal metastases [8], and orbital rhabdomyosarcomas [9] with good results. The aim of our study was to further evaluate the outcomes and dosimetry of PBT in the management of periorbital tumors. To the best of our knowledge, clinical experience using proton therapy specifically for periorbital tumors has not been reported to date.

Materials and Methods

To compare dosimetry and outcomes in periorbital tumors a retrospective review was conducted of the institutional review board–approved proton registry at our institution. Patients treated with curative intent PBT for tumors that had an epicenter within 2 cm of the orbit and had an intensity modulated radiation therapy (volumetric arc therapy [VMAT]) plan available for comparison were included. Both patients who received adjuvant RT and those that received definitive RT, with or without chemotherapy were included. Patients who received reirradiation were eligible as long as the dose delivered was considered to be curative. Patients were included if they received elective radiation to the ipsilateral neck. Of note, patients that require treatment to the bilateral neck are not treated with proton therapy at our institution.

From 2016-2019, 17 patients were treated who met study criteria. Target volumes were delineated primarily using computed tomography (CT) with or without contrast. Positron emission tomography/CT and magnetic resonance imaging information were also used when available. Passive scatter PBT and VMAT plans were generated with Pinnacle planning software (Philips Radiation Oncology Systems, Fitchburg, WI). Photon bean therapy planning was based on the clinical target volume (CTV). The number of beam angles chosen varied across patients from 2 to 4. The distal and proximal margins on the CTV were generated using a 3.5% range and 3 mm. The compensator smearing is calculated for each beam angle based on a setup error of 5 mm. VMAT plans were optimized using the planning target volume. Robust VMAT plans were produced not only for direct comparison, but also for clinical use as a backup in the event of proton machine downtime.

Maximum and mean doses to organs at risk (OARs) of interest, including optic nerves, optic chiasm, lens, globe, pituitary gland, cochlea, lacrimal gland, and surrounding brain, were recorded for both proton therapy and comparison VMAT plans. All patients were treated primarily with PBT and were immobilized using a custom thermoplastic face mask, head pad, and mouth piece. Daily, pretreatment alignment, orthogonal kilovoltage radiographs were obtained and compared with CT-generated digital reconstructed radiographs to ensure accurate delivery. In the event of machine downtime patients were treated with photons using VMAT technique with cone beam CT for image guidance.

Maximum and mean doses were collected for OARs. Paired structures were denoted as left or right. Doses were subsequently compared for proton and VMAT plans using a paired Wilcoxon signed rank test with corrections to control the false-discovery rate. A corrected P value ≤ .05 was determined to be statistically significant. Clinical follow-up data were retrospectively collected using chart review. Available information included clinical examinations, imaging, and toxicity assessments. Local control was recorded using pathologic information when obtained. However, local failure was recorded on the basis of clinical and/or radiographic findings when pathologic proof was not available. Overall survival was determined using available medical records and obituary reports and reported using the Kaplan-Meier method. All clinical outcomes are presented in an observational fashion. Acute and late toxicity are both reported using Common Terminology Criteria for Adverse Events, version 5 (US National Cancer Institute, Bethesda, MD).

Results

The median age of the 17 patients included was 67 (range, 38-91). Nine patients were male and 8 female. The most common histology was squamous cell carcinoma, which was present in 5 patients. The most common primary site was the nasal cavity. A full list of patient characteristics is given in Table 1. Fourteen of 17 patients underwent initial surgical resection and received postoperative radiation and 3 received definitive radiation. Concurrent chemotherapy was used in 1 patient who received definitive radiation and in 2 additional patients in the postoperative setting. One patient had elective neck radiation performed. Two patients received reirradiation to a median dose of 62 GyRBE.

Table 1.

Demographic and disease characteristics of patients with periorbital tumors treated with proton therapy.

Demographic and disease characteristics of patients with periorbital tumors treated with proton therapy.
Demographic and disease characteristics of patients with periorbital tumors treated with proton therapy.

All patients included had VMAT plans available for comparison. Results from comparative dosimetry are shown in Table 2. With respect to mean dose, there was a statistically significant reduction in dose to the optic nerves and chiasm, brain, pituitary gland, lacrimal glands, and cochlea with proton therapy. With respect to maximum dose, there was a statistically significant reduction in dose to the optic nerves and chiasm, pituitary gland, lacrimal glands, and cochlea with proton therapy. Coverage to the target structures was compared using the mean dose with the CTV as proton therapy plans were generated based on the CTV. The median mean dose to the CTV was 104.36% (102.10%-105.65%) of the prescribed dose with protons and 103.59% (100%-104.43%) with photons.

Table 2.

Dosimetric comparison of maximum and mean doses to OARs between photon and proton therapy.

Dosimetric comparison of maximum and mean doses to OARs between photon and proton therapy.
Dosimetric comparison of maximum and mean doses to OARs between photon and proton therapy.

The median follow-up of all patients included was 19.7 months (range, 4.8-42.4 months). The median follow-up for patients who remain living was 22.0 months. Currently, there have been 3 incidences of local failure, 1 with concomitant distant failure. There has been 1 distant only failure and 0 isolated regional failures. There were no patients who experienced local failure and received salvage local therapy. The cumulative incidence of local failure at 18 months was 19.1%, illustrated in Figure 1. There has been a total of 3 deaths to date, all in patients with recurrent/persistent disease. One patient died of distant disease without pathologic, radiographic, or clinical evidence of local failure. Overall survival at 12 months was determined to be 80.9% and is depicted in Figure 2.

Figure 1.

Local control of patients with periorbital tumors treated with PBT. Abbreviation: PBT, proton beam therapy.

Figure 1.

Local control of patients with periorbital tumors treated with PBT. Abbreviation: PBT, proton beam therapy.

Figure 2.

Overall survival of patients with periorbital tumors treated with PBT. Abbreviation: PBT, proton beam therapy.

Figure 2.

Overall survival of patients with periorbital tumors treated with PBT. Abbreviation: PBT, proton beam therapy.

Proton therapy was tolerated well overall. The most common acute toxicities to occur during or within 90 days of proton therapy were radiation dermatitis and mucositis. There were no acute toxicities related to the orbit, eye or visual apparatus, aside from dermatitis of the overlying or nearby skin. The overall incidence of acute grade III toxicity was low, occurring in only 2 patients (11.8%). There were 0 acute grade IV/V toxicities. A full list of acute toxicities is given in Table 3. At a median follow-up of 19.7 months, there have been a total of 7 late toxicities that occurred more than 90 days after completion of proton therapy. Only 1 late grade III toxicity has been observed to date and no grade IV/V toxicities. A full list of late toxicities is given in Table 4. With respect to visual toxicity, there has been 1 patient who developed asymptomatic dry eye as a late effect. No instances of cataracts, vision loss, or other ocular toxicity have been reported.

Table 3.

Acute toxicity in patients with periorbital tumors treated with PBT (within 90 days of PBT completion).

Acute toxicity in patients with periorbital tumors treated with PBT (within 90 days of PBT completion).
Acute toxicity in patients with periorbital tumors treated with PBT (within 90 days of PBT completion).
Table 4.

Late toxicity in patients with periorbital tumors treated with PBT (>90 days from date of PBT completion).

Late toxicity in patients with periorbital tumors treated with PBT (>90 days from date of PBT completion).
Late toxicity in patients with periorbital tumors treated with PBT (>90 days from date of PBT completion).

Discussion

The treatment of periorbital tumors generally depends on the size, specific location, and extent of invasion. The development of an optimal treatment regimen for each patient usually involves close cooperation between the surgeon and radiation oncologist. Surgery is often the preferred initial local modality for malignancies in this location, except in cases of large tumors, recurrent disease, deeply invasive tumors, tumors with perineural invasion, and tumors with orbital invasion [10].

Use of radiation therapy in periorbital locations has been previously reported. Petsuksiri et al [11] reported a local control rate of 88% in 42 eyelid squamous cell carcinomas treated with kilovoltage X-rays and electrons to a median dose 50 to 55.25 Gy. In another large series of 850 patients with eyelid cancers treated with contact therapy or conventional RT or electrons (45-70 Gy), Schlienger et al [2] reported a local control rate of 97.5%. Our local control rate with protons (80.9% at 18 months) was comparable to these reports of conventional RT. This was achieved with excellent sparing of the visual apparatus and other OARs.

The benefit of proton therapy has been well described for tumors that originate from the globe itself across several tumor types, such as rhabdomyosarcoma and uveal melanoma. Several series have reported low rates of toxicity when used in either the definitive [9], or postoperative setting [12]. In addition, definitive proton therapy has been shown to be a feasible strategy for organ preservation when the eye cannot be preserved with surgery [13, 14]. However, the benefit of proton therapy in periorbital tumors is not well described, despite the close proximity to similar OARs. This study has shown that there are numerous benefits to proton therapy in terms of dosimetry and patients experienced a low burden of both acute toxicity and late toxicity. Of note, these dosimetric benefits were observed without compromising coverage to the CTV. Unfortunately, there is no comparison group available to determine if side effects were reduced with the favorable dosimetric profile of protons. However, a prior study of patients with skin cancers in the same region treated with photons or electrons noted a 1.4% risk of serious complications, such as vitreous hemorrhage, glaucoma, and loss of the eye [2]. In addition, in this series, 2.4% of patients developed keratitis, 4% xerosis, 4.5% ectropion, and 11.5% watering of the eye(s). Another study of patients with periorbital lymphoma found that 19.1% of patients develop corneal toxicity and 21.3% developed dry eye, although serious complications, such as glaucoma, were rare [3]. While long-term follow-up is currently premature, outcomes with proton therapy in the current study appear favorable because no patients have developed symptomatic late or persistent toxicity of the eye or orbit.

While the dosimetry for the nonproton plans would be considered acceptable per most standards, it is important to consider the benefit of reducing integral dose to OARs. Many potential toxicities that occur from radiation of structures near the orbit do not have well defined threshold values, such as the risk of brain atrophy and secondary malignancy. The median follow-up in this study remains relatively short and the lack of a comparative group treated with photons precludes a comparative analysis of late adverse events from radiation. However, prior studies suggest that reductions in mean dose to the brain lead to less brain atrophy [15]. In addition, the risk of secondary malignancy after radiation to the brain is apparent even at low mean brain doses, with the risk increasing as mean dose to the brain increases [16]. This suggests that the relative reduction in mean brain dose seen in this study could reduce the risk of secondary malignancy, despite the overall low mean dose given to the brain using photon therapy. To better illustrate the reduction in integral dose using proton therapy, Figures 3 and 4 display the relative doses from corresponding proton and VMAT plans that were generated to treat 1 of the patients included in this study. The prescribed dose in this case was 50.4 GyRBE delivered in 1.8 GyRBE per fraction. A subtraction image is also included (Figure 5).

Figure 3.

Axial, sagittal, and coronal cross-sections taken from the VMAT plan of a representative patient. The CTV is shaded in teal, the brainstem is shaded in light green, and ipsilateral optic nerve is shaded in red. The 95% isodose line is shown in red, 50% isodose line in blue, 25% isodose line in green, and 10% isodose line in orange. Abbreviations: CTV, clinical target volume; VMAT, volumetric arc therapy.

Figure 3.

Axial, sagittal, and coronal cross-sections taken from the VMAT plan of a representative patient. The CTV is shaded in teal, the brainstem is shaded in light green, and ipsilateral optic nerve is shaded in red. The 95% isodose line is shown in red, 50% isodose line in blue, 25% isodose line in green, and 10% isodose line in orange. Abbreviations: CTV, clinical target volume; VMAT, volumetric arc therapy.

Figure 4.

Axial, sagittal, and coronal cross-sections taken from the PBT plan of a representative patient. The CTV is shaded in teal, the brainstem is shaded in light green, and ipsilateral optic nerve is shaded in red. The 95% isodose line is shown in red, 50% isodose line in blue, 25% isodose line in green, and 10% isodose line in orange. Abbreviations: CTV, clinical target volume; PBT, proton beam therapy.

Figure 4.

Axial, sagittal, and coronal cross-sections taken from the PBT plan of a representative patient. The CTV is shaded in teal, the brainstem is shaded in light green, and ipsilateral optic nerve is shaded in red. The 95% isodose line is shown in red, 50% isodose line in blue, 25% isodose line in green, and 10% isodose line in orange. Abbreviations: CTV, clinical target volume; PBT, proton beam therapy.

Figure 5.

Digital subtraction images that were generated to show differences in integral dose. Positive percentages indicate areas where VMAT delivered higher dose while negative percentages indicate areas where PBT delivered higher dose. Abbreviations: PBT, proton beam therapy; VMAT, volumetric arc therapy.

Figure 5.

Digital subtraction images that were generated to show differences in integral dose. Positive percentages indicate areas where VMAT delivered higher dose while negative percentages indicate areas where PBT delivered higher dose. Abbreviations: PBT, proton beam therapy; VMAT, volumetric arc therapy.

Another previously described risk of radiation to tumors in this region is late toxicity in the form of hypopituitarism [17]. The risk of hormone deficiencies as a result of radiation to tumors in the sella is high when the pituitary gland itself is often within the high-dose planning target volume. Hypopituitarism after radiation of nearby structures where the sella does not receive prescription dose is less well described. However, several series have shown that there is a linear dose response without a practical threshold, where increasing mean doses of radiation to the pituitary gland are more likely to cause hormone deficiencies [1820]. As a result, the reduction in dose with the use of proton therapy seen in this study could be hypothesized to reduce the risk of hypopituitarism.

A significant concern with PBT for periorbital tumors is uncertainty in dose delivery secondary to tissue changes during treatment. A large portion of patients included in this study had tumors located in the paranasal sinuses, nasal cavity, or nasopharynx. All of these locations are subject to changes in aeration of the sinuses. This has been previously shown to alter dose distributions in patients, which subsequently increased to dose to OARs [21]. Institutional strategies to reduce the risk of toxicity from such uncertainty include using multiple beams for treatment delivery as well as avoiding beam ranging into a common structure, particularly the optic apparatus or brainstem, which have well-established dose thresholds. A robustness analysis is also performed to account for range uncertainty. Patients who are at high risk for tissue changes, such as those with tumors arising in the paranasal sinuses or nasal cavity, are also scheduled to undergo repeat CT simulations during their treatment course. The dose distribution is then recomputed using the initial treatment plan to evaluate the maximum, minimum, and mean dose to the target area and organs at risk. Treatments for patients who exhibit significant changes are then replanned at the discretion of the treating physician.

We do acknowledge several limitations of our study. Being retrospective in nature, there may be an inherent selection bias to patients receiving PBT as only patients with insurance approval are treated with proton therapy. The comparison between proton and photon therapy is based on dosimetry and the lack of brain magnetic resonance imaging scans for most patients precludes analysis of dose to some OARs that cannot be defined using CT alone, such as the hippocampi. Although proton therapy was associated with reduced dose to several OARs, it can only be hypothesized that this differential reduces the burden of acute and/or late toxicity due to lower integral dose. In addition, clinical situations may arise where the lower integral dose associated with passive scatter PBT is not preferable to VMAT, which can generate sharper dose fall-off around irregularly shaped target volumes that are in close proximity to OARs. Despite this gradient consideration, it was encouraging that we did not observe any significant visual toxicity with PBT and reduction in both mean and maximum doses were noted. It is also possible that the risk or severity of cutaneous toxicity is higher in this location with proton therapy due to reduced skin sparing. However, no late effects to the skin were observed to date. A larger study with longer follow-up would be needed to help establish if late toxicities are acceptable. Last, the patients treated with proton therapy in this study were treated with passive scatter, not intensity modulated proton therapy. The latter has been shown to further reduce dose to OARs in certain locations [22, 23]. Despite the above limitations, we do believe that our study contributes positively to existing literature. To the best of our knowledge, our series is the first to report clinical experience and advantages of proton therapy specifically for tumors in the periorbital location.

In conclusion, early results of proton therapy in the management of periorbital tumors show excellent tumor control with an acceptable toxicity profile. Proton therapy can be used in primary and recurrent periorbital tumors in either the definitive or postoperative setting. Longer follow-up is needed to further assess tumor control endpoints and late toxicities, but preliminary results are encouraging. This modality is safe and should be considered an effective management option as adjunct or alternative to surgery in this challenging tumor location.

ADDITIONAL INFORMATION AND DECLARATIONS

Conflicts of Interest: Mitchell X. Machtay, MD reports travel funding from Mevion Inc. and Varian Inc., and grants and travel funding from Elekta Inc., outside the submitted work. The authors have no other relevant conflicts of interest to disclose.

Ethical Approval: All patient data were collected under internal review board–approved protocol.

References

References
1. 
Avril
MF,
Auperin
A,
Margulis
A,
Gerbaulet
A,
Duvillard
P,
Benhamou
E,
Guillaume
JC,
Chalon
R,
Petit
JY,
Sancho-Garnier
H,
Prade
M,
Bouzy
J,
Chassagne
D.
Basal cell carcinoma of the face: surgery or radiotherapy? Results of a randomized study
.
Br J Cancer
.
1997
;
76
:
100
6
.
2. 
Schlienger
P,
Brunin
F,
Desjardins
L,
Laurent
M,
Haye
C,
Vilcoq
JR.
External radiotherapy for carcinoma of the eyelid: report of 850 cases treated
.
Int J Radiat Oncol Biol Phys
.
1996
;
34
:
277
87
.
3. 
Bhatia
S,
Paulino
AC,
Buatti
JM,
Mayr
NA,
Wen
BC.
Curative radiotherapy for primary orbital lymphoma
.
Int J Radiat Oncol Biol Phys
.
2002
;
54
:
818
23
.
4. 
Hayashi
K,
Hatsuno
K,
Yoshimura
R,
Iida
T,
Ayukawa
F,
Toda
K,
Taniguchi
H,
Shibuya
H.
Electron therapy for orbital and periorbital lesions using customized lead eye shields
.
Ophthalmologica
.
2009
;
223
:
96
101
.
5. 
DeLaney
TF.
Proton therapy in the clinic
.
Front Radiat Ther Oncol
.
2011
;
43
:
465
85
.
6. 
Gragoudas
ES,
Lane
AM,
Regan
S,
Li
W,
Judge
HE,
Munzenrider
JE,
Seddon
JM,
Egan
KM.
A randomized controlled trial of varying radiation doses in the treatment of choroidal melanoma
.
Arch Ophthalmol
.
2000
;
118
:
773
8
.
7. 
Egger
E,
Zografos
L,
Schalenbourg
A,
Beati
D,
Bohringer
T,
Chamot
L,
Goitein
G.
Eye retention after proton beam radiotherapy for uveal melanoma
.
Int J Radiat Oncol Biol Phys
.
2003
;
55
:
867
80
.
8. 
Tsina
EK,
Lane
AM,
Zacks
DN,
Munzenrider
JE,
Collier
JM,
Gragoudas
ES.
Treatment of metastatic tumors of the choroid with proton beam irradiation
.
Ophthalmology
.
2005
;
112
:
337
43
.
9. 
Yock
T,
Schneider
R,
Friedmann
A,
Adams
J,
Fullerton
B,
Tarbell
N.
Proton radiotherapy for orbital rhabdomyosarcoma: clinical outcome and a dosimetric comparison with photons
.
Int J Radiat Oncol Biol Phys
.
2005
;
63
:
1161
8
.
10. 
Reddy
K,
Strom
T,
Chen
C.
Primary radiotherapy for locally advanced skin cancer near the eye
.
Pract Radiat Oncol
.
2012
;
2
:
63
72
.
11. 
Petsuksiri
J,
Frank
SJ,
Garden
AS,
Ang
KK,
Morrison
WH,
Chao
KS,
Rosenthal
DI,
Schwartz
DL,
Ahamad
A,
Esmaeli
B.
Outcomes after radiotherapy for squamous cell carcinoma of the eyelid
.
Cancer
.
2008
;
112
:
111
8
.
12. 
Holliday
EB,
Esmaeli
B,
Pinckard
J,
Garden
AS,
Rosenthal
DI,
Morrison
WH,
Kies
MS,
Gunn
GB,
Fuller
CD,
Phan
J,
Beadle
BM,
Zhu
XR,
Zhang
X,
Frank
SJ.
A multidisciplinary orbit-sparing treatment approach that includes proton therapy for epithelial tumors of the orbit and ocular adnexa
.
Int J Radiat Oncol Biol Phys
.
2016
;
95
:
344
352
.
13. 
Egger
E,
Zografos
L,
Schalenbourg
A,
Beati
D,
Böhringer
T,
Chamot
L,
Goitein
G.
Eye retention after proton beam radiotherapy for uveal melanoma
.
Int J Radiat Oncol Biol Phys
.
2003
;
55
:
867
80
.
14. 
Polishchuk
AL,
Mishra
KK,
Weinberg
V,
Daftari
IK,
Nguyen
JM,
Cole
TB,
Quivey
JM,
Phillips
TL,
Char
DH.
Temporal evolution and dose-volume histogram predictors of visual acuity after proton beam radiation therapy of uveal melanoma
.
Int J Radiat Oncol Biol Phys
.
2017
;
97
:
91
7
.
15. 
Guo
Z,
Han
L,
Yang
Y,
He
H,
Li
J,
Chen
H,
Song
T,
Qiu
Y,
Lv
X.
Longitudinal brain structural alterations in patients with nasopharyngeal carcinoma early after radiotherapy
.
Neuroimage Clin
.
2018
;
19
:
252
9
.
16. 
Thierry-Chef
I,
Simon
SL,
Land
CE,
Miller
DL.
Radiation dose to the brain and subsequent risk of developing brain tumors in pediatric patients undergoing interventional neuroradiology procedures
.
Radiat Res
.
2008
;
170
:
553
65
.
17. 
Darzy
KH,
Shalet
SM.
Hypopituitarism following radiotherapy
.
Pituitary
.
2009
;
12
:
40
50
.
18. 
Vatner
RE,
Niemierko
A,
Misra
M,
Weyman
EA,
Goebel
CP,
Ebb
DH,
Jones
RM,
Huang
MS,
Mahajan
A,
Grosshans
DR,
Paulino
AC,
Stanley
T,
MacDonald
SM,
Tarbell
NJ,
Yock
TI.
Endocrine deficiency as a function of radiation dose to the hypothalamus and pituitary in pediatric and young adult patients with brain tumors
.
J Clin Oncol
.
2018
;
36
:
2854
62
.
19. 
VanKoevering
KK,
Sabetsarvestani
K,
Sullivan
SE,
Barkan
A,
Mierzwa
M,
McKean
EL.
Pituitary dysfunction after radiation for anterior skull base malignancies: incidence and screening
.
J Neurol Surg B Skull Base
.
2020
;
81
:
75
81
.
20. 
Agha
A,
Sherlock
M,
Brennan
S,
O'Connor
SA,
O'Sullivan
E,
Rogers
B,
Faul
C,
Rawluk
D,
Tormey
W,
Thompson
CJ.
Hypothalamic-pituitary dysfunction after irradiation of nonpituitary brain tumors in adults
.
J Clin Endocrinol Metab
.
2005
;
90
:
6355
60
.
21. 
Fukumitsu
N,
Ishikawa
H,
Ohnishi
K,
Terunuma
T,
Mizumoto
M,
Numajiri
H,
Aihara
T,
Okumura
T,
Tsuboi
K,
Sakae
T,
Sakurai
H.
Dose distribution resulting from changes in aeration of nasal cavity or paranasal sinus cancer in the proton therapy
.
Radiother Oncol
.
2014
;
113
:
72
6
.
22. 
Boehling
NS,
Grosshans
DR,
Bluett
JB,
Palmer
MT,
Song
X,
Amos
RA,
Sahoo
N,
Meyer
JJ,
Mahajan
A,
Woo
SY.
Dosimetric comparison of three-dimensional conformal proton radiotherapy, intensity-modulated proton therapy, and intensity-modulated radiotherapy for treatment of pediatric craniopharyngiomas
.
Int J Radiat Oncol Biol Phys
.
2012
;
82
:
643
52
.
23. 
Zhang
X,
Li
Y,
Pan
X,
Xiaoqiang
L,
Mohan
R,
Komaki
R,
Cox
JD,
Chang
JY.
Intensity-modulated proton therapy reduces the dose to normal tissue compared with intensity-modulated radiation therapy or passive scattering proton therapy and enables individualized radical radiotherapy for extensive stage IIIB non-small-cell lung cancer: a virtual clinical study
.
Int J Radiat Oncol Biol Phys
.
2010
;
77
:
357
66
.
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