Supplementary Table 1: Clinical characteristics of the 41 NPC patients and 21 patients with NPC and unilateral TLN

Characteristic Value for the 41 NPC patients Value for the 21 NPC patients with unilateral TLNNumber 41 21

Gender

Male 31 16

Female 10 5

Age (years)

≤ 40 13 8

> 40 28 13

T stagea

T1 7 1

T2 9 1

T3 17 3

T4 8 16

N stagea

N0 6 4

N1 20 12

N2 11 5

N3 4 0

Overall stagea

I 2 1

II 11 1

III 16 3

IV 12 16

Radiation techniqueb

VMAT 17 0

Static IMRT 24 21

Chemotherapy

No 6 3

Yes 35 18

Involved laterality

Left side 13

Right side 8

Abbreviations: TLN, temporal lobe necrosis; IMRT, intensity modulated radiotherapy; VMAT, volumetric modulated arc therapyaAccording to the 7th AJCC/UICC staging system.bAll the patients were treated with IMRT including 17 with VMAT and 24 with static IMRT.

Supplementary Table 2: Comparison of dosimetric parameters between temporal lobes with and without TLN using the two contouring methods

Dosimetric parameters

Method 1a Method 2b

t Mean difference P-value t Mean difference P-valueD0.1ccc 6.15 10.46 <0.001 6.09 10.40 <0.001D0.5cc 5.08 8.03 <0.001 6.84 11.87 <0.001D1cc 6.98 12.84 <0.001 7.01 12.86 <0.001D5cc 7.12 14.28 <0.001 7.70 14.81 <0.001

D10cc 5.92 12.91 <0.001 6.55 13.45 <0.001D15cc 4.70 10.09 <0.001 5.08 10.49 <0.001D20cc 3.80 7.29 0.001 4.26 7.77 <0.001D25cc 3.52 5.44 0.002 3.96 5.79 0.001D30cc 3.44 3.45 0.004 4.18 4.24 0.001D35cc 2.42 1.97 0.025 4.42 3.03 <0.001D40cc 2.00 1.31 0.049 3.85 2.17 0.001

D1d 7.06 12.54 <0.001 7.14 12.90 <0.001D2 7.23 13.82 <0.001 7.25 14.12 <0.001D5 7.84 14.89 <0.001 8.04 15.05 <0.001D10 7.12 14.66 <0.001 7.01 14.16 <0.001D15 6.17 13.02 <0.001 5.46 11.66 <0.001D20 4.98 11.33 <0.001 4.58 9.12 <0.001D25 4.61 8.91 <0.001 4.20 6.84 0.001D30 4.21 7.05 0.001 4.23 4.96 <0.001D35 4.62 5.75 <0.001 4.81 3.98 <0.001D40 4.51 4.19 <0.001 4.39 3.00 <0.001D45 4.03 3.14 0.001 3.98 2.27 0.001D50 3.63 2.36 0.002 3.74 1.77 0.001D55 3.61 1.76 0.002 3.67 1.51 0.002D60 3.59 1.4 0.002 3.71 1.47 0.001V10e 3.32 4.88 0.003 3.17 5.28 0.005V20 5.13 5.86 <0.001 5.31 6.15 <0.001V25 5.95 7.16 <0.001 6.16 6.79 <0.001V30 6.97 8.72 <0.001 6.95 7.69 <0.001V35 6.77 9.71 <0.001 6.86 8.18 <0.001V40 6.18 10.01 <0.001 6.48 8.26 <0.001V45 5.84 9.89 <0.001 6.10 8.03 <0.001V50 2.72 3.37 0.013 5.81 7.78 <0.001V55 5.19 8.61 <0.001 5.39 7.02 <0.001V60 4.75 7.07 <0.001 4.78 5.75 <0.001V65 3.88 4.93 0.001 3.88 4.01 0.001V70 2.85 2.64 0.01 2.87 2.20 0.009V75 2.06 0.83 0.042 2.19 0.72 0.041

Volume 2.92 3.62 0.009 2.26 3.10 0.035Dmean 5.83 4.98 <0.001 5.83 4.36 <0.001

D1 of PRVf 7.35 11.48 <0.001 7.50 11.80 <0.001D5 of PRV 7.80 14.19 <0.001 8.20 14.73 <0.001D10 of PRV 6.80 14.18 <0.001 7.27 14.73 <0.001D15 of PRV 5.95 13.14 <0.001 5.72 12.45 <0.001

D20 of PRV 4.93 11.02 <0.001 4.71 9.59 <0.001D25 of PRV 4.30 8.60 <0.001 4.29 7.15 <0.001D30 of PRV 4.01 6.77 0.001 4.20 5.25 <0.001D35 of PRV 3.94 5.07 0.001 4.26 3.92 <0.001D40 of PRV 4.16 3.88 <0.001 4.38 3.06 <0.001D45 of PRV 3.89 2.93 0.001 4.13 2.35 0.001D50 of PRV 3.70 2.23 0.001 3.91 1.88 0.001D55 of PRV 3.72 1.66 0.001 3.76 1.59 0.001D60 of PRV 3.44 1.25 0.003 3.57 1.40 0.002V20 of PRV 5.31 5.66 <0.001 5.21 5.72 <0.001V25 of PRV 5.73 6.88 <0.001 6.01 6.70 <0.001V30 of PRV 6.94 8.77 <0.001 6.70 7.73 <0.001V35 of PRV 6.59 9.40 <0.001 6.82 8.28 <0.001V40 of PRV 6.22 9.61 <0.001 6.52 8.31 <0.001V45 of PRV 5.96 9.92 <0.001 6.31 8.06 <0.001V50 of PRV 5.74 9.17 <0.001 6.04 7.78 <0.001V55 of PRV 5.53 8.47 <0.001 5.76 7.18 <0.001V60 of PRV 5.05 7.16 <0.001 5.17 6.08 <0.001V65 of PRV 4.33 5,.30 <0.001 4.38 4.51 <0.001V70 of PRV 3.18 2.99 0.005 3.42 2.66 0.003V75 of PRV 2.45 1.10 0.024 2.55 0.98 0.019

Abbreviations: PRV=planning organ at risk volume; D mean= mean dose; TLN=temporal lobe necrosis;aTemporal lobe including the basal ganglia and insula, excluding parahippocampal gyrus and hippocampusbTemporal lobe including parahippocampal gyrus and hippocampus, excluding basal ganglia and insula.cD0.1cc is the minimum dose received by the ‘‘hottest’’ 0.1ml of the organ, the other D with suffixes

expresses the same meaning, but the suffix numbers represent the absolute volume.dD1 is the minimum dose received by the ‘‘hottest’’ 1% of the organ, the other D with suffixes express the same meaning, but the suffix numbers represent the percentage of volume.eV10 is the percentage of volume of temporal lobe that receives more than 10 Gy, the other V with suffixes express the same meaning, but the suffix numbers represent the doses received.f D1of PRV is the minimum dose received by the ‘‘hottest’’ 1% of the planning organ at risk volume of temporal lobe volume, the other Dx of PRV, Vx of PRV express the same meaning, but the prefix parameter represent the percentage of volume or the dose received.

Supplementary Table 3: Anatomic boundaries of the organs at risk in NPC.

Organ Standard TPS name [20]

Cranial Caudal Anterior Posterior Lateral Medial

TMJ TMjointa Disappearance of articular cavity

Appearance of the head of mandible or one slice superior to the sigmoid notch of the neck of mandible

Articular condyle of the temporal bone, ant. edge of mandibular condyle

Surface of fossa glenoid

Lat. edge of mandibular condyle or surface of fossa glenoid

Brainstem BrainStem Optic tract or the disappearance of posterior cerebral artery

Foramen magnum Post. edge of prepon- tine cistern or basilar artery

Ant. edge of forth ventricle or mesencephalic aqueduct

Posterior cerebral artery, anterior inferior cerebellar artery, cerebellar peduncle

Optic chiasm Chiasm One or two slices superiorly

Pituitary or suprasellar cistern

Optic canal Infundibulum Internal carotid arteries, middle cerebral arteries

Tongue(oral cavity)b

Tongue Post. edge of the hard palate or soft palate

Disappearance of anterior belly of digastric muscle

Post. edge of mandible or is free

Palate, oropharynx, the palatine tonsil, hyoid bone

Med. edge of the mandible or inferior alveoli socket

Larynx(larynx and laryngopharynx)

Larynx Cranial edge of epiglottis

Caudal edge of cricoid cartilage

Ant. edge of thyroid cartilage or cricoid cartilage

Including arytenoid cartilage, the superior and inferior horns of thyroid cartilage and post. edge of pharyngeal constrictor

Med. edge of hyoid bone, lat. edge of thyroid cartilage and cricoid cartilage， cervical vessels, nerves, and lateral thyroid

Upper Pharyngeal- Caudal edge of Cranial edge of hyoid Nasopharynx, Longus capitis m., Carotid sheath

pharyngeal constrictor [22]

Const_Upper pterygoid plates bone oropharynx, laryngopharynx, base of tongue

longus colli m., body of cervical vertebra

Middle pharyngeal constrictor [22]

Pharyngeal- Const_Middle

Cranial edge of hyoid bone

Caudal edge of hyoid bone

Laryngopharynx Longus capitis m., longus colli m., body of cervical vertebra

Hyoid bone

Inferior pharyngeal constrictor [22]

Pharyngeal- Const_Lower

Caudal edge of hyoid bone

Caudal edge of cricoid cartilage

Laryngopharynx or cricoids cartilage

Longus capitis m., longus colli m., body of cervical vertebra

Thyroid cartilage or thyroid gland

Trachea Trachea Caudal edge of cricoid cartilage

Two centimeters below the caudal edge of the clavicular head

Post. edge of isthmus of thyroid gland

Ant. edge of esophagus

Lateral thyroid gland One-two millimeters expanded from the lumen of trachea

Subman-dibular gland

Submandibulara Inferior edge of medial pterygoid or the level of C3

Appearance of fat space of submandibular triangle

Lat. surface of mylohyoid m. or hyoglossus m.

Parapharyngeal space, cervical vessels and post. belly of digastric m., sternocleidomastoid m.

Ramus of the mandible, subcutaneous fat or platysma

Cervical vessels, superior and middle pharyngeal constrictor m., hyoid bone, post. belly of the digastric m., mylohyoid m. or hyoglossus m.

Esophagus [22] Esophagus Caudal edge of cricoid cartilage

Two centimeters below the caudal edge of the clavicular head

Trachea Vertebral body or longus colli m.

Fat space or thyroid gland

Optic nerve [23] OpticNervea Below the superior rectus

Superior the inferior rectus

Posterior edge of the center of globe

Optic canal

Temporal lobe TemporalLobea Cranial edge of the Base of middle cranial Temporal bone and Petrous part of Temporal bone Cavernous sinus,

sylvian fissure fossa sylvian fissure， greater wing of sphenoid

temporal lobe, tentorium of cerebellum, incisura preoccipitalis

sphenoid sinus, sella turcica, and sylvian fissure（including parahippocampal gyrus and hippocampus

Parotid gland [21]

Parotida External auditory canal, mastoid process

Appearance post. part submandibular space

Masseter m. post. border mandibular bone, medial pterygoid m.

Ant. belly sternocleidomastoid m., lat. side post. belly of the digastric m. (posterior medial)， mastoid process

Submandibular fat, platysma

Post. belly of the digastric m., styloid process, parapharyngeal space， sternocleidomastoid

Spinal cord SpinalCord Disappearance of cerebellum

Two centimeters below the inferior edge of the clavicular head

Exclude the subarachnoid space

Brachial plexus [24]

BrachialPlexusa Caudal edge of C4 Caudal edge of T1 at neural foramina and one to two CT slices below the clavicular head as the posterior aspect of the neurovascularbundle

Anterior scalene muscle Middle scalene muscle

Fat space Spinal cord

Thyroid gland Thyroid Caudal edge of pyriform sinus or midpoint of thyroid

Body of fifth to seventh cervical vertebra

Sternohyoid or sternocleidomastoid

Cervical vessels or longus colli m.

Cervical vessels or sternocleidomastoid

Thyroid cartilage or cricoids cartilage or esophagus or

cartilage pharyngeal constrictor

Mandible Mandible The mandible be contoured as whole organ but not be divided into the left and the right. Contouring of the mandible should include alveolar bone and exclude the teeth.

Inner ear Ear_Innera Cochlea and IAC should be individually delineated and named.

Middle ear Ear_Middlea Tympanic cavity, bony part of ET should be individually delineated and named.

Eyes Eyesa Ensure the retina to be contoured completely.

Lens Lensa The boundary between the lens and the vitreum is obvious

Pituitary Pituitary The pituitary is located in the hypophysial fossa. Insure the organ be contoured completely but not beyond the surrounding bone. The pituitary is ovoid and can be visualized on 1-2 slices on CT scans of 3 mm thickness

Abbreviations: TMJ, temporomandibular joint; ET, Eustachian tube; IAC, internal auditory canal; m., muscle.a The organs should be divided into left and right, and the standard TPS name of laterality is indicated by appending an underscore character ( _ ), followed by L or R, respectively. For example, the left parotid is named Parotid_L; the right parotid is named Parotid_R.b include the base of the tongue, body of tongue and mouth floor.

Supplementary table 4: Abbreviations mentioned in the manuscript.

Abbreviations Full name

OAR organ at risk

TMJ temporomandibular joint

NPC nasopharyngeal carcinoma

PC pharyngeal constrictor

ET Eustachian tube

ROC receiver operating characteristic

TLN temporal lobe necrosis

IAC internal auditory canal

RT radiotherapy

GTV gross target volume

CTV clinical target volume

PTV planning target volume

PRV planning organ at risk volume

Dmean mean dose

Dmax maximum dose

S.E. standard error

SNHL sensorineural hearing loss

OME otitis media with effusion

IMRT intensity modulated radiotherapy

VMAT volumetric modulated arc therapy

AUC Area under the curve

Dx(xcc) minimum dose received by the ‘‘hottest’’ x% (or x ml) of the organ

Vx volume percentage of the organ receiving ≥ X Gy

Supplementary Figure 1. Receiver operating characteristic (ROC) curve analysis for the D1 of

the PRV using two different temporal lobe contouring methods in 21 NPC patients with

unilateral TLN.

Supplementary Figure 2. Recommended atlas of the tympanic cavity, Eustachian tube (ET), cochlea, IAC,

TMJ, temporal lobe, brainstem, parotid gland, spinal cord, optic nerve, chiasm, submandibular gland,

pituitary, mandible, eyes, lens, brachial plexus, tongue(oral cavity), larynx, pharyngeal constrictors and

trachea as OARs based on CT-MRI fusion in NPC patients.

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