The estimation of visual impairment after head and neck radiotherapy

Master thesis Medical SciencesC. de Groot

C. de Groot, s1726080Department of Radiation Oncology, University Medical Center Groningen (UMCG)September 2013 – January 2014

Supervisors:Dr. R.J.M. Steenbakkers, radiation oncologist, UMCGDr. H.P. Bijl, radiation oncologist, UMCG

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Abstract

Purpose: The purpose of this thesis is twofold: first, to analyse visual impairment in patients treated with radiotherapy for tumours adjacent the optic pathway, and to relate dose-volume histogram (DVH) parameters of optic structures to development of these visual deficits. Second, to evaluate current delineation and study delineation, based on a new guideline, of optic structures and analyse differences in DVH’s between these structures.

Methods and Materials: Between 2007 and 2013, 66 patients with tumours of the nasopharynx, nasal cavity, paranasal sinuses and skull-base were treated with curative intent, and received either definitive or postoperative (chemo)radiation using CT-planned radiotherapy. Patients were followed for at least 6 months after radiotherapy. Dosimetric parameters of the optic nerves, optic chiasm and optic tracts were derived from DVHs of both the original contours of the radiotherapy planning and the study contours according to the developed guideline.

Results: The median follow-up period was 31.5 months. Severe visual impairment occurred in 3.5% of cases. On average, maximum equivalent doses in 2-Gy fractionating (EQD2) to all optic structures were significantly higher for patients with any visual complication (mild to severe) (51,5 Gy) versus patients without complications (30.2 Gy, p=0,027). Of all optic structures, 22% received a maximum EQD2 exceeding the dose constraint of 56 Gy. The possibility of severe visual deficits increased remarkably when mean and maximum EQD2 doses exceeded 75 Gy and 65 Gy, respectively.The median chiasmal volume was 0.35cm³ (SD 0.05 cm³) and 0.64 cm³ (SD 0.38 cm³) for study an original contours, respectively. The average Dice and Jaccard coefficient were 0.18 (range, 0.00-0.61) and 0.11(range, 0.00-0.41). Among all original and study contours, mean and maximum doses to all structures were significantly different.

Conclusions: The results of this study suggest that currently used dose constraints to optic structures (Dmax <55-60 Gy) might be conservative since no severe visual impairment occurred when maximum EQD2 was <65 Gy. Poor consistency and accuracy in delineation of original optic structures for treatment planning was found, the use of a delineation guideline and fused MR-CT images in this study significantly improved these measures.

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Nederlandstalige samenvatting

Doel: Deze thesis beoogt twee doelen. Ten eerste het analyseren van visuele defecten bij patiënten die bestraald zijn voor tumoren nabij het optische systeem, en het relateren van dosis-volume histogram (DVH) parameters van individuele optische structuren aan het ontwikkelen van deze visuele problemen. Ten tweede het vergelijken van intekeningen van optische structuren en de bijbehorende DVH-parameters, enerzijds van de originele originele intekeningen en anderzijds van de studie-intekekingen, welke ingetekend zijn aan de hand van een nieuwe richtlijn.

Methoden en Materialen: Tussen 2007 en 2013 werden 66 patiënten met tumoren van de nasofarynx, neus(bij)holten en schedelbasis in curatieve opzet bestraald, al dan niet in combinatie met chirurgie of chemotherapie. De patiënten zijn minimaal 6 maanden gevolgd na de radiotherapie. Dosimetrische parameters van de nervi optici, het chiasma en de tracti optici werden afgeleid uit DVHs van zowel de originele intekening van de RT planning als studie intekeningen volgens de gemaakte richtlijn.

Resultaten: De mediane follow-up periode was 31.5 maanden. Van alle patiënten ontwikkelden 3.5% ernstige visuele beperkingen. De maximale equivalente dosis in fracties van 2 Gy (EQD2) was in alle optische structuren significant hoger bij alle patiënten die (milde tot ernstige) visuele klachten ondervonden (51,5 Gy) ten opzichte van patiënten zonder klachten (30.2 Gy, p=0,027). Van alle optische structuren ontving 22% een maximale EQD2 die de gehanteerde dosisrestrictie van 56 Gy overschreed. De kans op ernstige visuele beperkingen nam opmerkenswaardig toe wanneer de gemiddelde en de maximale EQD2 hoger waren dan respectievelijk 75 Gy en 65 Gy.De mediane vulumes van het chiasma waren respectievelijk 0.35cm³ (SD 0.05) en 0.64 cm³ (SD 0.38) voor studie en originele intekeningen. De gemiddelde en maximale EQD2 van beide intekeningen waren significant verschillend in alle optische structuren.

Conclusie: De resultaten van deze studie suggereren dat de dosis restricties die gehanteerd worden (Dmax <55-60 Gy) conservatief zijn omdat ernstige visuele problemen zich pas voordeden wanneer de maximale EQD2 <65 Gy was.De consistentie en de accuraatheid van de origineel ingetekende optische structuren was matig. Het gebruik van een intekenrichtlijn en gefuseerde MR-CT beelden voor de studie-intekeningen gaf een significante verbetering in deze metingen.

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Table of contents

ABSTRACT 3

NEDERLANDSTALIGE SAMENVATTING 4

TABLE OF CONTENTS 5

1. INTRODUCTION 6

1.1 Radiation-induced optic neuropathy 61.2 Radiotherapy techniques 111.3 Clinical relevance of clear tolerance doses and uniform delineation of optic structures 111.4 Aim of this study 12

2. METHODS AND MATERIALS 13

2.1 Study design 132.2 Patient identification and characteristics 132.3 Treatment planning 152.4 CT-MR fusion and revision delineation optic structures 162.5 Follow up and diagnosis of RION 192.6 Statistical methods 20

3. RESULTS 22

3.1 Survival and disease control 223.2 Visual deficits 223.3 Doses to optic structures 243.4 Evaluation of optic structure delineation 27

4. DISCUSSION 31

4.1 Rate of RION and dose 314.2 Delineation of optic structures 334.3 Radiosensitivity differences within structures 354.4 Further research 36

5. CONCLUSION 38

6. REFERENCES 39

7. ACKNOWLEDGEMENTS 43

8. APPENDIX 44

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1. Introduction

Each year, over 500.000 patients with head and neck squamous cell carcinomas (HNSCC) are diagnosed worldwide (1). Treatment consists of radiotherapy, either alone or in combination with surgery, chemotherapy, or both. Besides tumour control, the main goal of radiotherapy is the preserving the function of adjacent structures.Especially in the head and neck region, adequate treatment of these tumours is challenging for the radiation oncologist, because of the close proximity to several critical anatomic structures, such as the parotid and submandibular glands, brainstem, spinal cord, and optic structures. The doses needed to deliver curative radiation are often higher than normal tissue tolerance. As a consequence, radiation treatment of these tumours is associated with significant morbidity and mutilation, such as loss of voice, dry mouth, dysphagia, caries and visible defects in the head-and-neck area.

1.1 Radiation-induced optic neuropathy

Radiation-induced optic neuropathy (RION) is an infrequent but usually disabling late consequence of radiation to the optic pathways. It is an iatrogenic phenomenon, occurring in less than 1% of patients who have undergone radiation therapy for tumours in areas near the visual pathway, such as paranasal sinus (PNS)-, nasal cavity- and nasopharyngeal carcinomas, skull-base tumours, pituitary adenomas, parasellar meningiomas and other intracranial tumours (2,3). RION usually presents as rapid and painless decrease of visual acuity or visual fields. The damage is irreversible and can in severe cases lead to bilateral blindness, which is disastrous for quality of life (QOL). With improvements of radiotherapy treatment techniques, patients with head and neck tumours now have longer survival times (4). Because of this prolonged survival, more attention needs to be put in preventing RION, despite the fact that it is a rare consequence of radiotherapy.

1.1.1 PathophysiologyVascular damage due to radiation is a significant factor in developing RION. Although the exact pathogenesis is not fully understood, it is thought that injury is initiated by the generation of free radicals that damage normal tissues (3,5). It is likely that damage to both the vascular endothelium and the neuroglial cell progenitors is involved in the pathogenesis. Levin et al. (6) and Hudgins et al. (7) found significantly smaller numbers of vascular endothelial cells in human optic nerves of enucleated eyes that were treated with photon beam irradiation compared to unirradiated optic nerves. Whatever the exact cellular pathogenesis may be, the result is “3-H tissue”: hypovascular, hypocellular, and hypoxic (2,8). Pathologic specimens of optic nerves with RION are characterised by narrowed and occluded blood vessels, loss of axis cylinders and myelin, and the presence of fibrin exudates (9).RION is classified as anterior or posterior depending on the location of the injury. The anterior variant involves the optic nerve head and is characterised by optic disc swelling, peripapillary hemorrhages and retinal exudates. RION rarely presents as an anterior optic neuropathy, such cases occur in the setting of radiation retinopathy following treatment for orbital or intraocular

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lesions (9). All retrolaminar optic nerve and/or optic chiasm lesions are referred as posterior RION, in which the optic nerve head will appear normal (5). In both the anterior and posterior variant, optic nerve atrophy and pallor begins to develop between six and eight weeks after onset of visual deficits (10).

1.1.2 Clinical presentationRION presents with decline of vision or visual field defects in one or both eyes. Pain is exceptional (11). Characteristically, following the sudden onset, visual loss progresses over weeks (2). The visual field may show any pattern of optic nerve or chiasmal defects. Optic nerve injury can cause monocular vision loss (figure 1.1, no 1), a single central scotoma or altitudinal loss. Chiasmal injury can cause bitemporal heteronymous hemianopia (figure 1.1, no 2) if the lesion is located where the fibres of both nasal hemiretinas criss-cross. There will be loss of visual acuity in both temporal hemifields, unless the lesion limited to the inferior part of the central optic chiasm, which affect the upper quadrants. Injury of a lateral edge of the chiasm results in monocular nasal hemianopia (figure 1.1, no 3). The loss of a proximal optic tract causes homonymous lateral hemianopia (figure 1.1, no 4). It may affect all of the right or left visual hemifields. Because the optic tracts spread out on their way toward the occipital cortex, injuries along the way typically result in small visual field cuts (12,13).

Figure 1.1 Visual field defects.

The onset of visual symptoms associated with RION ranges from 3 months to more than 8 years after radiation exposure. However, the great majority of patients develop symptoms within 3

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years after completion of radiotherapy, with a peak incidence at 1-1.5 years (3,12,14). The latency of the onset of symptoms is usually shorter with higher doses of irradiation (11). 1.2.3 DiagnosisIn the literature, the criteria of Kline et al. (14) and Parsons et al. (11) are often used for diagnosing RION: 1) irreversible visual loss with visual field defects of optic nerve, chiasmal or optic tract origin; 2) absence of visual pathway compression caused by recurrence or progression of tumour, radiation induced neoplasm, arachnoidal adhesions around the chiasm, radiation retinopathy or other ophthalmologic disease; 3) absence of optic edema.For diagnosing RION, ophthalmologic examinations such a visual aquity test, visual field test (Goldman perimetry test) and fundoscopy must be performed. Visual fields may show altitudinal loss or central scrotoma, (bi)temporal- or (bi)nasal hemianopia, depending on the location of the injury (chapter 1.1.2). Acuity problems can result from several ophthalmologic pathologies. These include cataracts, refractory dry eye(s) and radiation retinopathy, which may be a consequence of radiotherapy as well (12). RION and radiation induced retinopathy are usually distinguishable by fundoscopic examination. Patients with RION initially have a normal appearing optic disc that subsequently becomes pale over 4-6 weeks. Fundoscopic findings for radiation retinopathy include retinal hemorrhages and exudates, cotton wool spots, neovascularisation and macular edema (11,14). As noted above, RION may rarely present as an anterior optic neuropathy. Anterior RION usually occurs in the setting of radiation retinopathy, these two conditions are almost indistinguishable.The diagnosis of RION is generally suspected from the clinical setting. Nevertheless, since tumour recurrence is the key differential diagnosis of RION, diagnostic imaging is required. Magnetic resonance imaging (MRI) with gadolinium- diethylenetriamine pentaacetic acid (DTPA) enhancement is the preferred modality. If RION is present, it shows segmental enhancement of the nerves, chiasm, or tracts, sometimes associated with enlargement of the affected region (7). However, the radiologic appearance of the optic structures in RION is nonspecific and may be indistinguishable from other infiltrative optic neuropathies (13,15,16). The enhancement fades within three months of symptom onset due to optic atrophy. Enhancement on a routine MRI in asymptomatic patients who developed RION weeks thereafter is reported (2). The CT scan is typically normal, as is the unenhanced T1- and T2-weighted MRI images.

1.2.4 TreatmentAttempts to treat radiation injury to the visual pathways with systemic corticosteroids, anticoagulation and hyperbaric oxygen has been generally unsuccessful to reverse or even halt the vision loss (3,4,12,17,18). Hyperbaric oxygen might be beneficial if treatment is initiated within 72 hours of visual loss (3,19). Recent studies of Finger et al. (20,21) showed encouraging results in patients with anterior RION who were treated with bevacizumab immediately after diagnose. The visual acuity was stable or improved in 9 (64%) of the 14 patients. Bevacizumab is an anti-vascular endothelial growth factor (anti-VEGF); inhibition of this growth factor with bevacizumab inhibits neovascularisation and normal vessel endothelial loss.

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1.2.5 Dosimetric dataBoth the total dose of radiation given and the daily fractionation size are important factors in determining the risk of RION development. Most investigators agree that a maximum total dose to an optic nerve of 50-55 Gray (Gy) in fractions 2 Gy or less provides an acceptably low risk (2,3,5,11,12,22-30). Jiang et al. (29) found no cases of RION when the dose was below 50 Gy in a retrospective study of 219 patients receiving radiation therapy for cancers of the paranasal sinuses and nasal cavity. In contrast, the 10-year actuarial risks for RION after doses of 50-60 Gy and 61-78 Gy were 5% and 30%, respectively.Parsons et al. (11) demonstrated no risk of RION when the maximum dose (Dmax) was less than or equal to 59 Gy. However, when the Dmax to the optic nerve was 60 Gy or higher, the dose per fraction was more important than the total dose in producing RION. The 15-year actuarial risk of RION was 11% when fraction size was less than 1.9 Gy, compared with 47% when fraction size was equal to or greater than 1.9 Gy. The QUANTEC data, published by Mayo et al. (12), show that the tolerance dose of the optic apparatus might be around 55-60 Gy. The incidence of RION in all retrospective studies was unusual for a Dmax <55 Gy, particularly for fraction sizes <2 Gy. The risk increases (3–7%) in the region of 55–60 Gy and becomes more substantial (>7–20%) for doses above 60 Gy when fractionations of 1.8–2.0 Gy are used.According to Bhandare et al. (5) hyperfractionation (twice-daily fractionating schedule) has lower incident rates of RION compared to once-daily fractionation. This is explained by the use of multiple smaller dose fractions (1.1-1.2 Gy/fraction) resulting in decreased normal tissue toxicity, provided that the interval between these fractions is sufficient for cellular repair (31). For single-fraction stereotactic radiosurgery (SRS), studies have indicated the incidence of RION is rare for a Dmax below 8 Gy, increases in the range of 8–12 Gy, and becomes >10% in the range of 12–15 Gy (12,25,32,33). Most studies of proton radiotherapy reported low incident rates of RION. In cases of RION the Dmax to the optic structures was above 55-60 cobalt gray equivalent (CGE) (34,35). The main studies on RION are summarised in table 1.1.

1.2.6 Risk factorsBeside total dose and fraction size, factors that increase the susceptibility to RION include increasing age and pre-existing compression to the optic nerves or chiasm by the tumour (5,11,12,23,36-40). It is thought that an impaired vascular condition lowers the threshold of optic structures to radiation injury, since the underlying pathophysiological base of RION is vascular endothelial damage (11,29). In contrast, data on co-morbidities like diabetes and hypertension have been found inconsistent (5,12,24,42). According to the radiobiology and the working mechanism of chemotherapeutic agents, it is plausible that (concurrent) chemotherapy treatment will affect the tolerance dose of the optic structures and the susceptibility of developing RION as well. Radiotherapy causes ionisation of molecules within cells (eject electrons). Ionised molecules (free radicals) are highly reactive and can disrupt the structure of macromolecules such as deoxyribonucleic acid (DNA). All cells have specialised repair systems for detecting and repairing this damage. If not repaired in time, this damaged DNA leads to severe consequences such as cell death during or after mitosis. In general, cancer cells are more sensitive to ionising radiation than normal tissues because of their higher rate of reproduction than most healthy cells and their diminished ability to repair sub-lethal damage. The mechanism of action in concomitant chemotherapy is cellular and molecular interaction with radiotherapy. Several chemotherapy agents, including cisplatin, have been shown to inhibit the repair of radiation damage (e.g. DNA or chromosomal damage). As a consequence, tumour cells will be more sensitive

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Table 1.1 Literature overview radiation-induced optic neuropathy (RION)Investigat

or ( ref)Study design N

umbe

r of

pa

tient

s

Patients characteristics.RT technique,

Prescribed treatment dose* and dose* per

fraction.

Bas

elin

e

RION endpoint

Vis

ual a

cuity

te

st

Vis

ual f

ield

te

st

Fund

us

exam

inat

ion

(gad

olin

ium

-en

hanc

ed)

Med

ian

FU

Doses* to optic structures and RION conclusions*

Bhandare et al. ¤ (5) Retrospective analysis

273

1964-2000: tumours of nasopharynx, PNS, nasal cavity and hard palate adenoid cystic carcinoma's. FU ≥1 year.

Non-IMRT. <50 to >70 Gy~1.8 or 1.1–1.2 Gy/fraction

Yes

Ophthalmologic diagnosis of RION.

Yes Yes Yes No 91 RION occurred in 9% of patients. Median and mean ON dose in patients who developed RION was 68 and 67 Gy (once daily: 67.5, twice daily 70.9). The 5 year rates of freedom from RION according to the total dose an d once- vs twice-daily fractionating were as follows:≤63 Gy once daily, 95%; ≤63 Gy twice daily, 98%; >63 Gy once daily, 78%; and >63 Gy twice daily, 91%.

Demizu et al. ◊ (24)Retrospective analysis

75 2001-2006, tumours of head-and-neck or skull-base adjacent to optic nerves. FU ≥1 year.

Carbon ion (n= 13) vs proton (n=62).57.6 vs 65 GyE 3.6 vs 2.5 GyE/fraction

No

Ophthalmologic diagnosis of RION.

Yes§

Yes§

Yes§

Yes§

25 Median Dmax to optic nerve for carbon ion and proton was respectively 48 GyE or 97 GyE3 and 52 GyE or 85 GyE3. Eight patients (11%) experienced vision loss resulting from RION, bilateral vision loss occurred in 1 patient. Most vision loss (78%) occurred in optic nerves irradiated > 110 GyE (approximately equivalent to 65 Gy).On univariate analysis, age (>60 years), DM and maximum dose on the optic nerve >110 GyE3 were significant.

Hasegawa et al. ‡ (41)Retrospective analysis

30 1994-2000: tumours of head-and-neck or skull-base. FU ≥4 year.

Carbon ion. Median 56 (48-64) GyE.3.0-4.0 GyE /fraction.

Yes

Ophthalmologic diagnosis of RION.

Yes Yes Yes Yes - Median Dmax ON was 50,1 GyE (1.1-3.5 GyE). When Dmax <57 GyE no visual loss occurred. The incidence of RION was 45% when Dmax was 57-65 GyE and 75% when a Dmax of >65 GyE was applied. The radiation doses associated with a 50% probability of visual loss were 63 GyE to 10%, 59 GyE to 30% and 51 GyE to 50% of ON volume. Average time to impaired vision was 19.6 (5-39) months, and for progression to eventual vision loss 25.6 (10-41) months.

Hoppe et al. (27) Retrospective analysis

85 1987-2005: tumours of PNS or nasal cavity treated with postoperative RT (or CTRT).

Conventional (28%), 3D-CRT (27%), IMRT (35%). Median BED to the tumour was 70 (48-72) Gy.

No

RTOG acute and late toxicity criteria.

No No No No 60 Median doses: Conventional chiasm: Dmax 53 Gy, ON: Dmax 56 Gy. 3D-CRT: chiasm: Dmax 51 Gy, D05 46 Gy, Dmed 52 Gy, ON: Dmax 52, D05 51, Dmed 32. IMRT: chiasm: Dmax 53, D05 48, Dmed 40, ON: Dmax 53, D05 51, Dmed 37. No patients developed RION.

Hoppe et al. (28) Retrospective analysis

37 2000-2006: tumours of PNS or nasal cavity treated with postoperative (chemo)RT.

IMRT and 3D-CT. 70 Gy (66-70 )Gy 2.12 Gy/fraction

No

RTOG acute and late toxicity criteria.

No No No No 28 Median doses to: Ipsilateral ON: Dmax 53 Gy, D05 49 Gy, Dmean 36 Gy, D95 17 Gy. Contralateral ON: Dmax 41 Gy, D05 34 Gy, Dmean 21 Gy, D95 10 Gy. Chiasm: Dmax 50 Gy, D05 46 Gy, Dmean 34 Gy, D95 26 Gy. No patients developed RION.

Jiang et al. (29)Retrospective analysis

219

1969-1985: tumours of PNS or nasal cavity .

Non-IMRT.-

No

visual acuity <20/100.

Yes§

Yes§

Yes§

No§ 8 Median Dmax to ON: 61.6 Gy, Chiasm: 57.1 Gy, Eight (8%) patients developed ipsilateral blindness due to optic neuropathy, and 11 patients (5%) had bilateral vision impairment secondary to chiasm injury. None of patients receiving a dose of <50 Gy developed optic neuropathy or chiasm injury. The 10-year actuarial incidences of RION were 5% and 30% for patients receiving 50-60 Gy and 61-78 Gy, respectively. LQ model yielded an α/β estimate of 1.6 Gy for optic neuropathy.

Leber et al. (32)Retrospective analysis

50 1992-1994: benign tumours of skull-base.

Stereotactic radiosurgery.18 (12-30) GySingle fraction

No

Ophthalmologic diagnosis of RION.

Yes Yes No Yes 40 The actuarial incidence of optic neuropathy was zero for patients who received a radiation dose of less than 10 Gy, 26.7% for patients receiving a dose in the range of 10 to less than 15 Gy, and 77.8% for those who received doses of 15 Gy or more (p , 0.0001).

Martel et al. (22)Retrospective analysis

20 1985-1992: tumours of PNS and nasal cavity. Postoperative. FU ≥ 2,5 years.

Non-IMRT.50.4-70.2 Gy1.8 Gy/Fraction

No

Visual field defects and/or unilateral of bilateral blindness.

Yes§

Yes§

No§ Yes§

64 Chiasm: 1 complication: Dmean 55.2 Gy, Dmax 59.5 Gy; Avarage Dmean and Dmax for patients without complications were 45.2 Gy and 53.7.ON: moderate/severe complications: Dmax ≥64 Gy, with at least 25% of the volume exceeding 60 Gy. Mild complications occurred at maximum doses of 48 and 57 Gy (below published tolerance dose, 60 Gy).

Parsons et al. (11)Retrospective analysis

131

1964-1989: extracranial head and neck tumours. FU ≥ 3 years.

Non-IMRT55 to 75 Gy1.2-2.6 Gy/fraction

No

Visual acuity <20/100.

Yes No No No 96 Anterior RION developed in 5 ONs and posterior RION developed in 12 ONs, after a median time of 29 months. No RION was observed when Dmax < 59 Gy. When Dmax was ≥ 60 Gy, the dose per fraction was more important than the total dose in producing optic neuropathy. The 15-year actuarial risk of optic neuropathy after doses ≥ 60 Gy was 11% when fraction size was < 1.9 Gy, compared with 47% when fraction size ≥ 1.9 Gy. The data also suggest an increased risk of RION with increasing age.

Stafford et al. (33)Retrospective analysis

215

1990-1998: meningioma’s.

Stereotactic radiosurgery.18 (12-30) GySingle fraction

No

- Yes No No Yes 40 The median Dmax to the ON was 10 (0.4 –16.0) Gy. Four patients (1.9%) developed RON at a median of 48 months after radiosurgery. All had prior surgery, and 3 of 4 had external beam radiotherapy (EBRT) in their management either before (n =2) or adjuvantly (n =1). The risk of developing a clinically significant RION was 1.1% for patients receiving 12 Gy or less. Patients receiving prior or concurrent EBRT had a greater risk of developing RON after radiosurgery (p=0.004).

* Absolute doses unless otherwise noted.§ Not performed routinely in all patients, only symptomatic patients were tested.¤ In the report by Bhandare et al.(5), 109 patients received#1.8 Gy/fx and 63 received >1.8 Gy/fx; 101 patients were treated with twice-dailyfractions at 1.1–1.2 Gy/fx.

◊In the report by Demizu et al. (24), the late effects were compared on basis of a BED2 (biologically effective dose with α/β = 3 GyE), because different dose fractionations were used for carbon ion and proton treatments.‡ In the report by Hasegawa et al. (41), carbon beam dose was expressed in terms of photon equivalent dose (gray equivalent (GyE)), defined as the physical dose multiplied by the relative biologic effectiveness of carbon ions.

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to irradiation which will cause more cell death. When these chemotherapeutic agents are administered, normal tissues become less effective at repairing DNA damage as well. In the clinical setting, this is expressed in higher incidence and severity of acute and late toxicity; the side effects of radiotherapy (43).Nevertheless, (concurrent) chemotherapy is no evident risk factor of RION in all studies (5,12,42).

1.2 Radiotherapy techniques

Over the past two decades, radiotherapy techniques have evolved from conventional to three-dimensional (3D) conformal radiotherapy (3D-CRT), to intensity modulated radiotherapy (IMRT), and intensity modulated stereotactic radiotherapy (IMSRT). Compared to conventional treatment, these newer techniques have allowed improved dose distributions with increased dose to the target volumes and reduced dose to the surrounding normal tissues (27,44,45). IMRT offers the potential to reduce the dose to critical structures such as the optic pathway by adding dose-volume constraints for these on CT delineated organs at risk (OARs) (46). Tumours of the skull base and sinonasal region appear to be especially well-suited to the use of IMRT, given the irregular contours of tumours and vital structures in this region and the lack of organ motion, allowing for accurate reproduction of field setup (23).

1.3 Clinical relevance of clear tolerance doses and uniform delineation of optic structures

Even with IMR(S)T, the dose to the planning target volume (PTV) is limited by the tolerance of the organs at risk. In some cases the radiation oncologist (and patient) needs to compromise between PTV target coverage and sparing of the visual pathway structures. If long-term tumour control is given priority, optic structures have to be sacrificed which could lead to severe RION and decreased quality of life. The other option is to underdose a part of the PTV and avoid the risk of (partial) blindness, with a higher probability of a recurrence.Sometimes, sacrificing ipsilateral vision can achieve better tumour coverage when compared to sparing both optical pathways (26,28,47). As a matter of course, this is only beneficial as the contralateral optic structures are not put at risk.

Data for radiation-induced optic nerve and chiasm injury have been reported in several retrospective descriptive studies. Many of these studies were performed in an era before the routine use of CT-MRI-based planning and had no uniform approach to define RION. Therefore, the actual tolerance doses of the optic nerves and chiasm are still uncertain. Dose-volume analysis in optic structures is barely performed, and doses to optic tracts were always disregarded. With improvement of techniques, radiotherapy has become more intensified. The target volume can be treated with higher radiation doses because of improved preciseness of the dose delivery and steep dose gradients. In order to treat patients safely, it is essential to gather more knowledge about the volumetric dose response of critical structures such as the optic pathway. In addition, accurate delineation of the optic system is critical for limiting complications without limiting tumour control. None of the previous studies gives clear descriptions on how delineation of various components of the optic structures was performed, for example the optic nerve thickness or optic chiasm

measurements. A contouring protocol of these structures is not yet available; despite the fact that the optic chiasm is poorly visible on planning-CT scan.

1.4 Aim of this study

The main goal of this retrospective study is to investigate the rate of visual deficits after radiotherapy in relation to the given dose to the optic pathway, for patients with T1-4 N 0-3 M0 nasopharyngeal, sinonasal and skull base tumours which received either definitive or postoperative (chemo)radiotherapy using 3D-CRT, IMRT and IMRST techniques. Furthermore, to relate dose and volume information (DVH parameters) for visual pathway structures to this complication data and evaluate other factors that may contribute to development of clinically significant radiation-induced neuropathy (RION), such as age, co morbidity and concurrent chemotherapy.The secondary goal is to evaluate delineation consistency and accuracy of different structures of the optic pathway, including optic nerves, optic chiasm and optic tracts, using CT-MR image fusion techniques, as well as to develop delineation guidelines for these optic structures. And consequently, to analyse differences in dose-volume distribution between original contoured optic structures and study optic structures contoured according to these guidelines.

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2. Methods and Materials

2.1 Study design

This is a retrospective descriptive study.

2.2 Patient identification and characteristics

Table 2.1 Patient characteristics (n = 66) From January 2007 to February 2013, a total of 87 patients with histological diagnosed tumours of the nasopharynx, nasal cavity, paranasal sinuses or skull-base were referred to the department of Radiotherapy, University Medical Center Groningen. All patients were treated with curative intent radiotherapy using three-dimensional CT-based-treatment-planning, including 3D-CRT, IMRT and IMRST. They received either postoperative or definitive radiotherapy, in some cases combined with neoadjuvant, concomitant or adjuvant chemotherapy. Patients with various histological types of non-metastatic stages of disease (T1-4 N0-3 M0, UICC TNM, 7th edition) were included in this study. The minimum follow-up was at least 6 months after radiotherapy completion.

Eighteen patients were excluded from the study because of prior external beam radiotherapy for tumours in head-and-neck area (7 patients, recurrent disease or second primary), or follow-up (FU) was incomplete or FU was less than 6 months (3 patients died during radiotherapy, 8 patients died less than 6 months after treatment).Three patients, whom received their treatment in the beginning of 2007, were excluded because either the original radiotherapy plans (1 patient, 3D-CRT plan) or essential data for treatment plan reconstruction (2 patients; both IMRST plans) were missing.

A total of 66 patients fulfilled the selection criteria and were included in this analysis.

Age (year), median (range) 60 (2-88)

Gender, n (%)MaleFemale

37 (56)29 (44)

Tumour site, n (%)NasopharynxNasal cavityMaxillary sinusEthmoid sinusSkull base

30 (46)18 (27)13 (20)3 (5)2 (3)

T-stage, n (%)T1T2T3T4Tx

8 (12)12 (18)6 (9)

25 (40)15 (23)

N-stage, n (%)N0N1N2a-cN3Nx

27 (41)5 (8)

20 (30)5 (8)

9 (14)Histology, n (%)

Sqamous cell carcinomaAdenocarcinomaUndifferentiated carcinomaLymphomaSarcomaNeuroblastomaMelanoma

29(44)11 (17)9 (14)8 (12)4 (6)4 (6)1 (2)

Diabetes Mellitus, n (%)(-)(+)

60 (91)6 (9)

Hypertension, n (%)(-)(+)

43 (65)23 (35)

Smoking, n (%)(-)(+)

36 (54,5)30 (45,5)

WHO score, n (%)012

58 (88)6 (9)2 (3)

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Patient characteristics are summarised in table 2.1. The median age was 60 years at diagnose, almost all patients were in good physical condition at the beginning of treatment (88% WHO 0). Most patients had locally advanced disease (stages II-IV, 72%). Primary tumour sites included nasopharynx (46%), nasal cavity (27%), paranasal sinus (25%) and skull-base (3%). Squamous cell carcinoma was by far the most frequent histological type (44%). Most patients received definitive radiotherapy, 23 patients (35%) had prior surgery. Resection or debulking of the primary tumour (n=14) and maxillectomy (n=5) were the most common procedures. None of these patients received chemotherapy (table2.2).Neck dissection was performed in two patients (3%). Nineteen patients (29%) were treated with elective cervical nodal irradiation, of which 13 patients (20%) received a boost in macroscopic pathologic lymph nodes as well. Mean prescribed doses to elective regions and pathologic lymph nodes were 52.9 (45-56) Gy and 65.5 (35-70) Gy, respectively. Chemoradiation was administered in 26 cases (39%). Most of them were patients with nasopharyngeal carcinomas (n=21), treated with a chemoradiation schedule consisting 35 fractions of 2 Gy (5 days a week for 7 weeks) with concomitant cisplatin in week 1, 4 and 7, and 3 adjuvant courses of cisplatin and fluoracil (5-FU). Three patients ended this chemotherapy courses prematurely because of severe side effects (acute renal insufficiency). Four patients, all diagnosed with diffuse large B-cell lymphoma, were treated with 3 cycles of R-CHOP (consists of retuximab, cyclophosphamide, doxorubicin, vincristine and prednisolone) prior to radiation (PTV dose of 15 x 2 Gy). More treatment specifications are shown in table 2.2.

Table 2.2 Treatment characteristics (n = 66)

Surgery primary tumour, n (%)(+)(-)

23 (35)43 (65)

Cervical lymph node dissection, n (%)(+)(-)

2 (3)64 (97)

Chemotherapy, n (%)(+)(-)

26 (39)40 (61)

Type chemotherapy, n (%)Cisplatin + 5FUCisplatin/5FU + CisplatinR-CHOP

19 (29)2 (3)4 (6)

Total radiation dose, n (%)70 Gy66 Gy60 Gy< 60 Gy

36 (55)12 (18)

5(8)13 (20)

Cervical nodal irradiation, n (%)(+) Elective (+) Elective and boost(-)

19 (29)13 (20)47 (71)

Radiotherapy technique, n (%)3D-CRTIMRTIMRST

10 (15)53 (80)3 (5)

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2.3 Treatment planning

For the purpose of radiation treatment planning, a contrast- enhanced CT- scan with a 2 mm slice thickness of the head and neck was obtained two weeks before the first radiation. Patients were scanned in treatment position; head, neck, and, in some cases, the shoulders were immobilised in a hyperextended position using a perforated thermoplastic 3- or 5-points head mask (Posicast® thermoplastics, CIVCO) in combination with a standard head support (Posifix® supine headrest, CIVCO). Treatment planning was performed using different computed tomography (CT)-based three-dimensional treatment planning systems, depending on the radiotherapy technique and the year of treatment. In general, Helax –TMS (version 5.0, Nuclectron Scandinavia, Uppsala, Sweden) was used patients who received 3D-CRT in the first part of 2007; thereafter treatment planning was performed using Pinnacle³ Treatment Planning System (TPS) (version 8.0, Philips Radiation Oncology Systems, Fitchburg, WI, USA). Except for IMRST treatment planning, this was performed in iPlanRTDose (version 4.1.1 BrainLAB AG, Feldkirchen, Germany). A simultaneous integrated boost (SIB) technique was used in all patients treated with (step-and-shoot) IMRT. For 3D-CRT, the boost was delivered by a separate plan using 3D-CRT or IMRST techniques. In most cases additional diagnostic imaging such as MRI and/or FDG-PET was also available and fused with the treatment planning CT for optimal delineation of the target volumes.

2.3.1 Target volume delineation Figure 2.1 Target volumesDelineation was done by a radiation oncologist specialised in head and neck cancer. The gross tumour volume (GTV) was defined as the primary tumour and all cervical lymph nodes metastases. Lymph nodes were considered to be pathological (metastasis) if its diameter was >10 mm on CT or MRI imaging, if it had focal necrosis, was spherically shaped or if it had abnormal focal FDG uptake in the staging PET-scan. In case of a dubious lymph node (diameter 7-9 mm, without any of the characteristics mentioned above) an ultrasound- guided biopsy had to be carried out. Dependant on the histopathology, the lymph node was considered pathological or not. In case of postoperative treatment, the tumour was reconstructed using preoperative CT or MRI. The clinical target volume (CTV1) of the initial field was defined as the GTV (primary tumor and eventual pathological lymph nodes) plus a 1.0 cm expansion and the elective nodal areas on both sides of the neck. The CTV for boost irradiation (CTV2) consisted of the GTV with an 0.5 cm expansion. In all cases, an 0.5 cm margin of was applied for the planning target volumes (PTV1 and PTV2) to account for patient setup error. For IMRST, this applied margin was 1 mm. Both CTV and PTV were constructed using auto- expansion and were manually adjusted by a radiation oncologist to anatomical structures like air, bone and critical organs, provided there was no tumour invasion.

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2.3.2 Dose specification and deliveryThe primary goal of treatment planning was to deliver a dose in the PTV of minimally 95% of the prescribed dose to at least 98% of the PTV. The volume that received 107% of the total dose had to be smaller than 1.8 cm³.Radiation therapy was delivered with a 6-MV photon linear accelerator (Elekta Precise or Synergy, Crawley, UK) with a multileaf collimator. Position verification was carried out by using a shrinking action level correction protocol (SAL), using an electronic portal imaging device (EPID).

2.3.3 Organs at risk Anatomical structures that are considered to be critically at risk in patients treated with radiotherapy for nasopharyngeal -, sinonasal- and skull-base tumours include the optic nerves, optic chiasm, eyes, retinae, lenses, brainstem, myelum and salivary glands.The applied absolute dose constraints for these important anatomical structures are listed in table 2.3.

Table 2.3 Applied absolute dose constraints organs at risk

Optic nerves Dmax ≤ 56 GyOptic chiasm Dmax ≤ 56 GyBrainstem Dmax ≤ 55 GyMyelum Dmax ≤ 50 GyEyes Dmax ≤ 50 GyRetinae Dmax ≤ 45 GySubmandibular glands Dmax ≤ 40 GyParotid glands Dmax ≤ 26 GyLens Dmax ≤ 10 Gy

2.4 CT-MR fusion and revision delineation optic structures

Mirada Medical (Denver, USA) was used for CT-MR image fusion in order to overhaul the delineation of the optic nerves and optic chiasm. The retrochiasmal optic tracts were contoured as well. Radiation plans, which were created in several other treatment planning programs, had to be reconstructed and imported and imported in Mirada to extract dose-volume histogram (DVH) parameters.

2.4.1 Treatment plan and dose reconstructionAll radiology data of the UMCG, including radiotherapy planning-CT scan, are archived in PACS (Picture Archiving and Communication System). Lately, all radiotherapy data are saved in PACS as well, clustered with the planning-CT as DICOM file (Digital Imaging and Communications in Medicine). These data include RTSTRUCT (structure set; target volumes and OARs), RTPLAN (radiotherapy plan; beams set-up, weighting, wedges, etc) and RTDOSE (dose distribution linked on the planning CT). When RTSTRUCT and RTDOSE were available in PACS, it could be imported in Mirada directly. In most patients, these data were missing in PACS and the radiation plan had to be reconstructed in Pinnacle³ by set up total monitor units, beam weighting and angle, motorised wedge, and so on. After reconstruction, the plan could be saved as 3 DICOM files (RTSTRUCT/PLAN/DOSE) and exported to Mirada.

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2.4.2 Multimodality fusionFusion of CT- and MR-scans was performed using “RTx Fusion Analytics” in Mirada, an application that has some tools for manual and automatic matching.To achieve optimal matching in the optic structures, the following sequence of actions was performed in each patient. When planning-CT and all MR-modalities that were helpful for delineation were loaded into the application, manual rigid matching was performed: a global process using patients’ outer contours. This was followed by automatic rigid matching. Hereafter, a box was positioned including the area of interest, and an automatic rigid matching within this box was performed. The box encompassed at least the retro-orbital optic pathway and some anatomic landmarks, such as bone structures, pituitary stalk and the internal carotid arteries (chapter 2.3.3). The purpose of this local matching was to achieve optimal fusion of the chiasm, optic tracts and the posterior part of the optic nerves. Because of their poor visibility on CT scan, delineation of these structures will be more precise when CT and MR are fused.Thereafter multimodal deformation inside the box was applied. The final step was verification; the landmarks had to be fused correctly. In the appendix (figure 8.1 and 8.2) an overview of this matching process is attached.

2.4.3 Delineation guideline optic pathwayBecause lack of consistency in delineation the optic nerves and chiasm, a contouring guideline for different elements of the optic pathway was designed with a neuro-radiologist. According to this guideline, all optic structures were overhauled.

ANATOMY AND CONTOURING GUIDELINE OPTICAL PATHWAY

The optic nerve usually 2-5 mm thick Figure 2.2 Optic chiasm and “landmarks” and for the greatest part clearly identifiable on CT scan (48). It has to be contoured all the way from the posterior edge of the eyeball, through the bony optic canal to the optic chiasm.

The optic chiasm receives the optic nerves by its anterior angles and emits the optic tracts by its posterior angles. In physiological point of view, the chiasm contains only the part where the nerve fibers from the two nasal hemiretina cross over. The chiasm is located in the chiasmal cistern. Typically, it is just superior to the sella turcia, with the nerves crossing just anterior to the pituitary stalk. It is bracketed laterally by the internal carotid arteries and is inferior to the third ventricle (48-50). The average normal dimensions of the chiasm measure 8 (4-13)mm from anterior to posterior notch, 12 (10-16) mm across, and 4 (3-5)mm in height. The volume of a normal chiasm amounts cm³ ranged from 0.22 cm³ to 0.48 cm³ (13,16). The internal carotid arteries and pituitary stalk are clearly identifiable on both MRI as (contrast-enhanced) CT-scan, which makes them particularly good “landmarks” (figure 2.2) for either

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matching these scans or contouring the poorly visible chiasm on CT scan. In the appendix (figure 8.3), these landmarks are denoted on a CT-, MRI- and fused slice of the scan.The optic tract is formed by the temporal bundle coming from the homolateral retina, and by the nasal bundle coming from the contralateral retina as well as the macular fibers originating in both retinas. The tractus optici starts at the posterior lateral angle of the chiasm. The optic tracts are visible on MRI for only 1-2 cm posterior the optic chiasm before the fibers spread and appear to blend into the rest of the brain parenchyma (12,13,51).It is essential to contour the optic pathway in continuity, because gaps in the structures (e.g., where the optic nerves pass through the optic canal) will result in exclusion of the dose from the missing volume fort that structure’s dose-volume histogram.

2.4.4 Doses to optic nerves and chiasmIn order to evaluate dose distributions in separate optic structures, dose-volume parameters were used. These parameters were derived from dose-volume histograms (DVHs). The maximum doses (Dmax), D05, D10, D20, D30, D40, D50, D60, D70, D80, D90, D95, minimum doses (Dmin), mean doses (Dmean) and median doses (Dmedian) to the chiasm, ipsilateral and contralateral optic nerves and tracts were obtained. If a tumour were located in the median-line, ipsilateral was defined as the side where the maximum dose on the optical nerve was higher.

For better comparison of different doses, because of different dose fractionations were used in treatment plans (all <2.5 Gy), the late effects of radiotherapy on the optic apparatus was displayed in equivalent dose in 2-Gy fractions (EQD2) as well. The EQD2 can be obtained using the following formula:

where EQD2 is the dose in 2-Gy fractions that is biologically equivalent to a total dose D given with a fraction size of d Gy. An α/β of 2 Gy was chosen, this was within the values found in the literature which ranged between 1.6 and 3 Gy (24,29,43).

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2.5 Follow up and diagnosis of RION

2.5.1 Follow upFollow- up was standardised (Standard Follow- up Program). During radiation treatment, a radiation oncologist saw patients weekly, to evaluate acute toxicity and treatment progression. Acute toxicity was also clinically evaluated 1 week and 5 weeks after completion of radiation treatment. Routine follow- up consisted of physical examination, flexible nasopharyngolaryngoscopy and a thyroid function blood test every 3 months during the 1st and 2nd year, and every 6 months during the 3rd, 4th

and 5th year after completion of treatment. Patients were seen by the radiation oncologist and ear, nose and throat (ENT) specialist alternately. Tumour response was assessed by means of a head and neck CT- scan 6-8 weeks after completion of treatment, followed by MR-scans 6, 12, 18 and 24 months post-treatment and thereafter yearly.

In follow-up, patients were asked whether or not they experienced problems with visual acuity or visual fields. If there were complaints, basic tests such as confrontation visual field exam (Donder's test) were performed. Patients were referred to ophthalmology department for further evaluation. No baseline examination was performed.

2.5.2 Collection and scoring data visual side effectsIn order to maximise follow-up duration, all patients –who were still alive - were contacted to collect anamnestic information of RION and other problems with the eyes or ocular adnexa. Patients were questioned about the presence of blurred vision, visual field deficits, cataracts, dry eyes, tearing and photosensibility. These complaints, and their gradation of severity, were summarised using the subjective section of the LENT SOMA scale (Late effects on normal tissues, Subjective Objective Management Analytic, table 2.4) (18,52). This scale is more detailed for late side effects of optic structures compared to CTCAE scale (Common Terminology Criteria Adverse Event, version 2.0 (53) and 3.0 (54) (18,55). Patients were referred for ophthalmologic examination if there was a serious subjective decrease of vision or visual fields, which was not reported or examined before. Charts were used in patients who were deceased.

2.5.3 Diagnostic criterion of RIONThe endpoint for RION in this study was decrease of visual acuity (SOMA grade ≥ 2) or visual field defects, and unilateral or bilateral blindness. It had to be expected that the reported symptoms were a result of radiation induced optic nerve or chiasmal injury.Symptoms had to be objectified by an ophthalmologist by means of a visual acuity test and a Goldmans visual field test. Fundus examination had to be performed as well to exclude radiation-induced retinopathy.Diagnostic imaging, such as a gadolinium-DTPA enhanced MRI, to demonstrate optic neuropathy and exclude other causes for vision loss (e.g. optic pathway compression by tumour) was not performed in this study.

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Table 2.4 SOMA scale (subjectibe)Grade 0 Grade 1 Grade 2 Grade 3 Grade 4

Vision Normal vision.

Indistinct colour vision.

Blurred vision, loss of colour vision, symptomatic visual field defect without decrease in central vision.

Severe loss of vision, symptomatic visual field defect with decrease in central vision, some ability to perform daily living activities.

Blind, inability to perform daily living activities.

Light sensitivity None. Photophobia, no change in vision.

Increased photophobia, decreased vision.

Photophobia, major loss of vision.

-

Pain/dryness  None. Occasional & minimal.

Intermittent & tolerable.

Persistent & intense Refractory & excruciating.

Tearing  None. Occasional. Intermittent. Persistent. -

2.6 Statistical methods

Descriptive statistics (maximum, mean, median, range, proportions) were calculated to characterise the patient, disease and treatment features as well as optic pathway toxicity associated with treatment. Results from dose-volume histogram analysis were displayed in graphs. To test for dose (EQD2) differences to all optic structures between patients with- and without visual deficits, t tests were implemented for normally distributed data and the Mann Whitney U-test for skewed data. For dose comparison between study and original structures a paired t test was used.P values less than 0.05 were considered statistically significant in this analysis. Durations were calculated from the last day of treatment. All statistical analyses were carried out using SPSS (version 20, SPSS Inc, Chicago).

For equality measures of the original and study delineations the Dice and Jaccard coefficient were calculated (figure 2.3). These coefficients are scalars with a value between 0 and 1. A value of 0 indicates that the structures are completely disjoined, whereas a value of 1 occurs when delineations are identical (56).

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Figure 2.3 Schematic diagram for 2 delineations A and B, Dice and Jaccard coefficient.

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3. Results

3.1 Survival and disease control

For the entire patient population (n= 87), local recurrence and regional recurrence developed in 20 patients (23.0%) and four patients (4.6%), respectively. Distant metastasis occurred in eleven patients (12.6%). Mean disease free survival time to relapse was four months (range, 0-46 months). Fifty-five patients (63.2%) are still alive.

3.2 Visual deficits

The median follow up period was 31.5 months (range, 6-79). Over the entire

FU period, 30 patients (45.5%) experienced mild to severe vision- or eye complaints. In the majority of cases, these were mild symptoms such as intermittent tearing or tolerable dryness of the eyes. Grade 4 vision scores on the SOMA-subjective scale occurred in two (3%) patients, who both developed unilateral blindness. Grade 3 and 2 were noted in one (1.5%) and five (7.6%) patients, respectively. A summary of maximum and mean equivalent doses in 2-Gy fractions (EQD2) to optic nerves and chiasm (study delineation) for all grades of SOMA vision outcomes are listed in table 3.1. One patient developed unilateral blindness before radiotherapy treatment due to a complication (bleeding) of tumour debulking. For SOMA-scoring, this eye is disregarded. For patients who experienced moderate to severe vision problems (SOMA vision grade ≥2), maximum EQD2 to all optic structures were significant higher (p<0.05), compared to patients with mild (grade 1) or without (grade 0) visual complaints. Mean EQD2 to ipsilateral optic nerves were higher in this first group as well, with a p-value of 0.009.

Table 3.1 SOMA visual outcomes with average maximum and mean EQD2 doses to optic structures (study contours). SOMA-subjective (n=66)

Grade 0 Grade 1 Grade 2 Grade 3 Grade 4

Vision, n (%) 50 (75.8) 8 (12.1) 5 (7.6) 1 (1.5) 2 (3.0)

IL-ON¹ Max EQD2Mean EQD2

32.8 Gy26.2 Gy

53,9 Gy45,4 Gy

58.5 Gy40.3 Gy

81.9 Gy68.5 Gy

78.6 Gy73.4 Gy

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CL-ON² Max EQD2Mean EQD2

26.1 Gy18.6 Gy

36,7 Gy29,1 Gy

37.0 Gy24.8 Gy

70.0 Gy41.1 Gy

54.4 Gy40.9 Gy

Chiasm Max EQD2Mean EQD2

24.9 Gy21.8 Gy

41,8 Gy34,3 Gy

37.6 Gy32.7 Gy

56.6 Gy53.8 Gy

48.9 Gy41.8 Gy

Light sensitivity, n (%) 47 (71.1) 13 (19.7) 5 (7.6) 1 (1.5)Pain/dryness, n (%) 53 (80.3) 3 (4.5) 6 (9.1) 3 (3.0) 3 (3.0)

Tearing, n (%) 48 (72.7) 2 (3.0) 11 (16.7) 4 (6.1)

1: ipsilateral optic nerve 2: contralateral optic nerve

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3.2.1 Risk factorsWhen patients were divided in two groups, one with visual deficits (defined as SOMA vision ≥ grade 2) and one without visual deficits (defined as SOMA vision < grade 2), visual deficits did not occur more frequently in patients with hypertension, diabetes or those who smoked cigarettes. Age was not found to be significantly different between the two groups as well (p=0.942). The mean age of patients with and without visual deficits was 58.0 years, and of patients with visual deficits 58.3 years. The distribution of age at the beginning of treatment was the same across all grades of the SOMA-vision scale (p=0.302).Only two patients who received chemotherapy developed mild (grade 1 and 2) visual deficits, both were treated with cisplatin/5FU courses because of nasopharyngeal cancer. The rate of visual deficits did not significantly differ when chemoradiation patients were compared to patients who were treated with (postoperative) radiotherapy. In patients treated with chemoradiation, significant lower doses (mean- and max EQD2) to both optic nerves and chiasm were measured compared to patients treated with either definitive or postoperative radiotherapy. Dosimetric data are listed in table 3.2. Doses to the optic tracts showed no differences between these groups.With adjustment for doses, no contribution of chemotherapy was found for development of visual deficits.

Table 3.2 Doses chemoradiation vs. non-chemoradiaton

1: ipsilateral optic nerve2: contralateral optic nerve

3.2.2 Patient reportsTwo patients developed unilateral blindness after radiotherapy for unresectable paranasal sinus tumours (T4). One of these patients experienced a quick and painless loss of ipsilateral vision 11 months after radiotherapy, which progressed to blindness within days. A few days before, a MRI (without gadolinium) and PET-scan were made because of head age and altered behavior. Besides radionecrosis of the frontal lobes, recurrent disease in ethmoid cells, sphenoid sinus and nasopharynx was detected. There was possibly growth in the skull-base and the ipsilateral bony optic canal as well. Another cause of the vision loss could be RION; maximum and mean equivalent dose in 2-Gy fractions (EQD2) were 81.9 Gy and 74.2 Gy. This patient was palliated and died 4 months after tumour recurrence. The other patient, treated for a maxillary sinus tumour with invasion of the orbita, experienced loss of visual acuity starting 7 months after treatment, accompanied with a dry and painful eye. Vision loss progressed over months to blindness 16 months after radiotherapy. Since the eye remained painful, it was enucleated. This eye was irradiated with a high dose (Dmax 72.9 Gy, Dmean 69.8 Gy), which exceeded the tolerance doses of the eye (50 Gy) and retina (45 Gy). Doses to the ipsilateral optic nerve were high as well, namely maximum and mean EQD2 were 75.2 Gy and 72.6 Gy, respectively. Because diagnostic imaging was not performed and fundoscopy

Structure Chemo +

Chemo - p-value

IL-ON¹ Mean EQD2 14.8 Gy 51.9 Gy 0.000Max EQD2 21.4 Gy 50.7 Gy 0.000

CL-ON² Mean EQD2 10.4 Gy 28.0 Gy 0.000Max EQD2 15.9 Gy 38.2 Gy 0.000

Chiasm Mean EQD2 14.9 Gy 31.5 Gy 0.000Max EQD2 19.3 Gy 35.1 Gy 0.002

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failed, it is hard to tell whether the vision loss was a result of RION, radiation-induced retinopathy or both.

Three patients experienced visual field defects. An incongruent homonymous left sided bilateral hemianopia with enlargement of the blind point occurred in a patient 5 months after postoperative radiotherapy for a nasal cavity tumour (pT3). On basis of these ophthalmologic findings, it was initially thought to be a consequence of a right sided optic tract lesion. EQD2 to the right optic tract was below the tolerance dose (EQD2max 43.9 and EQD2mean 26.1 Gy). On MR-imaging, no abnormalities of the optic tract were observed, but both optic nerves were slightly atrophic. Therefore, optic tract injury is not likely to cause the visual field defect. The defect is possibly the result of radiation-induced damage of the optic nerves (or chiasm), since doses to these structures were extremely high (doses are listed in table 3.1, SOMA vision grade 3). The second patient was treated with chemoradiation because of nasopharyngeal cancer, and presented with mild complaints of blurred vision and reduction of visual fields 5 years after treatment. Goldmans perimetry showed a minor reduction in superior visual field for the right eye, and moderate reduction in superior and inferior visual fields for the left eye. Visual acuity was decreased in both eyes (0.6, uncorrectable). Doses to all optic structures were beneath dose constraints for these OARs. EQD2s to the ipsilateral optic nerve were 46.3 Gy (max) and 28.9 Gy (mean). Chiasmal maximum and mean EQD2 were 33.5 Gy and 24.0 Gy, respectively. Tumour recurrence was not suspected in this patient. The last patient presented with restriction of the visual field of the left eye, 13 months after finishing definitive radiotherapy for a maxillary sinus carcinoma (T4). Findings of ophthalmologic examination were diminished visual acuity (0.5, correctable to 0.6) and defects of central vision (Goldmans perimeter) of the left eye, vital papils and normal retinae. The left (ipsilateral) optic nerve received an EQD2max of 65.0 Gy and EQD2mean of 51.8 Gy.

3.3 Doses to optic structures Table 3.3 Dose-volume histogram summary patients

The average EQD2max, -05, -mean and -95 to the ipsilateral optic nerve, contralateral optic nerve, optic chiasm, ipsilateral optic tract and contralateral optic tract (using study contours) are listed in table 3.3. Optic nerves and chiasm were contoured in all patients, the optic tracts were contoured in 46 patients (70%) since MRI was not available for each patient.

Thirty-seven patients (56 %) received a high radiation dose (EQD2max > 50 Gy) to one or more optic structures. In 25 patients (38%) both optic nerves exceeded 50 Gy and in 18 patients (27%) both nerves plus

1= dose received by 5% of the structure (volume)2= dose received by 95% of the structure (volume)

Structure Ipsilateral ConralateralAverage Range Average Range

Optic nerveEQD2-max, Gy 39.5 0.8-81.9 29.7 0.8-80.9EQD2-05, Gy¹ 38.7 0.8-81.8 28.8 0.7-80.9EQD2-mean, Gy 31.6 0.6-74.2 21.3 0.5-66.0EQD2-95, Gy² 22.0 0.4-62.1 13.4 0.5-43.7Optic chiasmEQD2-max, Gy 29.1 0.8-63.7 - -EQD2-05, Gy¹ 28.3 0.8-61.7 - -EQD2-mean, Gy 25.3 0.6-63.7 - -EQD2-95, Gy² 21.8 0.5-55.5 - -Optic tractEQD2-max, Gy 26.6 2.0-63.4 24.4 2.0-78.1EQD2-05, Gy¹ 25.6 1.7-59.7 22.7 1.8-62.9EQD2-mean, Gy 22.9 2.0-61.6 20.8 2.0-63.2EQD2-95, Gy² 18.7 1.6-52.3 16.8 1.6-54.7

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the optic chiasm received doses > 50 Gy. In 10 patients (15%) an EQD2max > 50 Gy was measured in all optic structures.Forty-six optic nerves (35%) received an EQD2max higher than 50 Gy. Figure 3.1 gives a summary of all optic nerves (both ipsilateral as contralateral) that received these high doses. The number of nerves in each dose category is displayed, along with the number of complications of these nerves. It should be noted that two of the three patients with symptomatic visual field defects represent complications (SOMA grade 2 and 3) of two optic nerves in figure 3.1; because both ipsilateral and contralateral nerves were affected (these cases are described in the patient report; first and second patient with visual field defects).However, several trends for optic nerve impairment may be noted. Maximum EQD2 was at least 65 Gy for patients with severe complications (SOMA ≥ 3). All patients who received an EQD2max to an optic nerve ≥ 75 Gy, developed visual impairment, which was severe in three of the four reported cases. When mean equivalent doses to optic nerves were ≥ 65 Gy, there was a substantially high risk to develop severe vision deficits.

Figure 3.1 Overview of all optic nerves that received high radiation doses

The 46 optic nerves that received high radiation doses (EQD2max >50 Gy) are divided into ascending dose categories. Mean EQD2 are displayed in the same manner. Optic nerves with and without complications (using SOMA-vision grades) are denoted using different colours. For both SOMA-vision grade 2 as 3 accounts that two optic nerves belong to the same patient (both patients experienced visual field deficits).

Trends toward increasing risk of developing optic nerve damage can be observed in the dosimetry plotted in figure 3.2. This figure displays all patients whose EQD2max measures of the ipsilateral optic nerve were ≥56 Gy (dose constraint to optic structures that was used for treatment planning). For each patient, the maximum EQD2 to the ipsilateral optic nerve is plotted versus the percentage of the nerve volume that exceeds this tolerance dose of 56 Gy. The sizes of the dots globally display

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the mean EQD2. Dots of patients with severe complications are coloured pink and purple, for SOMA-vision grade 4 and grade 3, respectively. As indicated in the figure, 27 ipsilateral optic nerves had maximum doses equal or greater than 56 Gy. Visual impairment did only occur when >50% of the structures volume was above this value. Furthermore, disabling (grade 3-4) visual deficits developed when maximum EQD2 exceeds 73 Gy, mild However, two optic nerves that developed complications of mild severity (SOMA-vision grade 2) are not presented in this plot since maximum EQD2 amounted only 41 Gy and 46 Gy.

Figure 3.2 Dosimetry of ipsilateral optic nerves with EQD2max > tolerance dose (56 Gy)

In the appendix (figure 8.4-8.11), bar charts of all patients that exceeded an absolute Dmax of 50 Gy to at least one of the optic structures (ipsilateral or contralateral optic nerve, chiasm and ipsilateral or contralateral optic tract) are presented. The mean and maximum values for absolute and equivalent doses in 2-Gy fractionation are shown for both study- and original delineations. Corresponding case numbers are used in all charts.

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3.4 Evaluation of optic structure delineation

3.4.1 Consistency and accuracy In the original treatment plan, optic nerves were delineated as critical organ in 45 patients (89 optic nerves). Only 11 nerves (12.4%) were contoured all the way through the bony optic canal and made a connection with the optic chiasm. The optic chiasm was contoured in 47 patients, with a large variability of delineation. It ranged from a small cross-like structure on one single CT-slide to a large sphere with the inferior edge located in the sella turcia and the superior edge directly underneath the third ventricle (outliers figure 3.3). This variability is clearly visible in the volumes of the chiasm that ranged from 0.08 cm³ to 1.94 cm³, with a median volume of 0.64 cm³ (SD 0.38 cm³). The overhauled optic chiasms (study chiasms, n=66), which were contoured according to the delineation guidelines of this study, were more consistent in shape. This resulted in a narrower range of the chiasmal volume, being 0.24 cm³ to 0.46 cm³. The mean volume was 0.35 cm³ (SD 0.05 cm³). All study chiasm volumes were within normal limits, in contrast to 23.4% of original chiasm volumes.

Figure 3.3 Optic chiasm volumes (study versus original delineation).

The original chiasm was in most cases delineated as a cross-like structure, with its anterior branches reaching the optic canal (figure 3.4). In fact these branches approximate the intracranial parts of the optic nerves. The majority of the delineated chiasms was positioned a bit more in anterior-caudal direction compared to the study chiasmal location on matched MR images. The median overlap between both optic chiasms was 0.10 cm³ (range, 0.00-0.29). This represented an overlap of 17.0% (range, 0-0.56) for the original contoured chiasm, and 25.2% (range, 0-100) for study chiasm. The average Dice and Jaccard coefficients were 0.18 (range, 0.00-0.61) and 0.11 (range, 0.00-0.41), respectively. In other words, the overall equality of the original and study delineation was poor: it ranged from completely disjoint (no overlap was present in these delineations) to moderate equality.

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Figure 3.4 Delineation of optic structures: study versus original contours and its dose-volume histogram

Legend Figure 3.4: the first row represents three slices of the CT-scan (left to right: cranial to caudal) of a patient with a nasal cavity tumour. The second row represents matched MR-images of the same patient. Original and study contours of the optic structures and the PTV are displayed on both the MR and CT slices. The third row includes a dose grid and a dose-volume histogram. The DVH shows the doses for different percentages of the volume, separate for each contoured structure.

Figure 3.4 shows a typical example of how the original and study optic structures have been delineated on CT and MR slices, as well as the absolute dose-volume distribution of these structures. This DVH shows substantial differences in dose-volume distributions when original optic structures are compared to the structures that are contoured according the study protocol. In this patient, maximum doses to the ipsilateral optic nerve remain more or less equal, but more than half of the structure receives a lower dose than initial expected. For the study optic chiasm applies here, that the dose over the entire structure comes out significant lower compared to the original values.

3.4.2 Dose discrepancies between original and study contoursWhen mean and maximum doses to the study- and original optic structures are compared for the entire study population, a few things stand out (figure 3.5). Doses to the ipsilateral optic nerve and optic chiasm were in the majority of cases lower when the study contouring was used. The reverse was true for the contralateral optic nerve.Contours of the ipsilateral optic nerve showed average (absolute) dose discrepancies between study and original contouring of 2.8 Gy (p=0.671) and 4.2 Gy (p=0.022) for maximum and mean EQD2, respectively. For the contralateral optic nerve this discrepancies were 4.4 Gy (p=0.037) for EQD2max and 5.4 Gy (p=0.094) for EQD2mean. Doses to the original and study optic chiasm were most dissimilar. The maximum and mean equivalent doses to these structures showed an average difference of 6.4 Gy (p=0.000) and 4.1 Gy (p=0.000), respectively.Dose discrepancies among contours and its outliers are shown in figure 4.1. The clinical relevance will be discussed later on (chapter 4.2).

Figure 3.5 Differences in mean and maximum EQD2 between study- and original optic structures.

Boxplots display discrepancies of maximum (max) and mean equivalent doses in 2-Gy fractionation (EQD2) between study- and original contours of optic structures. From the top down: ipsilateral optic nerve (IL-ON), contralateral optic nerve (CL-ON) and optic chiasm (Chiasm). Positive values represent contoured structures in which study EQD2 > original EQD2; for negative values study EQD2 < original EQD2. Circles denote outliers (more than 1.5 interquartile ranges); stars denote extreme outliers (more than 3 interquartile ranges).

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4. Discussion

4.1 Rate of RION and dose

The results of this study suggest that the currently used dose constraints to optic structures might be conservative. The prevalence of RION (≥ grade 2) was 4.5% in 66 patients, even though high radiation doses to optic structures were reported. Twenty-nine optic nerves (22%) received a maximum EQD2 exceeding the dose constraint of 56 Gy that is maintained in our department. According to the recently published QUANTEC data, the tolerance dose of the optic nerves and optic chiasm would be between 55-60 Gy when fraction sizes of 1.8-2.0 Gy are used (12). They reported a risk of 3-7% when the Dmax to optic structures was within this range, with the majority of cases reported in the top end (58-59 Gy). Most previous studies agree that maximum doses < 50 Gy to an optic structure provides a low risk of RION that approximates zero (3,5,23). Nevertheless, cases of unilateral blindness are reported when an optic nerve was irradiated with these “lower doses” (2). It remains inconsistent which factors may contribute to the development of RION when given doses are < 50 Gy.In the present study, when EQD2max to the optic nerves ranged from 50-65 Gy (20% of all nerves), no visual impairment (≥ grade 2) occurred. However, in this category 11.5% of the patients developed mild symptoms including blurred vision and minor (peripheral) visual field deficits (SOMA-vision grade 2). When EQD2 was <50 Gy, 6.0% of the patients experienced these mild complaints. Three patients developed severe visual impairment (≥ grade 3). Maximum EQD2 doses to the responsible optic nerve exceeded 65 Gy in all cases with >90% of the volume >56 Gy. The possibility of severe visual deficits increased remarkable when mean and maximum EQD2 doses exceeded 75 Gy and 65 Gy, respectively. According to these measures, it might be reasonable that tolerance doses of the optic nerves are slightly higher than reported in the QUANTEC data. Higher tolerance doses were reported as well in the retrospective analysis of Parson et al. (11) observed no RION in patients who received Dmax < 59 Gy to an optic nerve. In addition, Martel et al. (22) reported that moderate to severe complications occurred when Dmax ≥ 64 Gy, with at least 25% of the volume exceeding 60 Gy. Mild complications also occurred with lower doses (40-57 Gy). The latter dosimetric data appear to correlate with the results of the current study.

No patients developed bilateral blindness, two patients developed unilateral blindness, which was, with the onset of the first symptoms, not associated with RION. It was assumed that the vision loss was a result of optic nerve pressure by the tumour and a high radiation dose to the eye. Unfortunately, it was not possible to determine whether RION played a role as well, although this is plausible given the high dose to the ipsilateral optic nerve in both patients. Three patients developed major visual field deficits and decreased visual acuity, which were most likely a result of RION.

Figure 4.1, which is also used in chapter 3, displays all ipsilateral optic nerves that received a maximum equivalent dose >56 Gy. As mentioned before, for the two patients with grade 4 toxicity in SOMA vision scoring, it is uncertain whether or not RION provoked the vision loss. The figure illustrates the presence of optic nerves that received maximum EQD2s within the 65-75 Gy range

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(with >80% of the volume >56 Gy), without signs of RION. However, still no statement can be made on the safety of these high radiation doses because follow-up duration was not always sufficient; the five patients whose optic nerves that are circled with pink were followed for only 6-8 months. In contrast, the dot that is surrounded by a blue circle represents the ipsilateral optic nerve of a patient who is followed for as much as 72 months. The fact that this patient has not experience any visual acuity problems or visual field defects is encouraging.

Figure 4.1 High doses and short FU-period. It has been reported that RION can occur as late as 14 years after completion of radiation treatment (57). However, most cases RION present within 3 years after irradiation (23). Some patients had a short follow up period (< 1.5 years); these patients may develop vision loss resulting from RION after termination of the follow up period. With a median follow up period in this study of 31.5 months, it is reasonable that the rate of RION might be higher than reported.

In contrast to other data (11,12,23,36), increasing age did not significantly contribute to development of RION. No correlations were found between radiation induced visual deficits and hypertension, diabetes or smoking. The contribution of these preexistent factors was inconsistent in other studies, as reported before. The use of (concurrent) chemotherapy showed no association as well. A possible explanation for the latter is the significantly lower doses to the optic nerves for patients who received chemoradiation compared to patients who were treated with either definitive or postoperative radiotherapy.

The major shortcoming of this retrospective study was the absence of standardised ophthalmologic (baseline) testing. Since visual field assessment, visual acuity testing and fundoscopy were not performed routinely in all patients; subclinical injury could not be identified. In

addition, gadolinium-DPTA-enhanced MRI was not performed in this study, thus optic nerve enhancement could not be proved. Scoring of visual deficits was based on subjective complaints of patients. Although these patients’ experiences were not objectified and graded by the ophthalmologic examinations and imaging as described above, the experience of the patient and how the eventual visual problems affect the (quality) of the patients life remains an important outcome.

For detection of occult optic nerve injury, electrophysiological evaluation of the optic nerve function by the use of visual evoked potential (VEP) measures has been found to be more sensitive and objective, as compared with other ophthalmologic examinations (58). Kellner et al. (59) reported a higher abnormal rate of VEP than that of other ophthalmologic examinations (50% vs 18%) in patients treated with brachytherapy for uvual melanomas. This indicates that decreased optic nerve function due to radiation damage occurs more frequently than expected from the clinical findings.

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4.2 Delineation of optic structures

The optic nerves and optic chiasm are located in the base of skull and are difficult to delineate. The chiasm is small and poorly visible on CT-scan and the localisation can only be traced by the use of anatomical landmarks such as the pituitary stalk and internal carotid arteries. For delineation of the intracranial parts of the optic nerves and the optic tracts the same problem applies. Optic structures were originally delineated according to the expertise of a radiation oncologist, without the use of any guideline. The results of this study show that fusion of MRI and CT images in combination with the implementation of a delineation guideline result in a substantial improvement of consistency and alignment of optic structures. However, study structures have been contoured by only one observer whereas the original structures were delineated by multiple specialised head and neck radiation oncologists. The inter-observer variation in OAR contouring can be large, just as the substantial dose differences that result strictly from contouring variation (60). Therefore, a delineation study of inter observer variability using this guideline is needed. Brouwer et al. (61) recommended three potential measures to reduce current redundant variability in delineation practice, which includes (1) guideline development (2) joint delineation review sessions, and (3) application of multi-modal imaging.

Accurate segmentation is a time consuming but important step in the radiotherapy process. Because of the close proximity to the PTV, it is clear that variations in delineation of optic structures in patients with head and neck tumours will have a large impact on the dose to these optic structures and sometimes even to the tumour. Even recent publications have reported that, to avoid the risk of (partial) blindness, part of the PTV is frequently underdosed (62). In this study population, a concession was made to the PTV coverage in two patients in order to spare bilateral vision. Diminished PTV coverage leads to higher rates of locally recurrence (45). Although dose differences between original and study contours were most often less than 10 Gy (average absolute EQD2mean discrepancies ranged from 4.2 Gy – 6.4 Gy among all structures), it may still be of clinical importance in some cases. High dose discrepancies were also measured; most of them were outliers, these are identified in figure 4.2 with colours.

The EQD2 to the study contour of the optic chiasm was most frequently lower than expected on basis of the original structure measures. This can be explained by the anatomical position of both segmented structures with respect to the tumour; the study optic chiasm was, in the majority of cases, located in more posterior-cranial direction than was segmented primarily. As a consequence, the distance between the study optic chiasm and PTV was increased when compared to the original situation. This may be beneficial for lower doses to the optic chiasm, and therefore diminishing the probability of radiation-induced chiasmal injury as well.

Figure 4.2 EQD2 discrepancies: study optic structures compared to original optic structures.

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Discrepancies of maximum (max) and mean equivalent doses in 2-Gy fractionation (EQD2) between study- and original contours of optic structures, including the ipsilateral optic nerve (IL-ON), contralateral optic nerve (CL-ON) and optic chiasm (Chiasm). Positive values represent contoured structures in which study EQD2 > original EQD2; for negative values study EQD2 < original EQD2. Coloured symbols are outliers; symbols indicated with a letter represent measurements of corresponding patients.

In patient A (figure 4.2) the maximum and minimum EQD2 to the optic chiasm were 32.6 Gy and 7.5 Gy lower according the study contour compared to the original contour (EQD2 max was 28.1 Gy in stead of 60.7 Gy). The original contour amounted 1.2 cm³, and the EQD2max was located in a part of the structure that did not have any overlap with the study contour. If the study chiasm actually approached the “real” optic chiasm, the probability of RION development (from chaismal origin) in this patient will decrease significantly from approximately 7% to near- zero, according the meta-analysis of Mayo et al. (12). In patients B and C the optic chiasm was contoured originally as a sphere, which was localised caudal from the chiasm that was segmented using the contouring guidelines of this study. Although maximum and mean EQD2 were much lower in the study chiasm, it was of minor clinical importance given the initially low dose to the chiasm.

As mentioned before, the majority of original optic nerve contours were not segmented uninterrupted from the retina to the (physiological) optic chiasm. In general, only the optic nerve head and intraorbital part of the optic nerve were contoured, which means that the intracanalicular and intracranial parts of the nerve were disregarded. In most cases, the maximum dose to the ipsilateral optic nerve (hot spot) is located within the intraorbital optic nerve. This explains the small EQD2max differences (95% confidence interval of -1.3Gy – 2.0 Gy) between original and study contours. Measures of mean EQD2 were often lower in study ipsilateral optic nerves as result of a lower radiation dose to the volume that was excluded in original contours. Patient D received, according to the study delineation, a 19.3 Gy higher EQD2max on the ipsilateral optic nerve than was expected using the original structure. With this revised EQD2max of 75.0 Gy, the 10-year actuarial risks for RION will increase from 5% to 30% or more (29). This patient experienced a decrease of visual acuity 3 years after treatment (SOMA grade 2). Patients E and G, minimally exceed the applied dose constraint of 56 Gy to the optic nerve when the study contour is used. Patient G received a 25.0 Gy and 23.2 Gy higher EQD2mean and –max, respectively, to the study contralateral optic nerve contour in comparison with the original contour. As result, both ipsilateral and contralateral optic nerve received an EQD2max >60 Gy (SOMA grade 3, table 3.1), and the patient developed an incongruent homonymous left sided bilateral hemianopia with enlargement of the blind point. This patient is described in chapter 3.2.2.

Patients with large dose discrepancies have just been highlighted. In fact, each dose to an actual optic structure that appears to be higher than calculated, as result of improper delineation, is a potential danger and can increase the risk of RION. Just because improvement of delineation consistency and -accuracy can be accomplished, these risks should not be accepted. Furthermore, none of the previous studies defined how they contoured the optic structures. The degree of accuracy in which this is done is questionable creating more uncertainty about the assumed tolerance doses of these structures. With increasing sharpness of dose gradients in radiotherapy, differences in delineating OARs close to the tumour will result in higher dose discrepancies. Hence, accurate and consistent delineation of the optic structures becomes more important.

4.3 Radiosensitivity differences within structures

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4.3.1 Hot-spots Loss of information on the spatial dose-distribution in a DVH is a serious constraint in determining the relationship between local tissue damage and overall morbidity. A high-dose region in the histogram may represent a single hot-spot in the volume of interest or a number of smaller hot-spots from contiguous regions or from different regions. These could have quite different implications for tissue tolerance. In addition, because the loss of spatial information, DVHs do not provide information on how the dose is distributed across functionally of anatomically different subregions within an organ. This becomes particularly relevant if variations in radiosensitivity within the organ are evident (63).In addition, relatively low doses to a large volume (bath) combined with high doses to a small volume (shower) are associated with reduced tolerance doses (bath and shower effect). Bijl et al. (64) concluded that the spinal cord tissue tolerance dose in rats was especially determined by the shape of the dose contribution. High tolerance doses were observed for small regions (shower), however, if the adjacent tissue was irradiated with a low dose (bath), this tolerance dose significantly decreased. The same principles might be applicable to optic structures, but this has never been studied.

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4.3.2 Vascularisation of optic structuresSince radiation-induced vascular endothelial damage leading to vascular occlusion is thought to be the primary pathogenesis of RION, differences in vascularisation of optic structures might affect the radiosensitivity of these structures and the probability to develop RION.As mentioned before, a distinction is made between anterior and posterior RION. Besides differences in findings with (fundoscopic) examination, the vessels supplying the posterior optic nerve and chiasm are derived from different sources than that of the anterior part (9). The main source of the blood supply to the anterior optic nerve, including the retrolaminar optic part, is from the posterior ciliary artery, either by direct branches or through the peripapillary choroids arteries, with minor contributions from other sources (5). Posterior to the retrolaminar region, the arterial supply is from the peripheral centripetal vascular system, formed by pial vessels. For the purpose of describing the blood supply, the posterior part of the optic nerve can be divided into intraorbital, intracanalicular and intracranial parts. The intraorbital part is primarily provided by the pial vascular plexus, which is supplied by multiple small collateral arteries usually arising directly from the ophthalmic artery and less frequent from other orbital arteries. An axial centrifugal vascular system formed by the intraneural branches of the central retinal artery is present in approximately 10% of optic nerves. The intracanalicular part is supplied almost entirely by fine collateral branches from the ophthalmic artery lying inferior to the optic nerve. Once again, the intracranial part only has a pial vascular plexus, supplied by a variable number of branches coming from various surrounding arteries (including the anterior superior hypophyseal-, anterior cerebral-, anterior communicating- and ophthalmic arteries) (9,10,50). The optic chiasm is supplied by vessels arising from the anterior and posterior communicating artery, anterior and posterior cerebral artery and the basilar arteries (50,65). The lateral borders of the optic chiasm are better vascularised than its central part. The optic tracts are rich in capillary vessels (66). The variable arteriolar distribution in these segments of the optic pathway may possible cause differences in radiation tolerance doses for development of RION within these structures.

4.4 Further research

Prospective (multi-institutional) studies with pre and post treatment standardised ophthalmologic examination including a visual acuity test, visual field test (Goldman), fundoscopy, gadolinium-DPTA-enhanced MRI and eventually checks of the visual evoked potential (VEP) are needed to analyse the actual incidence rate of clinical and subclinical visual deficits after intensity-modulated radiotherapy. The relation between the given dose to individual optic structures and the prevalence of RION needs to be investigated to get more clarity regarding tolerance doses of these structures and the dose constraints that should be maintained in future treatment. Dose-volume histogram analysis of the optic nerves, chiasm and optic tracts are needed to examine the volumetric dose response. Evaluation of spatial distribution of hot spots within the optic structures is required as well.To determine this tolerance dose and dose volume effects correctly, it is essential that individual optic structures are delineated properly and consistent. This can be achieved through the implementation of a contouring guideline, such as provided in this study. In addition, application of multi-modal imaging could be beneficial for both tumour and OAR delineation. For reliability of MR- and CT-image fusion, it is recommended that MRI and planning CT are both made in treatment position using the fixation mask within a short time interval.

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Clear agreement within and among institutions in defining optic nerves, chiasm and optic tracts is needed. Furthermore, a more uniform approach to defining RION is needed that explicitly addresses the differences between changes in visual acuity and visual fields. Systems to grade radiation damage to the visual system must delineate the damage to the different structures of the eye that produce the same end point, that is, visual loss to develop strategies for decreasing morbidity.

Since vascular damage due to irradiation is a significant factor in developing RION, it would be interesting to evaluate tolerance doses of multiple segments of the optic nerve because of their differences in vascularisation. On basis of blood supply, the optic nerve could be divided and delineated in four parts, namely 1) the anterior optic nerve (retrolaminar part), and the sub regions of the posterior optic nerve including the 2) intraorbital part, 3) optic canal part and 4) intracranial part (9,10).

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5. Conclusion

Despite the high radiation doses on optic structures, low rates of visual deficits were reported. The currently accepted dose constraints (Dmax) to optic nerves and chiasm are thought to be within the range of 55-60 Gy (12). However, these dose constraints and might be conservative since no severe visual impairment occurred in the current study when maximum EQD2 was <65 Gy. The possibility of severe visual deficits increased remarkable when mean and maximum EQD2 doses exceeded 75 Gy and 65 Gy, respectively.Poor consistency and accuracy in delineation of original optic structures for treatment planning was found; the use of a delineation guideline and fused MR-CT images in this study significantly improved these measures. Among these original and study contours, mean and maximum doses to all structures were significantly different. Most often, the actual given dose appeared to be lower than expected in ipsilateral optic nerve and chiasm, whereas the dose to the contralateral nerve was usually higher.Further development and (inter observer) testing of a delineation guideline as well as profound prospective studies on RION are needed to obtain clarity about dose-volume effects in optic structures; which is of great value of clinical practice.

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6. References

(1) Parkin DM, Bray F, Ferlay J, Pisani P. Global cancer statistics, 2002. CA Cancer J Clin 2005 Mar-Apr;55(2):74-108.

(2) Lessell S. Friendly fire: neurogenic visual loss from radiation therapy. J Neuroophthalmol 2004 Sep;24(3):243-250.

(3) Danesh-Meyer HV. Radiation-induced optic neuropathy. J Clin Neurosci 2008 Feb;15(2):95-100.

(4) Zhao Z, Lan Y, Bai S, Shen J, Xiao S, Lv R, et al. Late-onset radiation-induced optic neuropathy after radiotherapy for nasopharyngeal carcinoma. J Clin Neurosci 2013 May;20(5):702-706.

(5) Bhandare N, Monroe AT, Morris CG, Bhatti MT, Mendenhall WM. Does altered fractionation influence the risk of radiation-induced optic neuropathy? Int J Radiat Oncol Biol Phys 2005 Jul 15;62(4):1070-1077.

(6) Levin LA, Gragoudas ES, Lessell S. Endothelial cell loss in irradiated optic nerves. Ophthalmology 2000 Feb;107(2):370-374.

(7) Hudgins PA, Newman NJ, Dillon WP, Hoffman JC,Jr. Radiation-induced optic neuropathy: characteristic appearances on gadolinium-enhanced MR. AJNR Am J Neuroradiol 1992 Jan-Feb;13(1):235-238.

(8) Nguyen V, Gaber MW, Sontag MR, Kiani MF. Late effects of ionizing radiation on the microvascular networks in normal tissue. Radiat Res 2000 Nov;154(5):531-536.

(9) Hayreh SS. Ischemic optic neuropathy. Prog Retin Eye Res 2009 Jan;28(1):34-62. (10) Hayreh SS. The 1994 Von Sallman Lecture. The optic nerve head circulation in health and

disease. Exp Eye Res 1995 Sep;61(3):259-272. (11) Parsons JT, Bova FJ, Fitzgerald CR, Mendenhall WM, Million RR. Radiation optic

neuropathy after megavoltage external-beam irradiation: analysis of time-dose factors. Int J Radiat Oncol Biol Phys 1994 Nov 15;30(4):755-763.

(12) Mayo C, Martel MK, Marks LB, Flickinger J, Nam J, Kirkpatrick J. Radiation dose-volume effects of optic nerves and chiasm. Int J Radiat Oncol Biol Phys 2010 Mar 1;76(3 Suppl):S28-35.

(13) Menjot de Champfleur N, Menjot de Champfleur S, Galanaud D, Leboucq N, Bonafe A. Imaging of the optic chiasm and retrochiasmal visual pathways. Diagn Interv Imaging 2013 Jul 23.

(14) Kline LB, Kim JY, Ceballos R. Radiation optic neuropathy. Ophthalmology 1985 Aug;92(8):1118-1126.

(15) Noble JH, Dawant BM. An atlas-navigated optimal medial axis and deformable model algorithm (NOMAD) for the segmentation of the optic nerves and chiasm in MR and CT images. Med Image Anal 2011 Dec;15(6):877-884.

(16) Wagner AL, Murtagh FR, Hazlett KS, Arrington JA. Measurement of the normal optic chiasm on coronal MR images. AJNR Am J Neuroradiol 1997 Apr;18(4):723-726.

(17) Guy J, Mancuso A, Beck R, Moster ML, Sedwick LA, Quisling RG, et al. Radiation-induced optic neuropathy: a magnetic resonance imaging study. J Neurosurg 1991 Mar;74(3):426-432.

(18) Gordon KB, Char DH, Sagerman RH. Late effects of radiation on the eye and ocular adnexa. Int J Radiat Oncol Biol Phys 1995 Mar 30;31(5):1123-1139.

41

(19) Levy RL, Miller NR. Hyperbaric oxygen therapy for radiation-induced optic neuropathy. Ann Acad Med Singapore 2006 Mar;35(3):151-157.

(20) Finger PT. Radiation retinopathy is treatable with anti-vascular endothelial growth factor bevacizumab (Avastin). Int J Radiat Oncol Biol Phys 2008 Mar 15;70(4):974-977.

(21) Finger PT. Anti-VEGF bevacizumab (Avastin) for radiation optic neuropathy. Am J Ophthalmol 2007 Feb;143(2):335-338.

(22) Martel MK, Sandler HM, Cornblath WT, Marsh LH, Hazuka MB, Roa WH, et al. Dose-volume complication analysis for visual pathway structures of patients with advanced paranasal sinus tumors. Int J Radiat Oncol Biol Phys 1997 May 1;38(2):273-284.

(23) Daly ME, Chen AM, Bucci MK, El-Sayed I, Xia P, Kaplan MJ, et al. Intensity-modulated radiation therapy for malignancies of the nasal cavity and paranasal sinuses. Int J Radiat Oncol Biol Phys 2007 Jan 1;67(1):151-157.

(24) Demizu Y, Murakami M, Miyawaki D, Niwa Y, Akagi T, Sasaki R, et al. Analysis of Vision loss caused by radiation-induced optic neuropathy after particle therapy for head-and-neck and skull-base tumors adjacent to optic nerves. Int J Radiat Oncol Biol Phys 2009 Dec 1;75(5):1487-1492.

(25) Hasegawa T, Kobayashi T, Kida Y. Tolerance of the optic apparatus in single-fraction irradiation using stereotactic radiosurgery: evaluation in 100 patients with craniopharyngioma. Neurosurgery 2010 Apr;66(4):688-94; discussion 694-5.

(26) Hoppe BS, Nelson CJ, Gomez DR, Stegman LD, Wu AJ, Wolden SL, et al. Unresectable carcinoma of the paranasal sinuses: outcomes and toxicities. Int J Radiat Oncol Biol Phys 2008 Nov 1;72(3):763-769.

(27) Hoppe BS, Stegman LD, Zelefsky MJ, Rosenzweig KE, Wolden SL, Patel SG, et al. Treatment of nasal cavity and paranasal sinus cancer with modern radiotherapy techniques in the postoperative setting--the MSKCC experience. Int J Radiat Oncol Biol Phys 2007 Mar 1;67(3):691-702.

(28) Hoppe BS, Wolden SL, Zelefsky MJ, Mechalakos JG, Shah JP, Kraus DH, et al. Postoperative intensity-modulated radiation therapy for cancers of the paranasal sinuses, nasal cavity, and lacrimal glands: technique, early outcomes, and toxicity. Head Neck 2008 Jul;30(7):925-932.

(29) Jiang GL, Tucker SL, Guttenberger R, Peters LJ, Morrison WH, Garden AS, et al. Radiation-induced injury to the visual pathway. Radiother Oncol 1994 Jan;30(1):17-25.

(30) Marks LB, Yorke ED, Jackson A, Ten Haken RK, Constine LS, Eisbruch A, et al. Use of normal tissue complication probability models in the clinic. Int J Radiat Oncol Biol Phys 2010 Mar 1;76(3 Suppl):S10-9.

(31) Galiana R, Boladeras A, Mesia R, Gomez J, de Juan A, Manos M, et al. Twice-a-day radiotherapy for head and neck cancer: the Catalan Institute of Oncology experience. Radiother Oncol 2002 Jul;64(1):19-27.

(32) Leber KA, Bergloff J, Pendl G. Dose-response tolerance of the visual pathways and cranial nerves of the cavernous sinus to stereotactic radiosurgery. J Neurosurg 1998 Jan;88(1):43-50.

(33) Stafford SL, Pollock BE, Leavitt JA, Foote RL, Brown PD, Link MJ, et al. A study on the radiation tolerance of the optic nerves and chiasm after stereotactic radiosurgery. Int J Radiat Oncol Biol Phys 2003 Apr 1;55(5):1177-1181.

(34) Weber DC, Chan AW, Lessell S, McIntyre JF, Goldberg SI, Bussiere MR, et al. Visual outcome of accelerated fractionated radiation for advanced sinonasal malignancies employing photons/protons. Radiother Oncol 2006 Dec;81(3):243-249.

42

(35) Noel G, Habrand JL, Mammar H, Pontvert D, Haie-Meder C, Hasboun D, et al. Combination of photon and proton radiation therapy for chordomas and chondrosarcomas of the skull base: the Centre de Protontherapie D'Orsay experience. Int J Radiat Oncol Biol Phys 2001 Oct 1;51(2):392-398.

(36) Bloch O, Sun M, Kaur G, Barani IJ, Parsa AT. Fractionated radiotherapy for optic nerve sheath meningiomas. J Clin Neurosci 2012 Sep;19(9):1210-1215.

(37) van den Bergh AC, Dullaart RP, Hoving MA, Links TP, ter Weeme CA, Szabo BG, et al. Radiation optic neuropathy after external beam radiation therapy for acromegaly. Radiother Oncol 2003 Aug;68(2):95-100.

(38) van den Bergh AC, Hoving MA, Links TP, Dullaart RP, Ranchor AV, ter Weeme CA, et al. Radiation optic neuropathy after external beam radiation therapy for acromegaly: report of two cases. Radiother Oncol 2003 Aug;68(2):101-103.

(39) van den Bergh AC, Schoorl MA, Dullaart RP, van der Vliet AM, Szabo BG, ter Weeme CA, et al. Lack of radiation optic neuropathy in 72 patients treated for pituitary adenoma. J Neuroophthalmol 2004 Sep;24(3):200-205.

(40) Acheson J. Optic nerve and chiasmal disease. J Neurol 2000 Aug;247(8):587-596. (41) Hasegawa A, Mizoe JE, Mizota A, Tsujii H. Outcomes of visual acuity in carbon ion

radiotherapy: analysis of dose-volume histograms and prognostic factors. Int J Radiat Oncol Biol Phys 2006 Feb 1;64(2):396-401.

(42) Pigeaud-Klessens ML, Kralendonk JH. Radiation retino- and opticopathy. A prospective study. Doc Ophthalmol 1992;79(3):285-291.

(43) Joiner MC, Van der Kogel A. Basic Clinical Radiobiology. 4th revised edition ed.: Taylor & francis Ltd; 2009.

(44) Huang D, Xia P, Akazawa P, Akazawa C, Quivey JM, Verhey LJ, et al. Comparison of treatment plans using intensity-modulated radiotherapy and three-dimensional conformal radiotherapy for paranasal sinus carcinoma. Int J Radiat Oncol Biol Phys 2003 May 1;56(1):158-168.

(45) Mock U, Georg D, Bogner J, Auberger T, Potter R. Treatment planning comparison of conventional, 3D conformal, and intensity-modulated photon (IMRT) and proton therapy for paranasal sinus carcinoma. Int J Radiat Oncol Biol Phys 2004 Jan 1;58(1):147-154.

(46) Claus F, De Gersem W, De Wagter C, Van Severen R, Vanhoutte I, Duthoy W, et al. An implementation strategy for IMRT of ethmoid sinus cancer with bilateral sparing of the optic pathways. Int J Radiat Oncol Biol Phys 2001 Oct 1;51(2):318-331.

(47) Tsien C, Eisbruch A, McShan D, Kessler M, Marsh R, Fraass B. Intensity-modulated radiation therapy (IMRT) for locally advanced paranasal sinus tumors: incorporating clinical decisions in the optimization process. Int J Radiat Oncol Biol Phys 2003 Mar 1;55(3):776-784.

(48) Celesia GG, DeMarco PJ,Jr. Anatomy and physiology of the visual system. J Clin Neurophysiol 1994 Sep;11(5):482-492.

(49) De Moraes CG. Anatomy of the visual pathways. J Glaucoma 2013 Jun-Jul;22 Suppl 5:S2-7. (50) Putz R, Pabst R. Sobotta - Atlas of human anatomy. 14th revised edition ed.: Elsevier Health

Sciences; 2008. (51) Becker KL, Bilezikian JP, Bremmer WJ. The optic chiasm in endocrinologic disorders. In:

Siatkowski RM, Glasker JS, editors. Principles and practice of endocrinology and metabolism. 3th edition ed.: Lippincott Williams & Wilkins; 2001. p. 204.

43

(52) Pavy JJ, Denekamp J, Letschert J, Littbrand B, Mornex F, Bernier J, et al. EORTC Late Effects Working Group. Late Effects toxicity scoring: the SOMA scale. Int J Radiat Oncol Biol Phys 1995 Mar 30;31(5):1043-1047.

(53) Trotti A, Byhardt R, Stetz J, Gwede C, Corn B, Fu K, et al. Common toxicity criteria: version 2.0. an improved reference for grading the acute effects of cancer treatment: impact on radiotherapy. Int J Radiat Oncol Biol Phys 2000 Apr 1;47(1):13-47.

(54) Trotti A, Colevas AD, Setser A, Rusch V, Jaques D, Budach V, et al. CTCAE v3.0: development of a comprehensive grading system for the adverse effects of cancer treatment. Semin Radiat Oncol 2003 Jul;13(3):176-181.

(55) Rubin P, Constine LS,3rd, Fajardo LF, Phillips TL, Wasserman TH. EORTC Late Effects Working Group. Overview of late effects normal tissues (LENT) scoring system. Radiother Oncol 1995 Apr;35(1):9-10.

(56) Kouwenhoven E, Giezen M, Struikmans H. Measuring the similarity of target volume delineations independent of the number of observers. Phys Med Biol 2009 May 7;54(9):2863-2873.

(57) Takeda A, Shigematsu N, Suzuki S, Fujii M, Kawata T, Kawaguchi O, et al. Late retinal complications of radiation therapy for nasal and paranasal malignancies: relationship between irradiated-dose area and severity. Int J Radiat Oncol Biol Phys 1999 Jun 1;44(3):599-605.

(58) Hu WH, Yu MZ, Long SX, Huang SZ, Gu MF, Zhou LS, et al. Impairment of optic path due to radiotherapy for nasopharyngeal carcinoma. Doc Ophthalmol 2003 Sep;107(2):101-110.

(59) Kellner U, Bornfeld N, Foerster MH. Radiation-induced optic neuropathy following brachytherapy of uveal melanomas. Graefes Arch Clin Exp Ophthalmol 1993 May;231(5):267-270.

(60) Nelms BE, Tome WA, Robinson G, Wheeler J. Variations in the contouring of organs at risk: test case from a patient with oropharyngeal cancer. Int J Radiat Oncol Biol Phys 2012 Jan 1;82(1):368-378.

(61) Brouwer CL, Steenbakkers RJ, van den Heuvel E, Duppen JC, Navran A, Bijl HP, et al. 3D Variation in delineation of head and neck organs at risk. Radiat Oncol 2012 Mar 13;7:32-717X-7-32.

(62) Rasch C, Eisbruch A, Remeijer P, Bos L, Hoogeman M, van Herk M, et al. Irradiation of paranasal sinus tumors, a delineation and dose comparison study. Int J Radiat Oncol Biol Phys 2002 Jan 1;52(1):120-127.

(63) Bijl HP, van Luijk P, Coppes RP, Schippers JM, Konings AW, van der Kogel AJ. Regional differences in radiosensitivity across the rat cervical spinal cord. Int J Radiat Oncol Biol Phys 2005 Feb 1;61(2):543-51.

(64) Bijl HP, van Luijk P, Coppes RP, Schippers JM, Konings AW, van der Kogel AJ. Unexpected changes of rat cervical spinal cord tolerance caused by inhomogeneous dose distributions. Int J Radiat Oncol Biol Phys 2003 Sep 1;57(1):274-281.

(65) Kennard C, Leigh J. Neuro-opthalmology. 1st edition ed.: Elsevier Medical Sciences; 2011. (66) Seceleanu A. Arterial microcirculation in the optic chiasm, optic tracts and lateral geniculate

bodies. Oftalmologia 2003;59(4):65-69.

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7. Acknowledgements

I would like to express my gratitude to my supervisors Roel Steenbakkers and Henk Bijl for their useful comments and remarks during the research project and the writing of this master thesis. But most of all I would like to thank them for their pleasant and enthusiastic guidance. They gave me confidence by encouraging me to implement my own ideas in the research project and gave direction when needed. I would also like to thank Bart Dorgelo for sharing his knowledge about imaging of optic structures and for his useful contribution to the delineation guideline. Furthermore, I would like to thank Roel Kierkels for his help with both finding the “untraceable” radiotherapy treatment plans as well as inventing (and teaching me) how these plans had to be reconstructed. The latter was a time-consuming process, but the positive consequence is that I gained some experience in working with both Pinnacle as Mirada. This can be useful during my final internship that also takes place at the department of radiation oncology of the UMCG.

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8. Appendix

Table 8.1 Frequently used abbreviations or terms

Abbreviation Term ExplanationBED Biologically effective dose In fractionated radiotherapy, the total dose that would be

required in very small dose fractions to produce a particular effect, as indicated by the linear-quadratic equation. Otherwise known as extrapolated total dose (ETD). BED values calculated for different α/β ratios are not directly comparable. For time–dose calculations, EQD2 is preferred.

CTV Clinical Target Volume GTV + margin for microscopic spread.CL Contralateral Opposite side of the tumourEQD2 Equivalent total dose in 2-

Gy fractions. Equivalent total dose in 2-Gy fractions.

Free radical A fragment of a molecule containing an unpaired electron, therefore very reactive.

Gy Gray 1 Gy is the SI unit equivalent to 1 J of energy per 1kg of mass. The gray is most commonly used to refer to absorbed radiation dose and has replaced the previous unit, the rad (1 Gy = 100 rad).

GyECGE

Gray Equivalents or cobalt gray equivalents

GyE or CGE for densely ionizing radiation is equal to the measured physical dose in gray multiplied by the RBE (relative biologic effectiveness) factor.

GTV Gross Tumor Volume Visible tumour on scans or tumour reconstruction; including pathological lymph nodes.

HBO Hyperbaric oxygen The use of high oxygen pressures (2–3 atm) to enhance oxygen availability in radiotherapy.

Hyperfractionation Reduction in dose per fraction below a conventional level of 1.8–2.0 Gy, >1 fraction/day with a higher total dose than conventional.

Hypofractionation The use of dose fractions larger than the conventional 2 Gy per fraction.

Image segmentation The process of separating out mutually exclusive (i.e. non-overlapping) regions of interest in an image, for example outlining the lungs on a computed tomography (CT) scan.

Incomplete repair Increased damage from fractionated radiotherapy when the time interval between doses is too short to allow complete recovery.

IMRT Intensity-modulated radiotherapy

Irradiation technique using non-uniform radiation beam intensities for delivering radiation therapy. This allows

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high conformality treatment plans often with considerable sparing of critical organs at risk.

IMSRT Intensity-modulated stereotactic radiotherapy

High precision IMRT.

Ionization The process of removing electrons from (or adding electrons to) atoms or molecules, thereby creating ions.

IL Ipsilateral Same side of the tumourLENT Late effects normal tissues Late toxicity scoring system

Late normal-tissue responses Radiation-induced normal-tissue damage that in humans is expressed months to years after exposure (per definition later than 90 days after the onset of radiotherapy). The α/β ratio tends to be small (5 Gy).

Latent time/period or latency interval

Time between (onset of) irradiation and clinical manifestation of radiation effects.

Local tumour control The complete regression of a tumour without later regrowth during follow-up; this requires that all cancer stem cells have been permanently inactivated.

ON Optic nerve Nerve from the retina through the bony optic canal to the optic chiasm.

OT Optic tract Retrochiasmal tracts, traceable on MRI.PTV Planning Target Volume CTV + margin for set up errors and organ motion.RION Radiation Induced Optic

NeuropathyDevastating late complication due to radiation induced injury of optic structures.

RT Radiotherapy The use of ionizing radiation, either photon beams or radioactive isotopes, to treat disease.

SOMA Subjective Objective Measurement Analytic

Divisions of the scoring system

3D-CRT Three-dimensional-conformal radiotherapy

CT-based conformal radiotherapy.

Tolerance dose The maximum radiation dose or intensity of fractionated radiotherapy that is associated with an acceptable complication probability (usually of 1–5 per cent). Actual values depend on treatment protocol, irradiated volume, concomitant therapies, etc., but also on the status of the organ/patient.

α/β α/β ratio The ratio of the parameters α and β in the linear-quadratic model; often used to quantify the fractionation sensitivity of tissues.

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Figure 8.1 Matching process using Mirada (part 1)

1. Manual rigid matching; CT and MRI were placed manually over each other in such a way that patients’ outer contours were matched as far as possible.2. Automatic rigid matching; the software computed the best matching on the basis of both the outer contour of the patient as various structures in the head.3. Box creation.

Figure 8.2 Matching process using Mirada (part 2)

4. Box positioning; this box included the area of interest.5. Select the box; all further matching will occur within the area of interest.6. Automatic rigid matching within the box.7. Multimodal deformation; select CT-MR.8. Perform multimodal deformation within the box.

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Figure 8.3 Landmarks for optic chiasm delineation on CT, MRI and fused images.

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Figure 8.4-8.11 include stacked bar charts of all patients that exceeded an absolute Dmax of 50 Gy for at least one of the optic structures. Separate charts of ipsilateral optic nerve, contralateral optic nerve, chiasm, ipsilateral and contralateral optic tract are presented for both study- as original delineations. The mean and maximum values are shown in stacked bars, for absolute and equivalent doses in 2-Gy fractionation

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(EQD2) (clustered). The horizontal Iine at 56 Gy represents the tolerance dose of optic structures that is implemented at the department of radiation oncology, UMCG. Corresponding case numbers are used in all charts.

SOMA-vision grade 4 was scored for patients 34 and 35; these patients developed unilateral blindness (ipsilateral). SOMA-vision grade 3 was scored for patient 35; this patient developed an incongruent homonymous left sided bilateral

hemianopia with enlargement of the blind point (with most likely both optic nerves involved). SOMA-vision grade 2 was scored for patient 16, 23 and 33; these patients developed decreased visual acuity or (peripheral)

visual field defects.

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Figure 8.4 Ipsilateral optic nerve study contour, absolute Dmax > 50 Gy

Figure 8.5 Ipsilateral optic nerve original contour, for patients in figure 8.4

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Figure 8.6 Contralateral optic nerve study contour, absolute Dmax > 50 GyFigure 8.7 Contralateral optic nerve original contour, for

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patients in figure 8.6Figure 8.8 Optic chiasm study contour, absolute Dmax > 50 GyFigure 8.9 Optic chiasm original contour, for

patients in figure 8.8

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Figure 8.10 Ipsilateral optic tract (study contour), absolute Dmax > 50 Gy

Figure 8.11 Contralateral optic tract (study contour), absolute Dmax > 50 Gy

XX Kopie literatuuroverzicht (EXCEL bestand) XX

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Toevoegen CTCAE en SOMA scoring (bij papieren versie)

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