Nasopharyngeal Cancer: A Practical Guide on Diagnosis and Treatment (Practical Guides in Radiation Oncology) 3030650367, 9783030650360

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Practical Guides in Radiation Oncology Series Editors: Nancy Y. Lee · Jiade J. Lu

Jun Ma Nancy Y. Lee Jiade J. Lu Editors

Nasopharyngeal Cancer A Practical Guide on Diagnosis and Treatment

Practical Guides in Radiation Oncology Series Editors Nancy Y. Lee Department of Radiation Oncology Memorial Sloan-Kettering Cancer Center New York, NY, USA Jiade J. Lu Department of Radiation Oncology Shanghai Proton and Heavy Ion Center Shanghai, China

The series Practical Guides in Radiation Oncology is designed to assist radiation oncology residents and practicing radiation oncologists in the application of current techniques in radiation oncology and day-to-day management in clinical practice, i.e., treatment planning. Individual volumes offer clear guidance on contouring in different cancers and present treatment recommendations, including with regard to advanced options such as intensity-modulated radiation therapy (IMRT) and stereotactic body radiation therapy (SBRT). Each volume addresses one particular area of practice and is edited by experts with an outstanding international reputation. Readers will find the series to be an ideal source of up-to-date information on when to apply the various available technologies and how to perform safe treatment planning. More information about this series at http://www.springer.com/series/13580

Jun Ma  •  Nancy Y. Lee  •  Jiade J. Lu Editors

Nasopharyngeal Cancer A Practical Guide on Diagnosis and Treatment

Editors Jun Ma Department of Radiation Oncology Sun Yat-sen University Cancer Center Guangzhou China

Nancy Y. Lee Department of Radiation Oncology Memorial Sloan Kettering Cancer Center New York USA

Jiade J. Lu Department of Radiation Oncology Shanghai Proton and Heavy Ion Center Shanghai China

ISSN 2522-5715     ISSN 2522-5723 (electronic) Practical Guides in Radiation Oncology ISBN 978-3-030-65036-0    ISBN 978-3-030-65037-7 (eBook) https://doi.org/10.1007/978-3-030-65037-7 © Springer Nature Switzerland AG 2021 This work is subject to copyright. All rights are reserved by the Publisher, whether the whole or part of the material is concerned, specifically the rights of translation, reprinting, reuse of illustrations, recitation, broadcasting, reproduction on microfilms or in any other physical way, and transmission or information storage and retrieval, electronic adaptation, computer software, or by similar or dissimilar methodology now known or hereafter developed. The use of general descriptive names, registered names, trademarks, service marks, etc. in this publication does not imply, even in the absence of a specific statement, that such names are exempt from the relevant protective laws and regulations and therefore free for general use. The publisher, the authors, and the editors are safe to assume that the advice and information in this book are believed to be true and accurate at the date of publication. Neither the publisher nor the authors or the editors give a warranty, expressed or implied, with respect to the material contained herein or for any errors or omissions that may have been made. The publisher remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. This Springer imprint is published by the registered company Springer Nature Switzerland AG The registered company address is: Gewerbestrasse 11, 6330 Cham, Switzerland

Contents

1 Diagnosis and Staging of Nasopharyngeal Cancer ��������������������������������   1 Wai Tong Ng, Shiobhon Y. Luk, Henry C. K. Sze, Brian O’Sullivan, and Anne W. M. Lee 2 Contouring Methods and Atlas of Organs at Risk����������������������������������  23 Xiao-Li Yu and Ying Sun 3 Management of Neck Disease in Early Stage Disease����������������������������  47 Ling-Long Tang 4 Multimodality Management for Locally Advanced Nasopharyngeal Cancer����������������������������������������������������������������������������  57 Liang Peng, Cheng Xu, Yu-Pei Chen, and Jun Ma 5 Intensity-Modulated Radiation Therapy for Nasopharyngeal Cancer ��������������������������������������������������������������������������������������������������������  71 Nancy Y. Lee, Lin Kong, Moses Tam, and Jiade J. Lu 6 Particle Beam Radiation Therapy for Nasopharyngeal Cancer������������  83 Lin Kong, Nancy Y. Lee, Michael F. Moyers, and Jiade J. Lu 7 Treatment of Metastatic Nasopharyngeal Cancer����������������������������������  95 Lin Kong and Jiade J. Lu 8 Salvage Radiation Therapy for Locally Recurrent Nasopharyngeal Cancer���������������������������������������������������������������������������� 103 Lin Kong and Jiade J. Lu 9 The Use of the EBV Blood Test in Clinical Management Decision ������������������������������������������������������������������������������������������������������ 113 Jin-Ching Lin 10 Management of Radiotherapy-Induced Acute Toxicities ���������������������� 133 Yingzhi Wu

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11 Management of Radiation-Induced Late Complications and  Evidence-Based Surveillance for Nasopharyngeal Carcinoma�������������� 155 Yingzhi Wu and Guan-Qun Zhou 12 Special Consideration in Pediatric Nasopharyngeal Cancer ���������������� 175 Enis Ozyar and Teuta Zoto Mustafayev

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Diagnosis and Staging of Nasopharyngeal Cancer Wai Tong Ng, Shiobhon Y. Luk, Henry C. K. Sze, Brian O’Sullivan, and Anne W. M. Lee

Contents 1.1  1.2  1.3  1.4  1.5  1.6 

Introduction Essential Anatomy of the Nasopharynx Natural History and Routes of Tumor Spread Presenting Symptoms Diagnostic Workup and Staging Investigations Staging of NPC—AJCC/UICC TNM Eighth Ed. 1.6.1  Definition of Primary Tumor (T) 1.6.2  Definition of Regional Lymph Node (N) 1.7  Summary References

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W. T. Ng · A. W. M. Lee (*) Department of Clinical Oncology, The University of Hong Kong and the University of Hong Kong-Shenzhen Hospital, Hong Kong, China e-mail: [email protected]; [email protected] S. Y. Luk Department of Diagnostic Radiology, Pamela Youde Nethersole Eastern Hospital, Hong Kong, China e-mail: [email protected] H. C. K. Sze Heal Oncology, Hong Kong, China e-mail: [email protected] B. O’Sullivan Department of Radiation Oncology, Princess Margaret Cancer Centre, University of Toronto, Toronto, ON, Canada e-mail: [email protected] © Springer Nature Switzerland AG 2021 J. Ma et al. (eds.), Nasopharyngeal Cancer, Practical Guides in Radiation Oncology, https://doi.org/10.1007/978-3-030-65037-7_1

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Introduction

• Nasopharyngeal carcinoma (NPC) is a highly malignant cancer with frequent local infiltration and early nodal metastasis. Due to its central location and innocuous presenting symptoms, early diagnosis is difficult. Both radiological imaging and endoscopic examination are essential to determine the disease extent. This chapter reviews the basic imaging anatomy of nasopharynx, natural history of disease spread, diagnosis, and staging of NPC.

1.2

Essential Anatomy of the Nasopharynx

• The nasopharynx is a cuboidal open chamber that begins at the choana and end at caudal border of C1 vertebra. The roof and the posterior wall are formed by the basisphenoid, the clivus, and the first cervical vertebra. The lateral and posterior walls of the nasopharynx are supported by the pharyngobasilar fascia, which is attached to the base of the skull. This fascia is interrupted at the level of sinus of Morgagni where the cartilaginous part of the Eustachian tube and the levator veli palatine muscle enter into the nasopharynx. This protrusion also creates a ridge called the torus tubarius. Behind the torus is a recess called the fossa of Rosenmüller, and this is the site where majorities of NPC arise. Figures 1.1, 1.2, 1.3, and 1.4 illustrate the radiological boundaries of the nasopharynx: • Anteriorly begins at the posterior choana and merges with the nasal cavity (Fig. 1.1). • Inferiorly extends to the caudal border of C1 vertebra (Fig. 1.2).

Fig. 1.1  Axial non-­ contrast T1-weighted image showing the anterior boundary of the nasopharynx (N), beginning at the posterior choana (C) and merges with the nasal cavity

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Fig. 1.2 Sagittal non-contrast T1-weighted image showing the inferior boundary of the nasopharynx (N), extending to the caudal border of C1 vertebra. The superior wall abuts the sphenoid sinus (S) floor and continues posterior-­ inferiorly along the clivus (C) to the C1 vertebra (Abbreviation: SP soft palate)

Figs. 1.3 and 1.4  Axial non-contrast T1-weighted image and coronal non-contrast T1-weighted image showing the lateral walls include the fossa of Rosenmüller (F) and mucosa covering the torus tubarius (T) forming the Eustachian for tube orifice (E)

• The superior wall abuts the sphenoid sinus floor and continues posterior-­ inferiorly along the clivus to the C1 vertebrae (Fig. 1.2). • Lateral walls include the fossae of Rosenmüller and mucosa covering the torus tubarius forming the Eustachian tube orifice (Figs. 1.3 and 1.4).

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Natural History and Routes of Tumor Spread

• Most common site of origin of nasopharyngeal carcinoma is the fossa of Rosenmüller, and early invasion to adjacent structures is common. Table  1.1 shows the frequency of involved adjacent structures at disease presentation [1]. • Disease extension is best depicted by magnetic resonance imaging (MRI) with gadolinium. • Anterior: nasal cavity (Fig. 1.5), nasal septum (Fig. 1.6), pterygopalatine fossa (Fig. 1.7). • Lateral: levator veli palatine infiltration (Fig.  1.8), parapharyngeal space (Fig.  1.9), pterygoid muscles (Fig.  1.10), masticator space, nasopharyngeal carotid space (Fig. 1.11). • Posterior: retropharyngeal space, prevertebral musculature (Fig.  1.12), vertebrae, spinal canal. • Inferior: oropharynx, soft palate, and tonsils. • Superior: clivus (Fig. 1.13), sphenoid sinus (Fig. 1.14), foramen lacerum, petrous bone (Fig. 1.15), foramen ovale, cavernous sinus (Fig. 1.16). • Nodal spread typically follows an orderly spread from upper neck node downward. Three main routes of nodal spread have been described: retropharyngeal node of Rouviere, deep cervical chain, and the posterior accessory chain. The

Table 1.1  Direction of local invasion and the frequency of involved adjacent structures (adopted with permission from Ref. [1]) Direction of invasion Anterior

Anterolateral

Lateral

Posterior Superior

Inferior

Structures involved Nasal cavity Nasal septum Orbit/ orbital fissure Maxillary antrum Pterygoid plate, Pterygomaxillary fissure, Pterygopalatine fossa Parapharyngeal, carotid space Pterygoid muscles Infratemporal fossa Prevertebral muscle Clivus Sphenoid sinus, foramen rotundum, and ovale Petrous bone, petrooccipital fissure Jugular foramen, hypoglossal canal Pituitary fossa, pituitary gland Cavernous sinus Cerebrum, meninges Ethmoid sinus Oropharyngeal wall/ soft palate Hypopharynx

Frequency (%) 87 3 4 4 27

68 48 9 19 41 38 19 4 3 16 4 6 21 2

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Fig. 1.5  Axial contrast-­ enhanced T1-weighted image showing anterior extension of the tumor (T) into left nasal cavity (N)

Fig. 1.6  Axial contrast-­ enhanced T1-weighted image showing anterior extension of the tumor (T) to nasal septum

incidences of nodal involvement at different radiological levels in order of frequency were (Fig. 1.17): 70.4% at Level II, 69.4% retropharyngeal, 44.9% III, 26.7% V, and 11.2% IV nodes. Level IB is rarely involved (2.7%) except in the presence of bulky jugulodigastric node, and skip metastasis is rare.

6 Fig. 1.7  Axial contrast-­ enhanced T1-weighted image showing anterior extension of the tumor (T) into left pterygopalatine fossa and left pterygomaxillary fissure

Fig. 1.8  Axial contrast-­ enhanced T1-weighted image showing lateral extension of the tumor (T) into right veli palatine (Abbreviation: M mastoid air-cells)

W. T. Ng et al.

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Fig. 1.9  Axial non-­ contrast T1-weighted image showing lateral extension of the tumor (T) into right parapharyngeal space (Abbreviation: P parapharyngeal space)

Fig. 1.10  Axial contrast-­ enhanced T1-weighted image showing lateral extension of the tumor (T) into left medial pterygoid muscle

• Concerning distant metastasis, less than 5% of cases presents with metastatic disease at the time of diagnosis. Subsequent risk of distant metastasis depends on the initial stage of disease. The most common sites of metastases are bone, lung, and liver (Figs. 1.18, 1.19, 1.20); and patients with lung metastasis alone have a relatively better prognosis compared with other sites of metastasis.

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Fig. 1.11  Axial contrast-­ enhanced T1-weighted image showing lateral extension of the tumor (T) into left medial carotid space

Fig. 1.12  Axial contrast-­ enhanced T1-weighted image showing posterior extension of the tumor (T) into prevertebral muscles (P)

1.4

Presenting Symptoms

• NPC is usually asymptomatic in its early stages. The most common presenting symptom prompting patient to seek medical assessment is a painless neck lump [2, 3]. It is followed by nasal (discharge, bleeding, or obstruction) and aural (tinnitus, hearing impairment) symptoms. The presence of headache usually indicates involvement of the skull base. Neurological symptoms can occur in locally advanced disease involving neural structures. The most commonly involved cranial nerves are the V and the VI cranial nerves, causing facial numbness and

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Fig. 1.13 Sagittal non-contrast T1-weighted image showing superior extension of the tumor (T) into clivus

Fig. 1.14 Coronal non-contrast T1-weighted image showing superior extension of the tumor (T) into left sphenoid sinus floor

diplopia, respectively. Their involvement is caused by direct tumor invasion into the cavernous sinus. Involvement of other cranial nerves is less common but can occur especially in advanced disease causing multiple cranial nerve palsies. Jugular foramen syndrome, as characterized by IX, X, and XI palsies causing slurring of speech and dysphagia, happens when there is extensive posterolateral extension of the primary tumor or nodal disease. Trotter’s syndrome is caused by the deep invasion to the lateral nasopharyngeal wall and is characterized by unilateral deafness, pain over the mandibular division of the trigeminal nerve, defective mobility of the ipsilateral soft palate, and trismus. Patients with distant metastases may have systemic upset including decreased appetite, lethargy, and weight loss. Very rarely, dermatomyositis as a paraneoplastic syndrome can be the initial manifestation.

10 Fig. 1.15  Axial contrast-­ enhanced T1-weighted image showing superior extension of the tumor (T) into left petrous bone and left foramen lacerum

Fig. 1.16 Coronal contrast-enhanced T1-weighted image showing superior extension of the tumor (T) into left foramen ovale and left cavernous sinus

W. T. Ng et al.

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Fig. 1.17 Schematic diagram demonstrating the incidence of nodal involvement at different radiological levels. “Adopted from Ho FC, Tham IW, Earnest A, Lee KM, Lu JJ. Patterns of regional lymph node metastasis of nasopharyngeal carcinoma: a meta-analysis of clinical evidence. BMC Cancer 2012;12:98. Open access”

1.5

Diagnostic Workup and Staging Investigations

• The primary tumor should be assessed by nasoendoscopy and biopsy should be obtained to confirm the diagnosis and histology. MRI of the nasopharynx and the neck is the modality of choice for assessment of the locoregional disease extent. MRI is preferred over computed tomography (CT) because of its superiority in soft tissue contrast which enables accurate delineation of small anatomical structures that make up the boundary of the nasopharynx. Involvement of the skull base and paranasal sinuses can also be clearly demonstrated. Fluorodeoxyglucose positron emission tomography integrated with CT (PET/CT) is a sensitive tool to detect distant metastases and may increase the accuracy of the assessment of cervical nodal metastases. Epstein-Barr virus deoxyribonucleic acid (EBV DNA) has been shown to carry prognostic value and may enhance risk categorization [4–8].

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Fig. 1.18  PET-CT image showing hypermetabolic lesion in left ilium, compatible with metastasis

Fig. 1.19  Axial CT image in lung window showing multiple nodules in both lungs, compatible with metastases

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Fig. 1.20  PET-CT image showing hypermetabolic lesions in the liver, compatible with liver metastases

1.6

Staging of NPC—AJCC/UICC TNM Eighth Ed.

• The TNM staging system is the only widely accepted staging classification. Recently the American Joint Committee on Cancer and Union for International Cancer Control (AJCC/UICC) cancer staging has been revised to its eighth ­edition [9] not only to clarify ambiguous anatomical areas but also reflect current knowledge about outcome [10]. Major modifications include the following: • Modification of the T2 Category: T2 category now includes adjacent muscle involvement—medial pterygoid, lateral pterygoid, and prevertebral muscles (Fig. 1.21). • Modification of the T4 Category: Previous “masticator space” and “infratemporal fossa” are replaced by specific description of soft tissue involvement. • The supraclavicular region, depicted in the shaded area in Fig. 1.17, is replaced by the level IV and Vb.

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Fig. 1.21  Axial non-­ contrast T1-weighted image showing modification of the T2 category. Yellow and green lines represent the T2 category in 7th and 8th Edition, respectively. Blue and red lines represent the T4 category in 7th and 8th Edition, respectively. (Abbreviations: CS carotid space, LP lateral pterygoid muscle, M masseter muscle, MP medical pterygoid muscle, PG partoid gland, PPS parapharyngeal space, PV prevertebral muscle, T temporalis muscle)

1.6.1 Definition of Primary Tumor (T) T-Criteria. TX: Primary tumor cannot be assessed. T0: No tumor identified, but EBV-positive cervical node(s) involvement. T1: Tumor confined to nasopharynx, or extension to oropharynx and/or nasal cavity without parapharyngeal involvement. • T2: Tumor with extension to parapharyngeal space, and/or adjacent soft tissue involvement (medial pterygoid, lateral pterygoid, prevertebral muscles) (Fig. 1.22). • T3: Tumor with infiltration of bony structures at skull base, cervical vertebra, pterygoid structures, and/or paranasal sinuses (Fig. 1.23). • T4: Tumor with intracranial extension, involvement of cranial nerves, hypopharynx, orbit, parotid gland, and/or extensive soft tissue infiltration beyond the lateral surface of the lateral pterygoid muscle (Fig. 1.24). • • • •

1.6.2 Definition of Regional Lymph Node (N) • Lymph nodes are subdivided into specific anatomic subsites and grouped into seven levels (IA, IB, IIA, IIB, III, IV, VA, VB, VI, and VII) [11]. Other lymph node groups are defined by their specific anatomic location—suboccipital, retropharyngeal (Fig.  1.25), parapharyngeal, buccinators, preauricular, periparotid,

1  Diagnosis and Staging of Nasopharyngeal Cancer Fig. 1.22  Axial contrast-­ enhanced T1-weighted image showing a T2 tumor (T) with extension to right parapharyngeal space and right prevertebral muscles

Fig. 1.23  Axial contrast-­ enhanced T1-weighted image showing a T3 tumor (T) with extension to clivus

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Fig. 1.24  Coronal contrast-enhanced T1-weighted image showing a T4 tumor (T) with extension along left foramen ovale, left cavernous sinus, and left middle cranial fossa Fig. 1.25  Axial contrast-­ enhanced T1-weighted image showing an enlarged left retropharyngeal lymph node (LN)

and intraparotid. The readers are reminded to note that this lymph node grouping is different from the consensus guideline adopted by radiation oncologists [12]. • The actual size (maximum dimension in any direction) of the enlarged lymph nodes (Fig.  1.26), laterality, and lowest level of neck involvement should be recorded. Midline nodes are considered ipsilateral nodes. Proposal has also been suggested on how to record the maximum nodal dimension for confluent and contiguous nodes [13].

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Fig. 1.26  Axial contrast-­ enhanced T1-weighted image showing N3 nodal involvement based on the maximum nodal dimension for confluent nodes

Fig. 1.27  Axial contrast-­ enhanced T1-weighted image showing N1 nodal involvement

• • • •

N-Criteria. NX: Regional lymph nodes cannot be assessed. N0: No regional lymph node metastasis. N1: Unilateral metastasis in cervical lymph node(s) and/or unilateral or bilateral metastasis in retropharyngeal lymph node(s), 6 cm or smaller in greatest dimension, above the caudal border of cricoid cartilage (Fig. 1.27).

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Fig. 1.28  Axial contrast-enhanced T1-weighted image showing N2 nodal involvement

• N2: Bilateral metastasis in cervical lymph node(s), 6 cm or smaller in greatest dimension, above the caudal border of cricoid cartilage (Fig. 1.28). • N3: Unilateral or bilateral metastasis in cervical lymph node(s), larger than 6 cm in greatest dimension, and/or extension below the caudal border of cricoid cartilage. • M-Criteria. • Mediastinal lymph node metastases below the clavicle are considered distant metastases. Other common metastatic sites include lung, bone, and liver. Brain metastasis is extremely rare. • M0: No distant metastasis. • M1: Distant metastasis (Fig. 1.29). • Incorporation of plasma EBV DNA into the staging system has been suggested. However, different cutoff points have been used: 500 copies/mL by Lee et al. [14], 2000 copies/mL by Guo et al. [15], and 4000 copies/mL by Zhang et al. [16]. This is likely due to the lack of assay standardization and a harmonized assay is necessary before its routine application in the staging of NPC [17]. Furthermore, tumor load [18], nomogram [18], MRI-based radiomics [19], gene expression based signature [20], and microRNA signature [21] have also been described for the prediction of treatment outcomes. In particular, nomograms enable the incorporation of both patient and disease characteristics into the calculation of simple numerical estimates of the survival outcomes, making it a convenient prognostic tool. Various proposals with the inclusion of different parameters have been suggested [18, 22–24].

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Fig. 1.29  PET-CT images showing multiple hypermetabolic lesions in the vertebral volumn and liver compatible with metastases

1.7

Summary

• Significant advancements have been made both in diagnostic methods and staging evaluation of NPC. Plasma EBV DNA testing is increasing being utilized not only for disease monitoring but also population screening. Several clarifications have been adopted in the current AJCC/UICC TNM classification and are helpful to minimize inter-observer variation in the staging process. Rapid development on the field of biomarkers would certainly help to complement the TNM staging system in the future. Acknowledgment  Conflict of Interest Statement: None declared.

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References 1. Chan JKC, et al. Nasopharyngeal carcinoma. In: Barnes L, Eveson JW, Reichart P, Sidransky D, editors. Pathology and genetics. Head and neck tumors. Lyon: IARC Press; 2005. p. 85–97. 2. Lee AW, Foo W, Law SC, et al. Nasopharyngeal carcinoma: presenting symptoms and duration before diagnosis. Hong Kong Med J. 1997;3(4):355–61. 3. Colaco RJ, Betts G, Donne A, et  al. Nasopharyngeal carcinoma: a retrospective review of demographics, treatment and patient outcome in a single Centre. Clin Oncol (R Coll Radiol). 2013;25(3):171–7. 4. Lin JC, Wang WY, Chen KY, et  al. Quantification of plasma Epstein-Barr virus DNA in patients with advanced nasopharyngeal carcinoma. N Engl J Med. 2004;350(24):2461–70. 5. Leung SF, Zee B, Ma BB, et al. Plasma Epstein-Barr viral deoxyribonucleic acid quantitation complements tumor-node-metastasis staging prognostication in nasopharyngeal carcinoma. J Clin Oncol. 2006;24(34):5414–8. 6. Chan AT, Lo YM, Zee B, et  al. Plasma Epstein-Barr virus DNA and residual disease after radiotherapy for undifferentiated nasopharyngeal carcinoma. J Natl Cancer Inst. 2002;94(21):1614–9. 7. Hui EP, Ma BB, Chan KC, et al. Clinical utility of plasma Epstein-Barr virus DNA and ERCC1 single nucleotide polymorphism in nasopharyngeal carcinoma. Cancer. 2015;121(16):2720–9. 8. Leung SF, Chan KC, Ma BB, et al. Plasma Epstein-Barr viral DNA load at midpoint of radiotherapy course predicts outcome in advanced-stage nasopharyngeal carcinoma. Ann Oncol. 2014;25(6):1204–8. 9. Amin MB, Edge S, Greene F. AJCC Cancer staging manual. 8th ed. New York: Springer; 2017. 10. Pan JJ, Ng WT, Zong JF, et al. Proposal for the 8th edition of the AJCC/UICC staging system for nasopharyngeal cancer in the era of intensity-modulated radiotherapy. Cancer. 2016;122(4):546–58. 11. Robbins KT, Shaha AR, Medina JE, et al. Consensus statement on the classification and terminology of neck dissection. Arch Otolaryngol Head Neck Surg. 2008;134(5):536–8. 12. Gregoire V, Ang K, Budach W, et al. Delineation of the neck node levels for head and neck tumors: a 2013 update. DAHANCA, EORTC, HKNPCSG, NCIC CTG, NCRI, RTOG, TROG consensus guidelines. Radiother Oncol. 2014;110(1):172–81. 13. Ai QY, King AD, Mo FKF, et al. Staging nodal metastases in nasopharyngeal carcinoma: which method should be used to measure nodal dimension on MRI? Clin Radiol. 2018;73:640–6. 14. Lee VH, Kwong DL, Leung TW, et al. The addition of pretreatment plasma Epstein-Barr virus DNA into the 8th edition of nasopharyngeal cancer TNM stage classification. Int J Cancer. 2019;144:1713–22. 15. Guo R, Tang LL, Mao YP, et al. Proposed modifications and incorporation of plasma Epstein-­ Barr virus DNA improve the TNM staging system for Epstein-Barr virus-related nasopharyngeal carcinoma. Cancer. 2019;125:79–89. 16. Zhang L, Tang LQ, Chen QY, et  al. Plasma Epstein-Barr viral DNA complements TNM classification of nasopharyngeal carcinoma in the era of intensity-modulated radiotherapy. Oncotarget. 2016;7(5):6221–30. 17. Kim KY, Le QT, Yom SS, et al. Clinical utility of Epstein-Barr virus DNA testing in the treatment of nasopharyngeal carcinoma patients. Int J Radiat Oncol Biol Phys. 2017;98(5):996–1001. 18. Pan JJ, Ng WT, Zong JF, et al. Prognostic nomogram for refining the prognostication of the proposed 8th edition of the AJCC/UICC staging system for nasopharyngeal cancer in the era of intensity-modulated radiotherapy. Cancer. 2016;122(21):3307–15. 19. Zhang B, Tian J, Dong D, et al. Radiomics features of multiparametric MRI as novel prognostic factors in advanced nasopharyngeal carcinoma. Clin Cancer Res. 2017;23(15):4259–69. 20. Tang XR, Li YQ, Liang SB, et  al. Development and validation of a gene expression-based signature to predict distant metastasis in locoregionally advanced nasopharyngeal carcinoma: a retrospective, multicentre, cohort study. Lancet Oncol. 2018;19(3):382–93.

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21. Liu N, Chen NY, Cui RX, et al. Prognostic value of a microRNA signature in nasopharyngeal carcinoma: a microRNA expression analysis. Lancet Oncol. 2012;13(6):633–41. 22. OuYang PY, Zhang LN, Xiao Y, et al. Validation of published nomograms and accordingly individualized induction chemotherapy in nasopharyngeal carcinoma. Oral Oncol. 2017;67:37–45. 23. Huang XD, Zhou GQ, Lv JW, et al. Competing risk nomograms for nasopharyngeal carcinoma in the intensity-modulated radiotherapy era: a big-data, intelligence platform-based analysis. Radiother Oncol. 2018;129(2):389–95. 24. Tang LQ, Li CF, Li J, et al. Establishment and validation of prognostic nomograms for endemic nasopharyngeal carcinoma. J Natl Cancer Inst. 2016;108(1):djv291.

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Contouring Methods and Atlas of Organs at Risk Xiao-Li Yu and Ying Sun

Contents 2.1  I ntroduction 2.2  W  indow Width and Window Level 2.3  Consensus on Major Disputable Organs at Risk 2.3.1  Temporal Lobe 2.3.2  Middle Ear 2.3.3  Inner Ear 2.3.4  Spinal Cord 2.4  Derivation of Delineation Atlas 2.5  Dose Constraints References

2.1

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Introduction

• Besides the target volumes, accurate delineation and precise dosage of organs at risk (OARs) is the key to successful radiotherapy for nasopharyngeal carcinoma (NPC). Many normal tissues close to the nasopharynx are defined as OARs, including the temporal lobe, brainstem, spinal cord, optic nerve, chiasm, etc.; therefore, treatment planning is difficult in NPC.  Furthermore, critical normal tissues such as the brainstem and temporal lobe are so close to the target volume that inaccurate delineation will mislead treatment planning, resulting in X.-L. Yu Department of Radiation Oncology, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, People’s Republic of China e-mail: [email protected] Y. Sun (*) Department of Radiation Oncology, Sun Yat-Sen University Cancer Center, Guangzhou, People’s Republic of China e-mail: [email protected] © Springer Nature Switzerland AG 2021 J. Ma et al. (eds.), Nasopharyngeal Cancer, Practical Guides in Radiation Oncology, https://doi.org/10.1007/978-3-030-65037-7_2

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i­ nadequate target volume coverage or OAR overdose. Thus, accurate and consistent OARs delineation in NPC is critical. • However, large variations were observed when contouring OARs [1, 2]. Furthermore, significantly different contouring methods are also recommended in the literature. For example, when contouring the inner ear, some clinicians delineate the cochlea alone, the internal auditory canal (IAC) in combination with the vestibule and cochlea, the IAC and cochlea, or the vestibule and cochlea [3–6]. Such diversity in OAR contouring will certainly generate unmatched dosimetric parameters, and prevents side effect correlation studies. Thus, guidelines for OARs delineation are necessary.

2.2

Window Width and Window Level

• More than 30 normal tissues are defined as OARs in nasopharyngeal carcinoma, including the temporal-mandibular joints (TMJ), brainstem, optic chiasm, tongue (oral cavity), larynx, upper pharyngeal constrictor, middle pharyngeal constrictor, inferior pharyngeal constrictor, trachea, submandibular glands, esophagus, optic nerves, temporal lobes, parotid glands, spinal cord, brachial plexuses, thyroid gland, mandible, inner ears, middle ears, eyes, lens, pituitary, etc. For showing clearly the structure boundary, different window width and window level should be used. For example, the middle ear, inner ear, and TMJ should be delineated on the bone window (1400–1600/400–600 HU or 3000–4500/600–800 HU), the temporal lobe and brainstem on the brain windows (80–100/35–50  HU); however, the lateral boundary of the temporal lobe and other organs should be delineated on the soft tissue window (300–400/20–120 HU) [4, 7].

2.3

Consensus on Major Disputable Organs at Risk

2.3.1 Temporal Lobe • In daily clinical work and literatures showing the OARs delineation, two methods were used to contour the temporal lobe. The first included brain tissue outside the Sylvian fissure and basal ganglia, excluding the parahippocampal gyrus and hippocampus (method 1); the other method contoured the temporal lobe including the parahippocampal gyrus and hippocampus, excluding the basal ganglia and insula (method 2). We suggest the temporal lobe includes the hippocampus, parahippocampal gyrus, and uncus; the basal ganglia and insula are located anteriorly and superiorly to the hippocampus and parahippocampal gyrus should be excluded. The reason and details were described in previous study [8]. Recently, more attention was pained to the injury of hippocampus, for its close relation with intelligence and memory. Thus, some researchers propose to identify the hippocampus as a critical organ at risk in the IMRT optimization process [9]. Gondi et  al. further elaborated on the location of the hippocampus on MRI [10].

2  Contouring Methods and Atlas of Organs at Risk

25

2.3.2 Middle Ear • The middle ear includes three parts: tympanum, Eustachian tube (ET), and mastoid process. Three contouring methods were identified: contouring the combination of tympanum and ET [4]; the tympanum and bony part of the ET, respectively [11]; or the ET, tympanic cavity, and mastoid process, respectively [12]. Radiationinduced middle ear damage is characterized by otitis media with effusion (OME), suffered by 26–40% NPC patients within 5 years after radiotherapy [11, 13]. Two factors contributed to OME: (1) damage to the ET, tensor veli palatini muscle, cartilage, or nerves; (2) direct radiation damage leading to noninfectious inflammation [12]. Therefore, the injuries of ET and tympanic cavity (including the otosteon) are relevant to the development of OME and should be contoured and protected individually. The mastoiditis is very common before and after NPC radiotherapy. Compared to the tympanum and ET, the mastoid has a much larger volume and a longer distance from the nasopharynx. Including the mastoid will underestimate the dose of ET and tympanum, and mislead the radiation planning evaluation. Thus, we suggest contouring the tympanic cavity and bony part of the ET individually. The tympanic cavity is delineated laterally by the tympanic membrane, defined by the ligature between the two bony structures with an increased density along the anterior and posterior walls of the most medial aspect of the outer air canal [4], the sharp narrow region connected interiorly to the ET, and the interface between the temporal bone and air at all other walls. The mastoid could be delineated and evaluated alone if necessary.

2.3.3 Inner Ear • The components of inner ear include the cochlea, IAC, vestibule, and the semicircular canal. As described above, four methods were observed for inner ear [3–6]. For the inner ear, we suggest delineation of the cochlea and IAC individually. The cochlea is located anteriorly to the IAC.  Inner ear radiation-induced injury is mainly responsible for sensorineural hearing loss, with morbidity rates of 11–40% [3, 14]. The precise mechanisms are obscure. Our recommendation to contour the cochlea and IAC individually is based on the inner ear function. During sound transmission, vibration passes from the tympanic membrane to the otosteon, fenestra vestibule and through the cochlea to vibrate the cochlear basilar membrane and produce nerve impulses, which are transported into the auditory center via the cochlear nerve to generate the auditory signal. Dysfunction in any structure of this conduction pathway may lead to sensorineural hearing loss. Thus, the cochlea and cochlear nerve should be contoured and protected individually.

2.3.4 Spinal Cord • In NPC radiation, the spinal cord delineation includes the cervical and thoracic cord. The accurate delineation and precise dosage for spinal cord is critical, for it maintaining the body’s sensory and motor functions. Two methods were observed:

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contouring the true spinal cord [15], or the bony limits of the spinal canal [16]. We suggested the visible true spinal cord being contoured from the foramen magnum (the level of the odontoid process of the axis) to 2 cm below the inferior edge of the head of the collarbone. Our recommendation to delineate the true spinal cord, while not the bony limits of the spinal canal for the following reasons: The transverse diameter of the cervical spinal cord is greater than the thoracic spinal cord, and is easier to visualize. In addition, a planning organ at risk volume was generated to insure the dose not to exceed the tolerance of spinal cord.

2.3.4.1 Parotid Gland • Xerostomia is one of the most common side effect of NPC radiation. Salivary flows are markedly reduced following 10–15 Gy of radiation delivered to most of the gland [17]. The recovery of the salivary function is possible over time even with doses up to 40–50  Gy. However, higher doses to most of the gland will result in irreversible and permanent xerostomia. The largest controversy of parotid gland contouring lies in the overlap between the parotid gland and CTV. The parotid gland receives a dose influenced by the size of the target volume and prescribed dose. Radiation-induced xerostomia in NPC patients can recover years after radiotherapy. Contouring the whole salivary gland minus the GTV may be more suitable for getting the better dosimetric parameters that correspond with the change of salivary function after radiotherapy. Thus, we suggested the whole parotid gland should be outlined, including the external carotid artery [18] and the region within CTV, but not the GTV. Water et al. elaborate further on definitive bordering of the parotid gland [19].

2.4

Derivation of Delineation Atlas

• By reviewing atlases of anatomy [20, 21], we defined 3D-boundaries for other OARs, and suggested representative contouring according to their anatomic locations on CT–MRI fusion. Baxi et al. briefly introduced OARs contouring in nasopharyngeal IMRT [18]. We contoured other organs such as the brainstem and optic nerve according to their 3D anatomical boundaries. The whole organs should be outlined, including those in CTV, but not GTV. According to ICRU report 50, the OARs are defined as critical normal structures. Thus, those ­overlapping with the GTV, which is considered as part of the tumor, should not be included. On the other hand, OARs within the CTV, lacking of evidence of tumor involvement, should be included. Furthermore, such OARs contouring has also been performed in patients with lung cancer undergoing radiotherapy [16]. • This book presented the atlas of OARs mainly based on CT and refers to MRI. It is well recognized that MRI has a better resolution for soft tissue, and is usually used to diagnose the soft tissue disease. Thus, glands, muscles, and other soft tissues should be contoured by referring to MRI. On the other hand, CT can more reliably indicate bone boundaries and joint structures. Thus, the TMJ, middle/ inner ear, and mandible, which are mainly defined by bone limit, could be contoured based on CT alone. The 3D anatomical boundary of the OARs is presented in Table 2.1 and the delineation atlas in Fig. 2.1.

Post. edge of the hard palate or soft palate Cranial edge of epiglottis

Caudal edge of pterygoid plates

Tongue(oral cavity)b Tongue

Larynx

PharyngealConst_Upper

PharyngealConst_Middle

Larynx(larynx and laryngopharynx)

Upper pharyngeal constrictor [23]

Middle pharyngeal constrictor [23]

Cranial edge of hyoid bone

One or two slices superiorly

Chiasm

Optic chiasm

Optic tract or the disappearance of posterior cerebral artery

Cranial Disappearance of articular cavity

BrainStem

Standard TPS name [22] TMjointa

Brainstem

Organ Temporomandibular joint

Caudal edge of hyoid bone

Cranial edge of hyoid bone

Disappearance of anterior belly of digastric muscle Caudal edge of cricoid cartilage

Pituitary or suprasellar cistern

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

Table 2.1  Anatomic boundaries of the organs at risk in NPC

Nasopharynx, oropharynx, laryngopharynx, base of tongue Laryngopharynx

Ant. edge of thyroid cartilage or cricoid cartilage

Post. edge of mandible or is free

Optic canal

Lateral Lat. edge of mandibular condyle or surface of fossa glenoid

Posterior cerebral artery, anterior inferior cerebellar artery, cerebellar peduncle Infundibulum Internal carotid arteries, middle cerebral arteries Palate, oropharynx, Med. edge of the the palatine tonsil, mandible or inferior hyoid bone alveoli socket Including arytenoid Med. edge of hyoid cartilage, the bone, lat. edge of superior and inferior thyroid cartilage and horns of thyroid cricoid cartilage, cartilage and post. cervical vessels, edge of pharyngeal nerves, and lateral constrictor thyroid Longus capitis m., Carotid sheath longus colli m., body of cervical vertebra Longus capitis m., Hyoid bone longus colli m., body of cervical vertebra

Posterior Surface of fossa glenoid

Post. edge of Ant. edge of forth prepontine cistern or ventricle or basilar artery mesencephalic aqueduct

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

(continued)

2  Contouring Methods and Atlas of Organs at Risk 27

Caudal edge of hyoid bone

PharyngealConst_Lower

Trachea

Submandibulara Inferior edge of medial pterygoid or the level of C3

Esophagus

OpticNervea

TemporalLobea

Trachea

Submandibular gland

Esophagus [23]

Optic nerve [24]

Temporal lobe

Below the superior rectus Cranial edge of the sylvian fissure

Caudal edge of cricoid cartilage

Caudal edge of cricoid cartilage

Cranial

Standard TPS name [21]

Organ Inferior pharyngeal constrictor [23]

Table 2.1 (continued)

Two centimeters below the caudal edge of the clavicular head Superior the inferior rectus Base of middle cranial fossa

Two centimeters below the caudal edge of the clavicular head Appearance of fat space of submandibular triangle

Caudal edge of cricoid cartilage

Caudal

Posterior edge of the center of globe Temporal bone and sylvian fissure, greater wing of sphenoid

Trachea

Post. edge of isthmus of thyroid gland Lat. surface of mylohyoid m. or hyoglossus m.

Laryngopharynx or cricoids cartilage

Anterior

Petrous part of temporal lobe, tentorium of cerebellum, incisura preoccipitalis

Optic canal

Vertebral body or longus colli m.

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

Longus capitis m., longus colli m., body of cervical vertebra Ant. edge of esophagus

Posterior

Temporal bone

Fat space or thyroid gland

Ramus of the mandible, subcutaneous fat or platysma

Lateral thyroid gland

Thyroid cartilage or thyroid gland

Lateral

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

One-­two millimeters expanded from the lumen of trachea Cervical vessels, superior and middle pharyngeal constrictor m., hyoid bone, post. belly of the digastric m., mylohyoid m. or hyoglossus m.

Medial

28 X.-L. Yu and Y. Sun

SpinalCord

BrachialPlexusa

Thyroid

Mandible

Ear_Innera Ear_Middlea Eyesa Lensa Pituitary

Spinal cord

Brachial plexus [25]

Thyroid gland

Mandible

Inner ear Middle ear Eyes Lens Pituitary

Two centimeters below the inferior edge of the clavicular head Caudal edge of T1 at neural foramina and one to two CT slices below the clavicular head as the posterior aspect of the neurovascular bundle Body of fifth to seventh cervical vertebra

Appearance post. part submandibular space

Anterior scalene muscle

Middle scalene muscle

Fat space

Ant. belly Submandibular fat, sternocleidomastoid platysma m., lat. side post. belly of the digastric m. (posterior medial), mastoid process Exclude the subarachnoid space

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

Spinal cord

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

Caudal edge of Sternohyoid or Cervical vessels or Cervical vessels or Thyroid cartilage or pyriform sinus or sternocleidomastoid longus colli m. sternocleidomastoid cricoids cartilage or midpoint of thyroid esophagus or cartilage pharyngeal constrictor The mandible be contoured as whole organ but not be divided into the left and the right. Contouring of the mandible should include alveolar bone and exclude the teeth. Cochlea and internal auditory canal should be individually delineated and named. Tympanic cavity, bony part of Eustachian tube should be individually delineated and named. Ensure the retina to be contoured completely. The boundary between the lens and the vitreum is obvious The pituitary is located in the hypophysial fossa. Insure the organ be contoured completely but not beyond the surrounding bone. The pituitary is ovoid and can be visualized on 1–2 slices on CT scans of 3 mm thickness

Caudal edge of C4

Disappearance of cerebellum

External auditory canal, mastoid process

Abbreviations: m. Muscle a The organs should be divided into left and right, and the standard TPS name of laterality is indicated by appending an underscore character (_), followed by L or R, respectively. For example, the left parotid is named Parotid_L; the right parotid is named Parotid_R b Include the base of the tongue, body of tongue and mouth floor

Parotida

Parotid gland [19]

2  Contouring Methods and Atlas of Organs at Risk 29

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Fig. 2.1  Recommended atlas of organs at risk (OARs) based on CT–MRI fusion in NPC patients

2  Contouring Methods and Atlas of Organs at Risk

Fig. 2.1 (continued)

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Fig. 2.1 (continued)

X.-L. Yu and Y. Sun

2  Contouring Methods and Atlas of Organs at Risk

Fig. 2.1 (continued)

33

34

Fig. 2.1 (continued)

X.-L. Yu and Y. Sun

2  Contouring Methods and Atlas of Organs at Risk

Fig. 2.1 (continued)

35

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Fig. 2.1 (continued)

X.-L. Yu and Y. Sun

2  Contouring Methods and Atlas of Organs at Risk

Fig. 2.1 (continued)

37

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Fig. 2.1 (continued)

X.-L. Yu and Y. Sun

2  Contouring Methods and Atlas of Organs at Risk

Fig. 2.1 (continued)

39

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Fig. 2.1 (continued)

X.-L. Yu and Y. Sun

2  Contouring Methods and Atlas of Organs at Risk

Fig. 2.1 (continued)

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Fig. 2.1 (continued)

X.-L. Yu and Y. Sun

2  Contouring Methods and Atlas of Organs at Risk

43

Fig. 2.1 (continued)

2.5

Dose Constraints

• As recommended by RTOG 0225 and 0615, Dose Volume Histograms must be generated for all critical normal structures, any corresponding planning organs at risk (PRVs), and the unspecified tissues. Institutions that use PRVs must clearly define them. Unspecified tissue outside the targets: