UICC Staging System

UICC Staging System

C H A P T E R 9 Staging of Nasopharyngeal Carcinoma Based on the 8th Edition of the AJCC/UICC Staging System Anne W.M. Lee1,3, Jing Feng Zong2, Jian ...

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C H A P T E R

9 Staging of Nasopharyngeal Carcinoma Based on the 8th Edition of the AJCC/UICC Staging System Anne W.M. Lee1,3, Jing Feng Zong2, Jian Ji Pan2, Horace C.W. Choi1, Henry C.K. Sze4 1

Department of Clinical Oncology, University of Hong Kong, Hong Kong, China; 2Department of Radiation Oncology, Fujian Provincial Cancer Hospital, Provincial Clinical College of Fujian Medical University, Fuzhou, China; 3Clinical Oncology Center, University of Hong Kong-Shenzhen Hospital, Shenzhen, China; 4Department of Clinical Oncology, Pamela Youde Nethersole Eastern Hospital, Hong Kong, China

O U T L I N E Introduction

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Historical Development and Important Milestones in the Tumor, Node, Metastases Classification

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Gene Expression Patterns Circulating Tumor Cells Lactate Dehydrogenase Tumor Volume Institutional Factor

191 191 191 191 192

Comparison of 7th AJCC Staging, Chinese Staging, and 8th AJCC Staging 181 Masticator Space Infiltration 185 Prevertebral Muscle Involvement 185 Cervical Lymph Node 186

Nomogram and Other Statistical Methods in Predicting Prognosis

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Future Direction

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Validation of the 8th Edition

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References

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Limitations of the 8th AJCC/UICC Staging System Histological Factor Intrinsic Heterogeneity Within Each Stage Group Measurement of Lymph Node Size Omission of Other Clinically Important Factors

188 188 188 189 189

Review of Other Prognostic Factors EpsteineBarr Virus DNA MicroRNA

190 190 190

Commentary on Chapter 9: Staging of Nasopharyngeal Carcinoma Based on the 8th Edition of the AJCC/UICC Staging System: The Evolution of the Nasopharyngeal Cancer Tumor, Node, Metastases Stage Classification: A Model of Adaptation, Harmonization, and Collaboration

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References

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Nasopharyngeal Carcinoma https://doi.org/10.1016/B978-0-12-814936-2.00009-2

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Copyright © 2019 Elsevier Inc. All rights reserved.

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9. STAGING OF NASOPHARYNGEAL CARCINOMA BASED ON THE 8TH EDITION OF THE AJCC/UICC STAGING SYSTEM

INTRODUCTION An accurate tumor, node, metastases (TNM) staging system is important for predicting the prognosis, guiding treatment decision, and comparing treatment results between centers. It should also evolve with the changing standards of tumor imaging and therapeutic advances. In nasopharyngeal carcinoma (NPC), the clinical staging of disease relies heavily on radiological assessment. The increasing use of magnetic resonance imaging (MRI) in the past decades allows more accurate delineation of local tumor extent and enables evaluation of the prognostic significance of individual anatomical structures surrounding the nasopharynx. The introduction of positron emission tomography computed tomography (PET CT) further enhances the accuracy of staging especially in the detection of nodal and distant metastases. For the primary treatment of NPC with radiotherapy (RT), the evolution of technology from two-dimensional (2D) RT to 3D conformal RT and intensity-modulated radiotherapy (IMRT) has substantially improved the precision of RT delivery and locoregional disease control. The incorporation of chemotherapy in combination with RT further enhanced the survival outcome. Novel biomarkers, including the serum EpsteineBarr virus (EBV) DNA level, help to further categorize patients into different risk groups and thus carry important prognostic impact. Nomograms are developed to integrate clinical and biological parameters to improve the prognostic power for individual patients. Staging of NPC is thus undergoing continuous revision and is becoming more accurate and personalized.

HISTORICAL DEVELOPMENT AND IMPORTANT MILESTONES IN THE TUMOR, NODE, METASTASES CLASSIFICATION The history of staging for NPC dated back to 1952, when Geist and Portman first described a stage classification as follows1: I. Tumor limited to nasopharynx; no palpable nodes and no neurological signs II. Palpable cervical nodes; no other evidence of metastases or extension and no neurological signs III. Local invasion of orbit, sinuses, or base of skull; neurological signs; general carcinomatosis It is overly simple and unsatisfactory in that stages II and III both cover too wide a range of involvement to serve any useful purpose. Since then, many staging systems have been suggested. The most widely used systems in western centers are those published by the American Joint Committee for Cancer (AJCC) and the Union for International Cancer Control (UICC). While these two organizations both recommended a TNM stage classification of malignant tumors, the criteria and grouping were different. The merging of these two systems to form the 3rd edition of the AJCC/UICC staging system in 1988 was an important historic milestone.2,3 This edition of the staging system defined tumor limited to one subsite (posterosuperior, lateral, and inferior wall) of nasopharynx as T1, while tumor invading more than one subsite as T2. A common set of N-staging criteria (nodal size, multiplicity, and laterality) is applied to all head and neck cancers, including NPC. However, the fossa of Rosenmuller, a frequent site of origin of the primary tumor, is included as part of the lateral wall, when in fact it is formed partly by the lateral wall and partly by the posterior wall. In practice, such classification of the primary tumor into T1 and T2 may be neither possible nor accurate. As the nasopharynx is a midline organ with frequent submucosal infiltration, the relevance of differentiation between ipsilateral and contralateral nodal involvement is low. Furthermore, since NPC follows an orderly pattern of lymphatic spread, the level of nodal involvement may strongly correlate with disease extensiveness. The natural behavior and treatment consideration of NPC is so different from the other head and neck cancers that a more customized system was highly desirable. Hong Kong is one of the areas with the highest incidence of NPC and is where Ho’s classification originated.4,5 In Ho’s staging system, nodal classification was defined by the level of lymph node involvement using clinical anatomical landmarks. The upper cervical level (N1) was bounded below by the skin crease extending laterally and backward from or just below the thyroid notch (Fig. 9.1). The supraclavicular fossa (SCF) (N3) was defined by three points: the superior margin of the sternal end of the clavicle, the superior margin of the lateral end of the clavicle, and the point where the neck meets the shoulder. Stage V was introduced to distinguish patients with distant metastases from other potentially curable cases.

COMPARISON OF 7TH AJCC STAGING, CHINESE STAGING, AND 8TH AJCC STAGING

(A)

181

(B)

FIGURE 9.1 Nodal levels according to Ho’s classification. Skin crease dividing N1 and N2 arrowed. From Ho JH. An epidemiologic and clinical study of nasopharyngeal carcinoma. Int J Radiat Oncol Biol Phys. 1978;4(3e4):182e198. Used with permission from Elsevier.

In 1997, the 5th AJCC/UICC staging system was revised by adopting most of the key concepts of Ho’s staging system.6 Subsite involvement of the nasopharynx was abandoned as a staging criterion. With more advanced imaging technique by CT and MRI, involvement of the surrounding structures can be better visualized and their prognostic significance becomes more readily identified. Invasion to the parapharyngeal space (PPS) was defined as T2b disease; tumor with intracranial extension and/or involvement of cranial nerves, infratemporal fossa (ITF), hypopharynx, or orbit was staged as T4 disease. Involvement of the ITF denotes extension of tumor beyond the anterior surface of the lateral pterygoid muscle or lateral extension beyond the posterolateral wall of the maxillary antrum and the pterygomaxillary fissure. This edition of the staging system also imported the definition of SCF involvement from the Ho’s classification. This should be considered the second milestone in the history of NPC staging. Since then, the AJCC/UICC system had been widely used in Hong Kong and other Southeast Asian countries. Studies from both the endemic areas and low incidence countries showed that the 5th edition of the AJCC/UICC staging system had a better distribution of patients as well as higher correlation with prognosis when compared with the previous editions of staging system or Ho’s classification.7e9 No significant change was made for the 6th edition except masticator space (MS) was added as a synonym for ITF, signifying T4 disease.10 In following years, with the extensive application of MRI, improvement of RT technique, and the broad administration of chemoradiotherapy, modification of the staging system was deemed necessary to maintain its applicability. The prognostic significance of PPS and its involvement being a criterion for T2b disease became controversial, because it could be adequately irradiated using IMRT.11 The prognostic value of retropharyngeal lymph node (RLN) was ambiguous. Moreover, the lack of significant difference in survival between stage II and III disease had been criticized.12 The 7th edition of the AJCC/UICC TNM staging system applied the following amendments: (1) tumor invasion of the oropharyngeal and/or nasal cavity without PPS involvement was shifted from the original T2a down to T1; (2) PPS invasion was classified as T2; and (3) RLN metastasis was classified as stage N1.13 Table 9.1 summarizes Ho’s classification and the 3rd to 7th editions of the AJCC/ UICC staging systems.

COMPARISON OF 7TH AJCC STAGING, CHINESE STAGING, AND 8TH AJCC STAGING The Chinese 2008 staging system for NPC was revised from the Chinese 1992 staging system in China.14 The Chinese 2008 and the 7th edition of the AJCC/UICC staging systems possess similarities and differences.15 For both systems, nasopharynx, PPS, skull base, cranial nerve, and intracranial extension were assigned to the corresponding T subgroups and RLN was denoted as N1 disease. However, there were some major differences: • Oropharynx and nasal cavity involvement were assigned to T1 in the 7th edition of the AJCC/UICC system, but they were classified as T2 in the Chinese 2008 system. • Paranasal sinus involvement was defined as T3 by the AJCC/UICC system, but it was considered as T4 in the Chinese 2008 system.

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TABLE 9.1

Ho’s Classification and the 3rd to 7th Editions of the AJCC/UICC Staging System for Nasopharyngeal Carcinoma

Ho’s Classification

AJCC/UICC Staging System: 3rd and 4th Edition

AJCC/UICC Staging System: 5th Edition

AJCC/UICC Staging System: 6th Edition

AJCC/UICC Staging System: 7th Edition

T1

Nasopharynx

One subsite of nasopharynx

Nasopharynx

Nasopharynx

Nasopharynx, OP, NF

T2

Extension to the NF, OP, or adjacent muscles or nerves below the base of the skull

More than one subsite of nasopharynx

OP and/or NF T2a: Without PPS extension T2b: With PSS extension

OP and/or NF T2a: Without PPS extension T2b: With PPS extension

PPS extension

T3

Extension beyond T2 limits T3a: Bone involvement below the base of skull T3b: Involvement of the base of skull T3c: Involvement of the CN T3d: Involvement of the orbit, laryngopharynx, or ITF

NF and/or OP

Bony structures and/or paranasal sinuses

Bony structures and/or paranasal sinuses

Bony structures and/or paranasal sinuses

T4

d

Tumor invades skull and/or CN

Tumor with intracranial extension and/or involvement of CN, ITF, HP, or orbit

Tumor with intracranial extension and/or involvement of CN, ITF, HP, orbit, or MS

Tumor with intracranial extension and/or involvement of CN, ITF, HP, orbit, or MS

N-CLASSIFICATION N0

No LN palpable

No regional LN metastasis

No regional LN metastasis

No regional LN metastasis

No regional LN metastasis

N1

LN wholly in the upper cervical level bounded below by the skin crease extending laterally and backward from or just below the thyroid notch

Single ipsilateral LN measuring <3 cm in greatest dimension

Unilateral metastasis in LN < 6 cm in greatest dimension above the SCF

Unilateral metastasis in LN < 6 cm in greatest dimension above the SCF

Retropharyngeal LN (regardless of laterality) Cervical LN: unilateral,< 6 cm, and above the SCF

N2

LN palpable between the crease and the SCF, the upper limit being a line joining the upper margin of the sternal end of the clavicle and

N2a: Metastasis in single ipsilateral LN 3e6 cm in greatest dimension N2b: Metastasis in multiple ipsilateral LN,

Bilateral metastasis in LN < 6 cm in greatest dimension above the SCF

Bilateral metastasis in LN < 6 cm in greatest dimension above the SCF

Cervical LN: bilateral, <6 cm, and above the SCF

9. STAGING OF NASOPHARYNGEAL CARCINOMA BASED ON THE 8TH EDITION OF THE AJCC/UICC STAGING SYSTEM

T-CLASSIFICATION

the apex of an angle formed by the lateral surface of the neck and the superior margin of the trapezius

N3

N3a: >6 cm in greatest dimension N3b: Extension to the SCF

N3a: >6 cm in greatest dimension N3b: Extension to the SCF

N3a: >6 cm N3b: extension to the SCF

M-CLASSIFICATION M0

No hematogenous metastases

No distant metastasis

No distant metastasis

No distant metastasis

No distant metastasis

M1

Hematogenous metastases present, and/or LN metastases below the clavicle

Distant metastasis

Distant metastasis

Distant metastasis

Distant metastasis

GROUP STAGING I

T1N0M0

T1N0M0

T1N0M0

T1N0M0

T1N0M0

II

T2 and/or N1, M0

T2N0M0

IIA: T2aN0M0 IIB: T1N1M0, T2aN1M0, or T2bN0-1M0

IIA: T2aN0M0 IIB: T1N1M0, T2aN1M0, or T2bN0-1M0

T1N1M0 or T2N0-1M0

III

T3 and/or N2, M0

T3N0M0 T1-3N1M0

T1N2M0, T2N2M0, or T3N0-2M0

T1N2M0, T2N2M0, or T3N0-2M0

T1-2N2M0 or T3N0-2M0

IV

N3 (any T), M0

T4N0-3M0, T1-4N23M0, or T1-4N0-3M1

IVA: T4N0-2M0 IVB: T1-4N3M0 IVC: T1-4N0-3M1

IVA: T4N0-2M0 IVB: T1-4N3M0 IVC: T1-4N0-3M1

IVA: T4N0-2M0 IVB: T1-4N3M0 IVC: T1-4N0-3M1

V

M1

d

d

d

d

CN, cranial nerve; HP, hypopharynx; ITF, infratemporal fossa; LN, lymph node; MS, masticator space; NF, nasal fossa; OP, oropharynx; PPS, parapharyngeal space; SCF, supraclavicular fossa.

COMPARISON OF 7TH AJCC STAGING, CHINESE STAGING, AND 8TH AJCC STAGING

LN palpable in the SCF and/or skin involvement in the form of carcinoma en cuirasse or satellite nodules above the clavicle

non > 6 cm in greatest dimension N2c: Metastasis in bilateral or contralateral LN, none > 6 cm in greatest dimension Metastasis in an LN > 6 cm in greatest dimension

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TABLE 9.2

The Chinese 2008 and the 8th Edition of the AJCC/UICC Staging Systems The Chinese 2008 Staging System

The 8th Edition of AJCC/UICC Staging System

T1

Nasopharynx

Nasopharynx, OP, NF

T2

NF, OP, PPS extension

PPS extension, adjacent soft tissue involvement (MP, LP, prevertebral muscles)

T3

Skull base, MP

Bony structures at skull base, cervical vertebra, pterygoid structures, paranasal sinuses

T4

CN, paranasal sinus, MS excluding MP, intracranial (cavernous sinus, dura, meninges)

Intracranial extension, CN, hypopharynx, orbit, parotid gland, extensive soft tissue infiltration beyond the lateral surface of LP

N0

None

None

N1

N1a: Retropharyngeal LN involvement N1b: Unilateral level Ib, II, III, Va involvement and diameter  3 cm

Retropharyngeal (irrespective of laterality) Cervical: unilateral, <6 cm, and above caudal border of cricoid cartilage

N2

Bilateral level Ib, II, III, Va above the SCF or diameter > 3 cm or with extranodal neoplastic spread

Cervical: Bilateral, <6 cm, and above caudal border of cricoid cartilage

N3

Level IV, Vb involvement

>6 cm and/or below caudal border of cricoid cartilage

I

T1 N0 M0

T1 N0 M0

II

T1 N1a-1b M0

T1 N1 M0 T2 N0eN1 M0

III

T1-2 N2 M0 T3 N0-2 M0

T1-2 N2 M0 T3 N0-2 M0

IV

IVa: T4 N0-2 M0 IVb: Any T N3 M0 IVc: Any T Any N M1

IVA: T4 or N3 M0 IVB: Any T Any N M1

T-CLASSIFICATION

N-CLASSIFICATION

GROUP STAGING

CN, cranial nerve; LN, lymph node; LP, lateral pterygoid; MP, medial pterygoid muscle; MS, masticator space; NF, nasal fossa; OP, oropharynx; PPS, parapharyngeal space; SCF, supraclavicular fossa.

• Medial pterygoid muscle extension was defined as T3 by the Chinese 2008 system, but it was considered as T4 in the AJCC/UICC system. • In the Chinese 2008 staging system, measurement of lymph node (LN) was based on MRI rather than clinical palpation. The definition of cervical nodal levels for head and neck cancers by Gregoire et al. was adopted,16 and the SCF region was replaced by levels IV and Vb on the basis of the cross-sectional MRI images.17,18 The site, size, laterality, and extranodal neoplastic spread of LN were all included in the criteria of N classification. In a study by Pan et al., 816 MRI-staged NPC patients were restaged according to both the Chinese 2008 and the 7th edition of the AJCC/UICC staging systems.19 The overall distribution pattern of the AJCC/UICC system was more even. The AJCC/UICC T-classification was better in predicting the 5-year local relapse-free survival, whereas the Chinese 2008 N-classification was superior in predicting the 5-year distant metastasis-free survival. The survival curves for the 5-year overall survival (OS) were comparable in both systems. In another study by OuYang et al., 2333 patients with NPC were analyzed and the Chinese 2008 system was compared with the 6th and 7th editions of the AJCC/UICC

COMPARISON OF 7TH AJCC STAGING, CHINESE STAGING, AND 8TH AJCC STAGING

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systems.20 The N-classification of the Chinese 2008 system was again demonstrated to have superior prognostic value. These data suggested further room for improvement of the 7th edition of the AJCC/UICC staging system.13 With an extensive literature review and comparison with other staging systems, the 8th edition of the AJCC/ UICC staging system was developed to achieve better prognostic value.21 Several major changes in the 8th edition were implemented.

Masticator Space Infiltration In the 5th edition of the AJCC/UICC staging system, involvement of the ITF, which was defined as the space beyond the anterior surface of the lateral pterygoid muscle or lateral extension beyond the posterolateral wall of the maxillary antrum and the pterygo-maxillary fissure, was one of the staging criteria for T4 disease. In the AJCC/UICC 6th edition, MS was added as a synonym for ITF with the same definition. In the AJCC/UICC 7th edition, there was a change in definition of MS to include all four masticatory muscles (medial pterygoid, lateral pterygoid, temporalis, and masseter muscles). This was consistent with the anatomical definition adopted in diagnostic radiology, but caused significant confusion as tumors with involvement of medial and/or lateral pterygoid muscles were all upstaged to T4 disease. In the China 2008 staging system involvement of medial pterygoid muscle is classified as T3 while those with invasion to the rest of the anatomical MS are classified as T4. The MS involvement that defines T4 disease according to the different classification systems is depicted in Fig. 9.2. Apart from ambiguity of nomenclature, reports of the frequency of masticator space involvement in NPC varied widely, ranging from 19.7% to 61%.22e25 Radiological definition of minor medial pterygoid muscle invasion may be difficult and subjective. Based on a cohort of 1104 NPC patients staged with MRI, Sze et al. found that patients with medial pterygoid/ lateral pterygoid muscle involvement had similar survival rates as with T1eT2 disease; they also had smaller tumor volume, better RT coverage of the target volume, and superior survival outcomes compared with patients with T3-4 disease.25 This result was confirmed by a multicenter study.26 It is thus accepted by the 8th edition of the AJCC/ UICC staging criteria that medial pterygoid/lateral pterygoid muscles involvement is defined as T2 disease.

Prevertebral Muscle Involvement With better soft tissue resolution by MRI, prevertebral muscle involvement can be readily distinguished from PPS spread or RLN metastasis.27 When the tumor infiltrates through the prevertebral fascia to involve the prevertebral muscle, it has the potential to penetrate the vertebral and perivertebral veins or lymphatics. As a result, the prevertebral muscle involvement could be associated with a higher risk of hematogenous dissemination.28 Retrospective studies showed that patients with prevertebral muscles involvement had poorer prognosis.28e31 In the study by Pan et al., a total of 1609 consecutive patients with non-disseminated NPC who were treated at Fujian Provincial Cancer Hospital and Pamela Youde Nethersole Eastern Hospital were analyzed. It was demonstrated that among patients without other T3/T4 involvement, there were no significant differences in overall survival between medial pterygoid muscle and/or lateral pterygoid muscle, prevertebral muscle, and parapharyngeal space involvement.26 Thus prevertebral muscles involvement was defined as T2 category in the 8th edition criteria (Fig. 9.3). FIGURE 9.2 Definition of T4 disease in nasopharyngeal carcinoma according to different systems. LP, lateral pterygoid muscle; M, masseter muscle; MP, medial pterygoid muscle; TP, temporalis muscle. From Sze H, Chan LL, Ng WT, et al. Should all nasopharyngeal carcinoma with masticator space involvement be staged as T4? Oral Oncol. 2014;50(12):1188e1195. Used with permission from Elsevier.

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Cervical Lymph Node There were limitations in the 7th edition AJCC/UICC N-classification criteria. First, with the development of cross-sectional images, the boundaries of Ho’s triangle can no longer be consistently defined by radiologic imaging.17,32 Second, the size of LN was assessed by palpation only. Finally, the prognostic significance of the two subcategories (N3a and N3b) of N3 was uncertain because of paucity of data.33,34 Two studies have reported that the predictive value of the N-classification of the Chinese 2008 staging was superior to the 7th edition of the AJCC/UICC staging system.19,20 In the Chinese 2008 staging system, radiologically defined boundaries and nodal size were used for nodal staging. Supporting the use of radiological landmarks, a study by Ng et al.17 demonstrated that replacing the SCF by the lower level, which includes radiological levels IV and Vb as defined by Som et al.,35 as one of the criteria for defining N3 was predictive for both distant control and OS. According to the study by Pan et al., the 5-year overall survival for NPC patients with extension to the lower neck was similar to that with extension to the SCF (70% vs. 69%).26 Only 2% of the patients had LN > 6 cm above the SCF and their outcomes resembled the outcomes of those with low extension. The presence of extracapsular spread was also used as a staging criterion in the Chinese 2008 system. However, the definition of extracapsular spread could be inconsistent among clinicians and might be subjective. Data about the prognostic significance of extracapsular spread in NPC is also conflicting.32,36 Therefore, the 8th edition of the AJCC/UICC staging system changed the N3 criterion from involvement of the Ho’s SCF to involvement of the lower neck, which is defined as an extension below the caudal border of the cricoid cartilage and includes levels IV and Vb (Fig. 9.4).

FIGURE 9.3 Comparison of T2 and T4 definitions between the AJCC/UICC 7th and 8th Editions. CS, carotid space; LP, lateral pterygoid muscle; M, masseter muscle; MP, medial pterygoid muscle; PG, parotid gland; PPS, parapharyngeal space; PV, prevertebral muscle; T, temporalis muscle. From 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 intensitymodulated radiotherapy. Cancer. 2016;122(4):546e558. Used with permission from Wiley.

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VALIDATION OF THE 8TH EDITION

FIGURE 9.4 Comparison of definition of N3 between the AJCC/UICC 7th edition (i.e., below the superior border of the supraclavicular fossa [blue]), and the proposed 8th edition (i.e., below caudal border of cricoid cartilage [red]). From 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):546e558. Used with permission from Wiley.

VALIDATION OF THE 8TH EDITION Validation of the staging system by different institutions with divergent imaging equipment and treatment schedules can ascertain its robustness and generalizability. Since the publication of the 8th edition of the UICC/AJCC staging system, it has been validated by multiple datasets in different centers. In a study by Kang et al., a total of 608 patients with nonmetastatic NPC treated with IMRT were retrospectively reviewed.37 The patient distribution by the 8th edition of the staging system was more balanced than that by the 7th edition. Using the 8th edition, the distant metastasis-free survival between N0 and N1, N1 and N2, and N2 and N3 differed significantly, while no significant difference in survival was observed between N3a and N3b in the 7th edition, indicating that the combination of N3a and N3b into N3 is appropriate. Using the 8th edition also achieved good segregation between stages II and III and between stages III and IVa for OS, but not between stages I and II (P ¼ .419). When the 7th edition was used, the overall survival curves showed no significant difference between stages I and II, and between stages II and III (P ¼ .465 and P ¼ .198). Thus the total difference between stages I and IV was slightly larger when the 8th edition rather than the 7th edition was used. In another series by OuYang et al., 899 patients with NPC were retrospectively reviewed.38 All the patients were staged with MRI and treated with IMRT with or without chemotherapy. The 7th and 8th UICC/AJCC staging system and other proposed staging systems from Hong Kong, Guangzhou, and Guangxi were compared. In this study, the 8th edition was shown to have better separation ability across adjacent classification groups and discrimination ability in predicting treatment outcomes when compared with the 7th edition. In this cohort, the proposed staging system from Guangzhou might further improve the prognostic accuracy.

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9. STAGING OF NASOPHARYNGEAL CARCINOMA BASED ON THE 8TH EDITION OF THE AJCC/UICC STAGING SYSTEM

Tang et al. reported a study including 1790 patients with localized NPC treated with IMRT.39 The performance of staging systems was compared using the Akaike information criterion (AIC) and Harrell’s concordance index (cindex). It demonstrated that the 8th edition had higher AIC and c-index values for all endpoints than the 7th edition for the N-category. For the T-category, it was difficult to differentiate T2 and T3, and the AIC and c-index values were similar for the 7th and 8th editions. Similarly, the overall survival and disease-free survival curves for stage II and III disease were not clearly separated for either the 8th or 7th editions. Overall, the 8th edition of the UICC/AJCC staging system is more accurate than the 7th edition as demonstrated by these validation studies. Nonetheless, there is still room for further refinement to improve its validity and generalizability.

LIMITATIONS OF THE 8TH AJCC/UICC STAGING SYSTEM The 8th edition of the AJCC/UICC staging system has achieved significant improvement from previous editions and is well validated by multiple clinical cohorts. However, there are still limitations that could hamper its clinical applicability and generalizability.

Histological Factor Based on the current World Health Organization pathologic classification, NPC is grouped into keratinizing squamous cell carcinoma (K-SCC) and nonkeratinizing carcinoma (NK-SCC). The latter group is further divided into nonkeratinizing differentiated carcinoma and nonkeratinizing undifferentiated carcinoma. Studies from nonendemic regions suggested that patients with K-SCC had a worse prognosis than those with NK-SCC.40e42 In a retrospective study by Vazquez et al., the United States National Cancer Institute’s Surveillance, Epidemiology, and End Results registry was used to extract data from a total of 1624 NPC cases: 76% NK-NPSCC and 24% cases of K-SCC.42 Regression analysis showed that K-SCC was a poor prognostic factor (HR 2.1; 95% CI, 1.8e2.6; P < .0001). The 5-year relative survival was significantly longer for NK-SCC (60.6% vs. 40.5%). However, majority of the literature originate from endemic regions where more than 95% of patients have undifferentiated carcinoma. The effect of histology on the prognosis of NPC patients in endemic regions was rarely addressed. This may have impact on the generalizability of the staging system in nonendemic regions.

Intrinsic Heterogeneity Within Each Stage Group Certain stage groups include patients with very heterogeneous clinical characteristics. For stage II disease, it covers T2N0, T1N1, and T2N1 subgroups without distant metastasis. Primary tumors with or without PPS involvement and nodal involvement ranging from absent nodal disease or just small RLN to sizable (up to 6 cm), unilateral upper to mid-cervical nodal disease were included in the same category. Xiao et al., using the Chinese 1992 staging system, reported that the 5-year OS for T1N1, T2N0, and T2N1 patients was 91.3%, 85.8%, and 73.1% (P < .05), respectively.43 Luo et al. also demonstrated that 3-year overall survival was significantly poorer in T2N1 than in T1N1 and T2N0 patients (74.5 vs. 100.0%; P ¼ .01), using the 6th edition of the AJCC/UICC staging system.44 Although different staging systems were used, there is evidence showing that significant within-group heterogeneity for such early stage disease exists. In particular, T2N1 patients appear to constitute a unique subgroup characterized by worse survival. Similarly, T3 disease includes patients with tumor involving surrounding bony structures in various degrees including minimal extension to the nasal septum to frank invasion to the clivus or skull base. Studies have tried to categorize involvement of different skull base structures into subgroups in different ways and have shown their implication in predicting the prognosis.45,46 It has also been suggested that involvement of the paranasal sinus carries independent prognostic value and some tumors with paranasal sinus involvement should be upstaged.47,48 For T4 disease, cranial nerve involvement is one of the criteria and is usually elicited by physical examination. In a study by Zong et al., it has been shown that the incidence of MRI-detected cranial nerve involvement was 60.8%.49 The survival outcomes appeared not to be affected by the presence of MRI detected cranial nerve involvement. To classify all patients with MRI-detected cranial nerve involvement as T4 category may cause overtreatment.

LIMITATIONS OF THE 8TH AJCC/UICC STAGING SYSTEM

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Within stage IVa in the current staging system, NPC with T4 or N3 diseases are all included without substaging. Such grouping takes no account of the different pattern of failure where T4 tends to fail locally while N3 has a higher risk of distant metastasis. In fact, patients with T4N0-1 disease have been found to have a more favorable prognosis.50 As the stage of disease is often linked with treatment strategy, such grouping may hamper tailoring of treatment according to the commonest mode of failure for this group of patients.

Measurement of Lymph Node Size The maximum size of cervical LN being assessed by clinical palpation in the current AJCC/UICC staging system has been criticized for years and remains an unresolved issue. A more reliable evaluation method is expected in this 3D cross-sectional imaging era. However, maximum size of involved LN measured by imaging was usually just based on the axial plane only. Significant interobserver variation in size measurement could occur when the involved LNs are matted together. In a study by Ai et al., maximum dimension of metastatic neck nodes was measured by four methods: a single node in the axial plane; a single node in the axial/coronal plane; a single and/or confluent nodes in the axial/coronal plane; and a single and/or confluent and/or contiguous nodes in the axial/coronal plane, respectively. It was found that the inclusion of a single and/or confluent and/or contiguous nodes in the axial/coronal plane was the best method as it had the strongest correlation with nodal volume and was the only independent predictor of overall survival, disease-specific survival, and distant metastasesefree survival.51 Therefore, the current recommendation to obtain the maximum size of LN for staging is to incorporate not only single and confluent, but also contiguous, metastatic nodes measured in the plane with the maximum dimension.

Omission of Other Clinically Important Factors Despite the advancement of IMRT, which can deliver a highly conformal dose distribution with a steep dose gradient, delivering even the minimum tumoricidal dose level to the entire target volume is not always possible without exposing the neurological structures to high dose in T3eT4 disease. While the standard recommendation is to give 70 Gy to the gross tumor, the maximum tolerance dose of most neurological structures including the brainstem is 50e54 Gy. This could cause underdosing of the tumor, especially for advanced staged disease, if these dose

FIGURE 9.5 Inadequate dose coverage of gross tumor volume (GTV) due to close proximity to the planning organ at risk volume (PRV) of the brain stem. From Ng WT, Lee MC, Chang AT, et al. The impact of dosimetric inadequacy on treatment outcome of nasopharyngeal carcinoma with IMRT. Oral Oncol. 2014;50(5):506e512. Used with permission from Elsevier.

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constraints to the organs-at-risk (OAR) are given top priority. In a series of NPC patients treated with IMRT, with the aim to deliver at least 66.5 Gy (i.e., 95% of 70 Gy) to 95% of the primary gross tumor volume (GTV-P) while keeping all the critical neurological OAR within dose tolerance, Ng et al. demonstrated that degree of underdosing could affect the survival outcomes, and an underdosed GTV-P volume of 3.4 cm3 was found to be prognostically important (Fig. 9.5).52 Such dosimetric inadequacy leading to treatment failure is not addressed in the current staging system. Moreover, important patient factors including age and comorbidities are not taken into account. It is well known that elderly patients represent a unique challenge for radical treatment in NPC because of limited organ reserve, poorer performance status, and comorbid conditions.53 In a study by Sze et al., elderly NPC patients (>70 years old) were found to have higher rates of acute reaction, incompletion of radiotherapy and early mortality at 90 days (7.8% vs. 1.2%, P < .001) compared with younger patients.54 Comorbidity as assessed by Adult Comorbidity Evaluation 27 (ACE-27) was identified as a critical factor to predict early mortality and overall survival. The prognostic role of ACE-27 was confirmed in subsequent studies.55e57 Other tools for comorbidity assessment including the Charlson Comorbidity Index have also been demonstrated to be useful in predicting prognosis.58,59 Such prognostic patient information could be helpful if they are integrated into the staging system to achieve personalized prognostication.

REVIEW OF OTHER PROGNOSTIC FACTORS Advances in basic scientific research and clinical studies allow identification of novel markers to predict prognosis, with the potential to supplement the traditional TNM staging system and allows a personalized risk assessment.

EpsteineBarr Virus DNA Early studies indicated a significant association between NPC and an elevated level of EBV DNA in plasma.60,61 In a study by Lin et al., EBV DNA levels were measured by a real-time quantitative polymerase-chain-reaction assay in a cohort of stage III or IV NPC patients. It was demonstrated that overall survival (P < .001) and relapse-free survival (P ¼ .02) were significantly lower among patients with pretreatment plasma EBV DNA concentrations of >1500 copies/mL than among those with concentrations of <1500 copies/mL.62 Leung et al. also demonstrated that the EBV DNA load in plasma correlated inversely with prognosis. In their series, segregation of patients with early-stage disease by a pretreatment cutoff of 4000 copies/mL could readily identify a poor-risk subgroup with survival similar to that of stage III disease and a good-risk subgroup with survival similar to stage I disease, with 5-year survival rates of 63% and 90% (P ¼ .0003), respectively.63 Other studies have subsequently confirmed the prognostic value of EBV DNA levels measured at different time points (pretreatment, midtreatment, posttreatment) and in both endemic and nonendemic regions.64e70 It has also been shown to maintain its validity in the era of IMRT.71 One major hurdle of integrating the pretreatment EBV DNA level into the TNM staging system is the lack of assay standardization; the cutoff points have varied, making it difficult to compare the results across studies.72,73 After a harmonized assay for EBV DNA is made available, the application of EBV DNA in NPC staging should be reexamined.

MicroRNA MicroRNAs (miRNAs) are short noncoding ribonucleic acid molecules involved in posttranscriptional gene regulation. It has been demonstrated that miRNAs play a significant role in the pathogenesis of NPC.74 Expression levels of miRNAs that were altered in NPC could potentially be involved in the pathogenesis by targeting different genetic pathways involved in cell cycle progression, cell differentiation, apoptosis, invasion, and metastasis.75 In a study by Liu et al. from Guangdong, a signature of five miRNAs (miR-142-3p, miR-29c, miR-26a, miR-30e, and miR93), each significantly associated with disease-free survival, was identified to calculate a risk score for patients with NPC. Patients with high risk scores in the training set had significantly shorter disease-free, distant metastasisefree, and OS. A combination of this signature and TNM stage had better prognostic value than did the TNM stage alone.76 The same group subsequently identified another signature of four miRNAs (miR-22, miR-572, miR-638, and miR1234), which was again shown to add prognostic value to the TNM staging system.77 In a study from Toronto by Bruce et al., a 4-miRNA signature (miR-154, miR449b, miR-140, and miR34c) was shown to be associated with

REVIEW OF OTHER PROGNOSTIC FACTORS

191

risk of developing distant metastasis.78 Zhao et al. retrieved the datasets from Guangdong and Toronto as training and validation cohorts. They identified subtypes of NPC and developed a microRNA-based prognostic model that could stratify patients into high- and low-risk groups of distant metastasis.79 These data on miRNA for its prognostic significance is encouraging. Future analysis on additional independent datasets would be required to definitively determine the optimal signature.

Gene Expression Patterns Assessing the prognosis and assigning treatment according to tumor molecular characteristics is an increasingly promising approach. Wang et al. used support vector machine (SVM)-based methods to develop a prognostic classifier for NPC that integrated patient sex and the protein expression level of seven genes, including EBV latency membrane protein 1, CD147, caveolin-1, phospho-P70S6 kinase, matrix metalloproteinase 11, survivin, and secreted protein acidic and rich in cysteine. The NPC-SVM classifier distinguished patients with NPC into low- and high-risk groups with significant differences in disease-free survival.80 In another study by Tang et al., a total of 937 patients with locoregionally advanced NPC from three Chinese hospitals were analyzed. They identified 137 differentially expressed genes between metastatic and nonmetastatic locoregionally advanced NPC tissues, and a distant metastasis gene signature that consisted of 13 genes was developed to classify patients into high-risk and low-risk groups. Patients with high-risk scores were shown to have shorter distant metastasis-free survival (hazard ratio [HR] 4.93, 95% CI 2.99e8.16; P < 0$0001), disease-free survival (HR 3.51, 2.43e5.07; P < .0001) and overall survival (HR 3.22, 2.18e4.76; P < .0001).81 These advanced molecular techniques add prognostic value to the traditional clinicopathological risk factors and allow personalized risk assessment.

Circulating Tumor Cells Circulating tumor cells (CTCs) have been used as a tumor burden landmark in cancer. Studies from other head and neck cancers found that CTCs do have prognostic value,82 while the clinical relevance of CTCs in NPC is less certain. In a small study by He et al., CTCs were detected in 22 out of 33 (66.7%) NPC patients with mostly stage IIIeIV disease. The presence of CTCs was not associated with TNM stage but appeared to correlate with IgA antibody titers to the EBV viral capsid antigen (EBV IgA-VCA). No survival analysis was performed.83 Further studies are warranted to evaluate the prognostic value of CTCs in NPC.

Lactate Dehydrogenase Studies have demonstrated an inverse correlation between pretreatment lactate dehydrogenase (LDH) level and survival outcome in NPC.84e87 In a meta-analysis that included a total of 18 studies involving 13,789 patients, serum LDH level was found to be associated with worse outcome in NPC patients. The combined HR for overall survival was 1.86 (95% confidence interval [CI]: 1.66e2.08; P < .01), and the pooled HRs for disease-free survival, distant metastasisefree survival and distant local relapse-free survival were 1.64 (95% CI: 1.45e1.86), 2.64 (95% CI: 2.15e3.25), and 2.59 (95% CI: 1.74e3.87), respectively.88 While many of the other biomarkers in NPC require further optimization of assay or clinical validation, serological LDH level as an independent prognostic factor for NPC is an attractive adjunct to the TNM staging system because it is readily available in most parts of the world.

Tumor Volume Tumor size is one of the staging criteria for many cancers. In NPC, volume of the primary tumor has also been shown to have prognostic significance by many studies.89e93 Sze et al. reported the risk of local control was estimated to decrease by 1% for every 1 cm3 increase in the primary tumor volume.89 In addition, studies have also demonstrated the prognostic role of cervical nodal volume.94,95 In a series by Liang et al., the total tumor volume including the primary tumor and the nodal tumor volumes was evaluated. The mean total tumor volume was 11.1 cm3 (range, 0.3e27.9 cm3) in stage I, 22.5 cm3 (1.3e92.4 cm3) in stage II, 40.6 cm3 in stage III (3.2e129.2 cm3), and 77.5 cm3 in stage IVaeb (7.1e284.1 cm3). Total tumor volume was an independent prognostic factor for all the survival endpoints.96 However, there is large variation in the cutoff of tumor volumes across different series and the assessment of tumor volume has hardly been defined.

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Institutional Factor In the era of high precision radiotherapy, the expertise of the radiation oncologist could have a great impact on the treatment outcome because the planning and delivery of radiotherapy has become very sophisticated and requires substantial knowledge and experience. Studies have indeed demonstrated a positive correlation between case volume and survival of patient.97e99 In a global perspective, accessibility and quality of radiotherapy have also been shown to affect the survival of patients. In a study by Lam et al., a review of survival outcome of NPC in a total of 112 countries was carried out. A significant correlation between relative survival and the availability of radiotherapydincrease in radiotherapy equipment and oncologist per million populationdis associated with better relative survival.100 The same group demonstrated that while NPC is highly curable by radiotherapy with excellent outcomes in developed countries, the outcomes in low- and middle-income countries are disappointing.101 These factors are highly relevant when a single system for prognostication has to achieve high generalizability and applicability worldwide.

NOMOGRAM AND OTHER STATISTICAL METHODS IN PREDICTING PROGNOSIS A nomogram is a pictorial representation of a complex mathematical relationship and provides a valuable tool for refining prognostication and working toward personalized medicine. Nomograms enable incorporation of both patient and disease characteristics into the calculation of a simple numerical estimate of the event probability. In addition to the anatomical disease extent, nomograms incorporate other key prognostic factors into the estimation of survival outcomes. These can tremendously facilitate individualized risk stratification and decision making.102e104 In NPC, several nomograms have been developed,105e110 mostly based on the older versions of the AJCC/UICC staging system, and two of them actually lacked external validation limiting their robustness and applicability.106,108 A contemporary nomogram was recently published by Pan et al. based on 1197 patients from Fujian Provincial Cancer Hospital in China with another 412 patients from Pamela Youde Nethersole Eastern Hospital in Hong Kong serving as the validation cohort.111 It demonstrated that age, GTV-P, and LDH were independent prognostic factors for overall survival in addition to the stage grouping according to the 8th AJCC/UICC staging system (Fig. 9.6). However, plasma EBV DNA, which is now known to be a powerful prognostic factor, had not been incorporated in this study as this was not a mandatory test during the study period. Lack of harmonization is another issue that limits its incorporation in the nomogram.

FIGURE 9.6 Nomogram for 5-year and 8-year overall survival including overall stage of disease, age, gross tumor volume of the primary tumor (GTV-P) and lactate dehydrogenase (LDH) as parameters. From 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):3307e3315. Used with permission from Wiley.

FUTURE DIRECTION

(A)

193

(B)

FIGURE 9.7 (A) Recursive partitioning algorithm for overall survival of the whole series based on the score derived from the nomogram; (B) KaplaneMeier plots for overall survival of risk groups by nomogram. From 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):3307e3315. Used with permission from Wiley.

Recursive partitioning algorithm (RPA) is another commonly used statistical technique helping to reduce the complexity of statistical modeling by splitting multiple covariates into discrete categories based on the expected event probabilities or risks.112 A previous study by Zhang et al. showed that RPA could further split N-stage 0-1 patients into two risk groups by standardized uptake value for primary tumor for predicting metastasis in NPC.113 In the study by Pan et al., scores (Fig. 9.7A) estimated from the nomogram were used to categorize patients into different groups. It was found that the resulting risk group categorization showed both superior discriminatory ability and more even pattern in patient distribution in comparison with TNM staging alone (Fig. 9.7B).111

FUTURE DIRECTION Anatomical staging using the TNM system has been the most widely adopted tool for the assessment of prognosis of patients with NPC. However, as pointed out by previous sections, certain limitations and further refinement are possible. Even for anatomical staging, prognostic significance of different degree of involvement of individual fine structures remains to be determined. Table 9.3 summarizes some examples of more detailed characterization of current staging criteria, which may allow subcategorization of patients. Entering the age of molecular stratification, apart from EBV DNA assay, genetic profiling could stratify patients according to different genetic makeup. Moreover, integration of important patient and treatment factors in the form of nomograms can further enhance the clinical applicability. With advances in bioinformatics and development of tools that can help scientists collect and analyze masses of clinical and genetic information, the big data approach could become a promising strategy to change the face of prognostication in cancer medicine. The Hong Kong Cancer Registry has been established for central collection of clinical data and similar projects are underway in mainland China. With the highest incidence of NPC in the world, this is invaluable to allow detection of specific patterns in a huge population of patients. Integration of data from different sources allows the development of more accurate and powerful models to predict patients’ prognosis. Mobile and web-based applications can further enhance the accessibility and convenience. In the future, it is hopeful that the unmet need of a more personalized assessment of prognosis can be satisfied by a comprehensive prognostic tool incorporating all known tumor-, host-, and facility-related factors derived from exabytes of worldwide data.

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TABLE 9.3

Examples of Potential Substaging According to the Degree of Involvement of Current Stage-Defining Structures Structure

Possibly Better Prognosis

Possibly Worse Prognosis

PPS

Minimal bulging to PPS

Encasement of carotid vessels

Masticatory muscles

MP

LP

T-CLASSIFICATION T2

T3

Bony structures

T4

CN

Minor nasal septum or sphenoid sinus invasion Minor medial pterygoid plate involvement

Extensive skull base involvement Gross PNS invasion

Subtle radiological CN involvement

Frank clinical CN involvement

Up to 6 cm bulky LN

N-CLASSIFICATION N1

LN

Mildly enlarged RLN

N3

LN

? >6 cm versus lower cervical LN

CN, cranial nerve; LN, lymph node; LP, lateral pterygoid muscle; MP, medial pterygoid muscle; PNS, paranasal sinus; PPS, parapharyngeal space; RLN, retropharyngeal lymph node.

References 1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14. 15. 16. 17. 18. 19. 20. 21. 22. 23.

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Plasma Epstein-Barr viral DNA complements TNM classification of nasopharyngeal carcinoma in the era of intensity-modulated radiotherapy. Oncotarget. 2016;7(5):6221e6230. 72. Le QT, Jones CD, Yau TK, et al. A comparison study of different PCR assays in measuring circulating plasma epstein-barr virus DNA levels in patients with nasopharyngeal carcinoma. Clin Cancer Res. 2005;11(16):5700e5707. 73. Yip TT, Ngan RK, Fong AH, Law SC. Application of circulating plasma/serum EBV DNA in the clinical management of nasopharyngeal carcinoma. Oral Oncol. 2014;50(6):527e538. 74. Chen HC, Chen GH, Chen YH, et al. MicroRNA deregulation and pathway alterations in nasopharyngeal carcinoma. Br J Cancer. 2009;100(6): 1002e1011. 75. Lee KT, Tan JK, Lam AK, Gan SY. MicroRNAs serving as potential biomarkers and therapeutic targets in nasopharyngeal carcinoma: a critical review. Crit Rev Oncol Hematol. 2016;103:1e9. 76. 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):633e641. 77. Liu N, Cui RX, Sun Y, et al. A four-miRNA signature identified from genome-wide serum miRNA profiling predicts survival in patients with nasopharyngeal carcinoma. Int J Cancer. 2014;134(6):1359e1368. 78. Bruce JP, Hui AB, Shi W, et al. Identification of a microRNA signature associated with risk of distant metastasis in nasopharyngeal carcinoma. Oncotarget. 2015;6(6):4537e4550. 79. Zhao L, Fong AHW, Liu N, Cho WCS. Molecular subtyping of nasopharyngeal carcinoma (NPC) and a microRNA-based prognostic model for distant metastasis. J Biomed Sci. 2018;25(1):16. 80. Wang HY, Sun BY, Zhu ZH, et al. Eight-signature classifier for prediction of nasopharyngeal [corrected] carcinoma survival. J Clin Oncol. 2011; 29(34):4516e4525. 81. 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):382e393. 82. Wang Z, Cui K, Xue Y, Tong F, Li S. Prognostic value of circulating tumor cells in patients with squamous cell carcinoma of the head and neck: a systematic review and meta-analysis. Med Oncol. 2015;32(5):164. 83. He C, Huang X, Su X, et al. The association between circulating tumor cells and Epstein-Barr virus activation in patients with nasopharyngeal carcinoma. Cancer Biol Ther. 2017. 84. Cheng SH, Yen KL, Jian JJ, et al. Examining prognostic factors and patterns of failure in nasopharyngeal carcinoma following concomitant radiotherapy and chemotherapy: impact on future clinical trials. Int J Radiat Oncol Biol Phys. 2001;50(3):717e726. 85. Zhou GQ, Tang LL, Mao YP, et al. Baseline serum lactate dehydrogenase levels for patients treated with intensity-modulated radiotherapy for nasopharyngeal carcinoma: a predictor of poor prognosis and subsequent liver metastasis. Int J Radiat Oncol Biol Phys. 2012;82(3):e359e365. 86. Wan XB, Wei L, Li H, et al. High pretreatment serum lactate dehydrogenase level correlates with disease relapse and predicts an inferior outcome in locally advanced nasopharyngeal carcinoma. Eur J Cancer. 2013;49(10):2356e2364. 87. Wei Z, Zeng X, Xu J, Duan X, Xie Y. Prognostic value of pretreatment serum levels of lactate dehydrogenase in nonmetastatic nasopharyngeal carcinoma: single-site analysis of 601 patients in a highly endemic area. OncoTargets Ther. 2014;7:739e749. 88. Zhai C, Gu K, Zhai X, Wang J, Zhang J. Prognostic value of serum lactate dehydrogenase in patients with nasopharyngeal carcinoma: a metaanalysis. Clin Lab. 2017;63(11):1777e1785. 89. Sze WM, Lee AW, Yau TK, et al. Primary tumor volume of nasopharyngeal carcinoma: prognostic significance for local control. Int J Radiat Oncol Biol Phys. 2004;59(1):21e27.

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90. Feng M, Wang W, Fan Z, et al. Tumor volume is an independent prognostic indicator of local control in nasopharyngeal carcinoma patients treated with intensity-modulated radiotherapy. Radiat Oncol. 2013;8:208. 91. Wu Z, Zeng RF, Su Y, Gu MF, Huang SM. Prognostic significance of tumor volume in patients with nasopharyngeal carcinoma undergoing intensity-modulated radiation therapy. Head Neck. 2013;35(5):689e694. 92. Qin L, Wu F, Lu H, Wei B, Li G, Wang R. Tumor volume predicts survival rate of advanced nasopharyngeal carcinoma treated with concurrent chemoradiotherapy. Otolaryngol Head Neck Surg. 2016;155(4):598e605. 93. Guo R, Sun Y, Yu XL, et al. Is primary tumor volume still a prognostic factor in intensity modulated radiation therapy for nasopharyngeal carcinoma? Radiother Oncol. 2012;104(3):294e299. 94. Yuan H, Ai QY, Kwong DL, et al. Cervical nodal volume for prognostication and risk stratification of patients with nasopharyngeal carcinoma, and implications on the TNM-staging system. Sci Rep. 2017;7(1):10387. 95. Ai QY, King AD, Mo FKF, et al. Prediction of distant metastases from nasopharyngeal carcinoma: improved diagnostic performance of MRI using nodal volume in N1 and N2 stage disease. Oral Oncol. 2017;69:74e79. 96. Liang SB, Teng JJ, Hu XF, et al. Prognostic value of total tumor volume in patients with nasopharyngeal carcinoma treated with intensitymodulated radiotherapy. BMC Canc. 2017;17(1):506. 97. Lee CC, Huang TT, Lee MS, et al. Survival rate in nasopharyngeal carcinoma improved by high caseload volume: a nationwide populationbased study in Taiwan. Radiat Oncol. 2011;6:92. 98. Yoshida EJ, Luu M, David JM, et al. Facility volume and survival in nasopharyngeal carcinoma. Int J Radiat Oncol Biol Phys. 2018;100(2): 408e417. 99. Ha B, Cho KH, Moon SH, et al. The effect of hospital case volume on clinical outcomes in patients with nasopharyngeal carcinoma: a multiinstitutional retrospective analysis (KROG-1106). Cancer Res Treat. 2018. 100. Lam KO, Lee AW, Choi CW, et al. Global pattern of nasopharyngeal cancer: correlation of outcome with access to radiation therapy. Int J Radiat Oncol Biol Phys. 2016;94(5):1106e1112. 101. Lam KO, Lee AW, Ng WT, Hopkins KI. The International Atomic Energy Agency global initiatives on nasopharyngeal cancer treatment. Chinese Clin Oncol. 2016;5(2):27. 102. Iasonos A, Schrag D, Raj GV, Panageas KS. How to build and interpret a nomogram for cancer prognosis. J Clin Oncol. 2008;26(8):1364e1370. 103. Balachandran VP, Gonen M, Smith JJ, DeMatteo RP. Nomograms in oncology: more than meets the eye. Lancet Oncol. 2015;16(4):e173e180. 104. Greiner M, Pfeiffer D, Smith RD. Principles and practical application of the receiver-operating characteristic analysis for diagnostic tests. Prev Vet Med. 2000;45(1e2):23e41. 105. Cho JK, Lee GJ, Yi KI, et al. Development and external validation of nomograms predictive of response to radiation therapy and overall survival in nasopharyngeal cancer patients. Eur J Cancer. 2015;51(10):1303e1311. 106. Zeng L, Guo P, Li JG, et al. Prognostic score models for survival of nasopharyngeal carcinoma patients treated with intensity-modulated radiotherapy and chemotherapy. Oncotarget. 2015;6(36):39373e39383. 107. Wu S, Xia B, Han F, et al. Prognostic nomogram for patients with nasopharyngeal carcinoma after intensity-modulated radiotherapy. PloS One. 2015;10(8):e0134491. 108. 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). 109. Yang L, Hong S, Wang Y, et al. Development and external validation of nomograms for predicting survival in nasopharyngeal carcinoma patients after definitive radiotherapy. Sci Rep. 2015;5:15638. 110. Zeng Q, Hong MH, Shen LJ, et al. Nomograms for predicting long-term survival in patients with non-metastatic nasopharyngeal carcinoma in an endemic area. Oncotarget. 2016;7(20):29708e29719. 111. 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):3307e3315. 112. Zhang H, Singer BS. Recursive Partitioning and Applications. Springer-Verlag New York Inc; May 01, 1999. 113. Zhang Y, Li WF, Mao YP, et al. Establishment of an integrated model incorporating standardised uptake value and N-classification for predicting metastasis in nasopharyngeal carcinoma. Oncotarget. 2016;7(12):13612e13620. 114. Ho JH. An epidemiologic and clinical study of nasopharyngeal carcinoma. Int J Radiat Oncol Biol Phys. 1978;4(3e4):182e198.

Commentary on Chapter 9: Staging of Nasopharyngeal Carcinoma Based on the 8th Edition of the AJCC/UICC Staging System: The Evolution of the Nasopharyngeal Cancer Tumor, Node, Metastases Stage Classification: A Model of Adaptation, Harmonization, and Collaboration Shao Hui Huang, Brian O’Sullivan Department of Radiation Oncology, Princess Margaret Cancer Centre/ University of Toronto, Toronto, Canada

Keywords: Nasopharyngeal carcinoma; Nomograms; Prognostic groups; Social determinants of health; TNM stage.

INTRODUCTION Chapter 9 of this book1 summarizes the developments and processes underlying the most recent evolution of the stage classification for this unique disease. Although rare beyond the confines of Southeast Asia, nasopharyngeal carcinoma (NPC) is an exemplar of the importance of appreciating anatomic disease involvement and description, as well as understanding disease natural history in terms of routes of spread and propensity for regional and distant metastasis (DM). Not many diseases, if any, replicate the critical linkage between anatomic disease extent and outcome and the essential relationship to treatment variables that continue to improve the outcome of this disease. Moreover, as discussed by Lee et al.,1 the interplay of these immutable parameters have continued to a point that the stage classification itself, if it is to remain relevant, needs to reflect the impact of improved outcomes. This relates to the incalculable advances in disease assessment with contemporary medical imaging, the impact of combined modality approaches, and more accurate radiotherapy planning, delivery, and guidance approaches available today; all of these have combined to influence the prognostic importance of previously adverse disease presentations. In addition, while NPC remains a major health problem in its classic endemic regions, it is becoming more common elsewhere due to migratory patterns throughout the world and is certainly no longer the underemphasized disease that existed in the era up until the 4th edition, following which the classification received its first major modification.

PRINCIPLES OF STAGE CLASSIFICATION Cancer stage classification has been a cornerstone of cancer care and research for decades and this is particularly the case in NPC. It provides a synoptic structure for communication about cancer extent relevant to its prognosis. Various staging systems have existed, the most prevalent being the UICC/AJCC TNM classification that depicts cancer anatomic extent based on assessment of three componentsdT, primary tumor extent; N, absence or presence and extent of regional lymph nodes; M, absence or presence of DMdand combines them into prognostically relevant stage groups. To ensure effectiveness of the staging system, including its value as a tool to assist communication among different users and across different parts of the world, clarity and precision using harmonized and unambiguous language for disease extent is essential. In addition, to maintain its clinical relevance, periodic updates to the staging classification are important. The updates should be meaningful and practical, as well as reproducible in most jurisdictions across the world. Moreover, for an evidence-based stage classification, any update should rely on a robust, large, populationbased dataset (containing the full disease spectrum). The evolution of NPC staging has exemplified this sound principle and reflects the requirement of harmonization and collaboration for cancer stage classification.

HISTORICAL PERSPECTIVE Historically, various NPC stage classifications existed among Asian countries including mainland China, Hong Kong, and Singapore, which were different from the Union for International Cancer Control (UICC)/American Joint

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Committee for Cancer (AJCC) staging system used in the western world.2e4 Variations in T and N definitions hindered meaningful comparison of results between centers from different jurisdictions. Mounting enthusiasm for revision of the UICC/AJCC tumor, node, metastases (TNM) commenced in the early 1990s in preparation for the publication of the 5th edition in 1997. This initiative arose from a recognition that the staging system in frequent use in Southeast Asia was that of Ho and that it, and other classifications, were superior to the UICC/AJCC TNM.5e7 The consequence was a complete revision of the earlier UICC/AJCC 4th edition8,9 by consultation involving an International Task Force comprised mainly of radiation oncologists in Hong Kong, Singapore, and mainland China, and led by the UICC in collaboration with the AJCC. The work of this task force resolved many of the most contentious issues in NPC staging at the time to create the UICC/AJCC 5th edition TNM classification for the disease. This effort represented a milestone that effectively weathered the next 20 years. Since then, collaboration has continued to underpin measures to achieve further refinement.

THE IMPORTANCE OF THE 8TH EDITION TUMOR, NODE, METASTASES As discussed in Chapter 9, the recent 8th edition TNM includes refinements of T and N based on a combined dataset from mainland China and Hong Kong. This effort was led by Professors Pan and Lee, and represents the continued contribution of cancer staging from Asia to the world. It reflects the improved prognostic performance of a modified NPC classification as a result of improved contemporary management.10 This new stage classification has been validated in several independent datasets.11,12 The rationale for refining T and N classification in the 8th edition for NPC is well described in the chapter.1 The improved accuracy of MRI in optimizing the T-classification is recognized due to its superiority in detecting disease extension at the skull base, perineural disease without bone involvement, as well as marrow infiltration and tumor extension to the paranasal sinuses and orbit.13,14 18F-FDG-PET has also been shown to improve the accuracy of the N and M classification.15e18 The introduction of intensity-modulated radiotherapy (IMRT) greatly improved tumor radiotherapy target volume inclusion for a subgroup of patients with adjacent soft tissue involvement who now have much improved outcomes, who have been separated from those with extensive soft tissue involvement by reclassification from previous T4 to the current T2 category. Furthermore, the ongoing benefit of concurrent chemotherapy, which was not part of the treatment when the earliest iteration of the modern NPC TNM stage classification was introduced in 1997, has also influenced outcome. It mitigates risk of DM, including disease subsets (e.g., the aforementioned migration of some T4 categories to new T2), and also provides radiotherapy sensitization for more advanced local disease that is more readily eradicated with IMRT. In this way, previous higher categories of disease can be reallocated to lower categories based on validated improved outcomes. The improved coverage of neck disease as well as employment of chemotherapy also may explain the lack of difference between N3a (>6 cm nodes) and N3b (lower neck lymph nodes).

REFINING AND USING CONSISTENT TERMINOLOGY In an optimal stage classification, the definition of terms should avoid ambiguity or redundancy. For this reason, two important modifications emerge in the 8th edition, one addressing the definition of the low neck and the other relating to extensive lateral extension of disease conforming to the T4 category. In NPC, low neck disease has traditionally been described with respect to the supraclavicular zone or fossa originally described by Ho (a.k.a. “Ho’s triangle”). This iconic feature of the NPC classification has guided practitioners for countless decades in the era where neck description was largely based on clinical examination of the patient.19 Lee et al. point out that the legacy use of the historical Ho’s triangle as a criterion for N-categorization is no longer crucial for clinical and practical application, and that it is reasonable to depart from this approach in favor of the more usual topographic convention used for other head and neck sites. In essence, with contemporary crosssectional imaging conventions for the description of the neck, the boundaries of Ho’s triangle can no longer be consistently defined radiologically. This change recognizes progress in patient evaluation over the succeeding decades since Professor Ho’s original description, and, while the importance of lower neck disease is still acknowledged in the classification, the N3 criterion for the lower neck has been replaced by a new definition. This revised description solely addresses extension below the caudal border of the cricoid cartilage and includes levels IV and Vb.20

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The elimination of masticator space and/or infratemporal fossa in the 8th edition also facilitates reduction of uncertainty about definitions. In truth, these were largely vestigial terms that eventually fostered distraction inherent to anatomic definitions that might not be consistent among medical disciplines, whether they involved medical imaging, anatomy, or surgical concepts. While these descriptions may be relevant within these constructs, in reality the underlying details are not important for the stage classification. They are now replaced by specific descriptions of soft tissue involvement to avoid ambiguity, including extensive soft tissue infiltration beyond the lateral surface of the lateral pterygoid muscle. For the latter, this change underpins the fact that what impacts prognosis most is the degree of extension from the original disease area as a measure of bulk rather than precise descriptions of anatomic structures that may be invaded as the tumor extends laterally. Newer terms and procedures also need to be appreciated, or merit caveats about whether or not they should have been included in the revised TNM, and essential conventions or rules need to be observed in determining categories within TNM. For example, prevertebral muscle involvement has now been included in the 8th edition based on evidence of adverse prognosis due to better resolution of MRI, which can distinguish this attribute from parapharyngeal spread or retropharyngeal lymph node metastasis. However extranodal disease extension, which had been included in the Chinese 2008 stage classification, was not included in the UICC/AJCC system due to the need for further refinement and interpretation of imaging techniques and evidence of greater consistency in conferring prognosis across studies. Finally, for neck staging, practitioners need to be mindful that clinical evaluation requires assessment of the maximum dimension (in any direction) of a nodal mass to define its size for classification21 and is not restricted to axial cross-sectional imaging measurements, which may be a preferred approach in some imaging reports.

ACCOMMODATING VARIOUS STAKEHOLDERS As mentioned earlier, the TNM classification is widely used to facilitate patient consultation, outcome prediction, clinical trial design, and cancer control activities throughout the word. As such, it must accommodate the needs of numerous constituents and stakeholders that include clinicians, researchers, and the cancer surveillance community as well as patients and their support partners. In the creation of the TNM, a strong emphasis is given to safeguarding that the classification is both useful for all users while also being applicable in regions of the world where NPC has its highest incidence. These goals may engender conflict between the latest scientific discoveries and practical application in jurisdictions where such advances are difficult to implement. Compromise is often needed to permit all stakeholders to embrace an international classification that is feasible, useful, and practical.

ADDITIONAL CANDIDATE VARIABLES FOR CONSIDERATION Primary gross tumor volume has been shown to be prognostic for NPC in several studies and has been proposed for inclusion in the T classification.22e34 However, this factor was not included in the 8th edition due to lack of consensus about who should determine this component (radiology vs. radiation oncology), uncertainty about optimal cutoffs, and which imaging modality (CT, MRI, or PET) should be used as a basis for evaluation, as well as concerns about interrater variation and applicability on a worldwide basis. Another prognostic factor under consideration, but eventually not included in the new staging classification, is EpsteineBarr virus (EBV) DNA copy number. The prognostic value of circulating EBV DNA in the blood (plasma or serum) has long been recognized in many studies.35,36 However, large variation exists in terms of sensitivity and specificity37 and there is a not insignificant proportion (20%e30%) of NPC patients with undetectable EBV DNA at time of presentation, even in endemic regions.38e40 The optimal cutoff value of EBV DNA also remains elusive.35,41,42 It seems that harmonizing testing methods among laboratories to ensure test/retest reliability43 and improving sensitivity and specificity would be required before considering the inclusion of this parameter in future NPC staging. Several other attractive candidates have also been described, partly due to the advanced technology and biology underpinning their development and assessment. MicroRNA expression, gene expression patterns, and circulating tumor cells are examples, but further studies are needed to determine independence across different datasets as well as reproducibility and wider application across different jurisdictions of the world where NPC is found. A more practical assessment mentioned by Lee et al. includes the use of pretreatment levels of serum lactate dehydrogenase,

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which has independent significance for prognosis of NPC.44 It is available readily in most regions of the world but potentially may not be considered a prime candidate for inclusion in the staging classification due to its very traditional nature, albeit used already in several other diseases including lymphoma, melanoma, and seminoma.

PERSONALIZED MEDICINE Numerous additional parameters beyond anatomic disease extent, or even pathology/molecular features, can influence the prognosis of patients with cancer, including NPC. Obvious features include age, performance status, and social determinants of health that are far ranging and include access to care or quality of treatment. These are outlined further by Lee et al.1 Due to the complexity of addressing heterogeneous and multidimensional prognostic factors, several groups have approached the difficulty of addressing individualized risk stratification and decision making in NPC by developing algorithms to calculate numerical estimates of event probability. Typically these take the form of pretreatment nomograms with emphasis on personalized medicine and have become increasingly popular and an active research area in many diseases including NPC.10,45e48 A nomogram allows incorporation of anatomic with nonanatomic prognostic factors and permits individualized case prognostication. It gives the clinician a tool to discuss potential treatment options and anticipated prognosis at the individual patient level. However it is also important to emphasize that nomograms are not able to replace many functions of the TNM staging system, although may facilitate individual patient decision-making. Furthermore, tumor anatomic extent, captured by TNM stage classification, is an essential part of most nomograms. Unfortunately limitations of nomograms are that they do not realistically aggregate groups of patients for comparison of results across institutions, between jurisdictions, or for entry, stratification, or comparison in clinical trials. In addition, patients may be subjected to different treatments and different intended goals and with different outcomes (e.g., local-regional recurrence vs. distant metastases) even if survival, as a basis for creating such groups, may be the same. In oncology generally, such calculation algorithms are also frequently generated from data addressing specific subsets of the disease (e.g., early vs. more advanced stage, or primary presentation vs. recurrent/metastatic situations) and may not be relevant to the disease overall. Another challenge concerns the statistical underpinnings of various nomograms that require careful scrutiny, including the degree of uncertainty surrounding the point estimates, lack of published confidence intervals, and limited validation studies.49

CONCLUSIONS The TNM staging system of NPC has seen significant change since its earliest formulations many decades ago. These changes have always recognized the need for appropriate decision-making for patients and the recognition of the challenge of treating this disease in such a critical anatomic location. While the 5th edition TNM in 1997 represented a landmark change for staging NPC, the most recent 8th edition classification has again demonstrated dramatic modifications that reflect the improved outcomes resulting from superior medical imaging, vastly improved radiotherapy planning and delivery, and enhancement of treatment efficacy through the use of systemic treatment approaches. It is anticipated that future developments will witness incorporation of nonanatomic factors into prognostic models and algorithms that will further enhance decision-making for patients and prediction of outcome in a more tailored and personalized manner.

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