NEW AJCC/UICC STAGING SYSTEM

Jean-Pascal Machiels

Cliniques universitaires Saint-Luc, Brussels

With the help of Brian O’Sullivan

The Princess Margaret Hospital / University of Toronto, Canada

UICC TNM Committee, and Liaison to the AJCC

DISCLOSURE SLIDE

Advisory board member or speaker with honoraria (managed by my Institution): Pfizer,

Roche, Astra/Zeneca, Bayer, Innate, Merck Serono, Boerhinger, BMS, Novartis, Janssen,

Incyte, …

Travel expenses: Amgen, BMS, Pfizer, MSD, …

Data safety monitoring board with honoraria: Debio, Nanobiotix

Institutional conflict of interest (Funding to institution for research support): all companies

Uncompensated advisory role: MSD

EORTC: investigator and study coordinator

Learning Objectives

▪ To understand background and purpose of TNM

▪ To appreciate the process of updating the TNM

▪ To discuss major changes, rationale, and caveats

concerning the 8th edition TNM

Clinical Applications of New TNM

ResearchRegistry

▪ Cancer control activities, e.g. • Time trends• Surveillance

Research

▪ Predict prognosis▪ Communication

▪ Framework for future guidelines

Clinical Care

▪ Clinical trial design▪ Comparing outcomes

T1: < 2cmT2: 2-4 cmT3: > 4 cmT4: Invasion of adjacent structure

Simplified TNM classification

N1: One single lymph node, <3cmN2a: One single lymph node, 3-6 cmN2b: Several ipsilateral lymph node, <6cmN2c: Bilateral lymph node, < 6 cmN3: Lymph node > 6 cm

Higher is the T, lower is the prognosis

Higher is the N, lower is the prognosis

T N

Stage I: T1 Stage II: T2 Stage III: T3 or N1 Stage IVa: T4a or N2 Stage IVb: T4b or N3Stage IVc: M1

Simplified TNM classification

Reasons for Periodic Staging “Updates”

▪ Emergence of a new disease requiring new classification

• e.g. HPV+ oropharyngeal cancer

▪ Validation of new prognosis markers prompts new parameters in TNM classification

• e.g. importance of extra-nodal extension (ENE) for non-viral HNC, depth of invasion (DOI) for oral cavity SCC

▪ Improvement in tumor assessment and/or treatment triggers T-and N-classification refinement

• e.g. MRI for staging / target delineation in NPC; IMRT/chemo improved NPC outcomes

Changes in 8th Edition TNM

▪ New staging systems

• HPV+/p16+ OPC

▪ Relocation:

• Thyroid cancer Endocrine

• Lip (except ‘wet lip’) skin

▪ Modification of T-category

• Nasopharynx

• Oral Cavity (DOI)

▪ Modification of N-category

• Nasopharynx

• Non-viral HNC (ENE)

• HN unknown primary (CUP)

➢ Viral-related (EBV, HPV )

➢ Non-viral related mucosal

9

A New Classification:

HPV+ OPC / CUP

cTNM - ICON-S

pTNM

OS by 7th edition TNM Stage Groups (PMH 2000-2010)

Huang, Xu, Siu, Waldron, O’Sullivan, et al. JCO, March, 2015

HPV(–) OPC (n=237)

HPV(+) OPC (n=573)

HPV(+) Stage IV disease does not have the

same outcome than smoking-related OPC

80.4%

HPV+ OS by 7th T- & N-category (multi-institutional dataset: n=1907)

T Events/Total 5-year OS P value N Events/Total 5-year OS P value

Total 395 / 1907 80% (78-82) Total 395 / 1907 80% (78-82)

T1 60 / 504 89% (87-92) <0.001 N0 32 / 173 80% (73-87) <0.001

T2 116 / 716 83% (80-87) N1-N2a 59 / 416 87% (83-90)

T3 106 / 412 76% (72-81) N2b 136 / 749 83% (80-86)

T4a 93 / 231 58% (51-65) N2c 112 / 436 74% (70-79)

T4b 20 / 44 57% (44-75) N3 56 / 133 59% (51-69)

O’Sullivan, Huang et al 2016

N3

N2c

T4b

T4a

Unilateral Neck LNs, <6 cm

Bilat/contralatNeck LNs, <6 cm

ICON-S Study: Canada, with international collaboration from Europe and USA for validation

T4

Training Cohort (n=661)5-year OS: 85%5-year OS: 78%5-year OS: 53%

Validation Cohort (n=1246)

5-year OS: 88%5-year OS: 81%5-year OS: 65%

ICON-S StudyO’Sullivan, Huang

et al 2016

ICON-S Study: Canada, with international collaboration from Europe and USA for validation

N1 = unilateral lymph node; N2 = Bilateral lymph node; N3: > 6 cm

External Validation of ICON-S Staging

Study Sample Size

Primary Treatment

No. at risk and 5-yr OS by ICON-S Stage

I II III IV (M1)

ICON-S(O’Sullivan) N=1907

Sx: 2%RT: 98%

85%(n=962)

78% (n=564)

53% (n=381)

NA

Australia(Porceddu) N=279

Sx: --RT: 100%

94%(n=132)

82%(n=82)

69%(n=65)

NA

US JHH(Malm) N=435

Sx: 38%RT: 62%

92%(n=281)

87%(n=77)

74%(n=72)

40%(n=5)

US NCDB(Husain) N=5626

Sx: 42%RT: 56%

3-yr: 90%(n=3631)

82%(n=1242)

72%(n=753)

NA

Germany (Wurdemann) N=150

Sx: 69%RT: 31%

94%(n=79)

77%(n=31)

64%(n=31)

25%(n=9)

US 5 centers(Haughey)

N=704 Sx: 100%RT: --

90% 79% 70% NA

Comments About HPV+ cTNM (clinical)

▪ The 8th ed HPV+ cTNM reflects prognosis with current treatment

• Many received intensified treatment (even stage 1)

• Treatment modification may influence

▪ Stage I disease does very well

• Stage I could be considered de-intensification trial candidates

Derivation of HPV+ pTNM

OS (UVA) N (%) HR p

pT1 (7th)

pT2

pT3

pT4

279 (40)

290 (41)

92 (13)

43 (6)

1.00

1.77 (1.08-3.05)

2.67 (1.38-5.16)

5.69 (2.67-11.31)

0.039

0.004

<0.001

pN0 (7th)

pN1

pN2a

pN2b

pN2c

pN3

44 (6)

91 (13)

141 (20)

337 (48)

52 (7)

39 (6)

1.00

0.89 (0.23-3.47)

1.24 (0.35-4.40) 1.89 (0.59-6.08)

3.56 (1.01-12.65)

2.70 (0.64-11.31)

0.870

0.737

0.285

0.049

0.174

pENE(-)

pENE(+)

233 (35)

427 (65)

1.00

1.61(0.98-2.63) 0.060

≤4 pN+

≥5 pN+

589 (84)

115 (16)

1.00

2.93 (0.21-0.53) <0.001

Definition of pN

pN0 No regional LNs

pN1 ≤4 pN+ LNs

pN2 ≥5 pN+ LNs

Haughey el al Oral Oncology 2016

MVA: adjusting for age, treating centers, and treatment

• 3745 HPV+ OPC in NCDB

• All had ND in 2010-2014• pT0 4%; pT1: 47%; pT2: 39%; pT3: 7%, pT4: 3%

• pN0 4%, pN1: 76%; pN2: 13%

• 4-yr OS: I: 92%; II: 81%; III: 62%

2017

OS by 7th Edition Stage OS by 8th Edition Stage

Zhan et al Oral Oncol2017

• Presence of pENEappeared to be prognostic within HPV+ pN1 and pN2

NDCB Data - Influence of ENE within pN1, pN2

OS: pN1(by pENE)

OS: pN2(by pENE)

8th Edition cTNM and pTNM for HPV+ OPC / CUP

cTNM 1-4 LNs ≥5 LNsUnilat Bilat

Huang, O’Sullivan Curr Treat Options in Oncol. 2017

Lydiatt, Patel, O’Sullivan et al, CA Cancer J Clin. 2017

pTNM

Rationale for Revising a Stage Classification

Better understanding of disease behavior

Introducing new parameters in TNM classification

19

Extranodal Extension (ENE) in the N Classification for All Non-

viral HNC (United States, Canada)

Depth of Invasion (DOI) in Oral Cavity

(Australia, Asia, Europe, America)

Extranodal extension (ENE)

Pathological ENE

Low power High powercENE/rENE

▪ pENE is prognostically important for regional failure and distant metastasis

▪ pENE is an important indicator for adjuvant concurrent chemotherapy with radiotherapy (Level 1 evidence: pooled analysis of EORTC 22931 and RTOG 9501)

Major pENE (pENE (ma)(> 2 mm from the nodal capsule)

>2 mm

AJCC TNM 8th Edition

Extranodal extension (ENE) (for non-viral HNC)

▪ OS in surgically treated HNSCC based on N classification that incorporate pENE as a

prognostic factor. (NCDB Data 2010-2011 excluding NPC and HPV+ OPC).

OS by pN status(NCDB Data: All sites)

N0

N1

N3A

N2a, N2b, N2c

N3B

Return to the 4th edition

Formerly N1

Formerly N2a, N2c

CLINICAL N-categories (cN)

PATHOLOGICAL

cENE: invasion of skin, infiltration of musculature, fixation to adjacent structures on clinical examination, cranial nerve or brachial plexus invasion with dysfunction

Formerly N1

PATHOLOGICAL N-categories (pN)

Formerly N2a, N2b, N2c

Measuring DOI

A “plumb line” from the basement membrane of the closest intact squamous mucosa to the greatest invasion

DOI on a Exophytic Tumor DOI on an Ulcerated Tumor

Lydiatt, Patel, O’Sullivan et al, CA Cancer J Clin. 2017

Horizon

Plumb Line for DOI

HorizonTT

Plumb Line for DOI

Plumb Line for DOI

Horizon

Oral Cavity –DOI Ebrahimi et al JAMA OtolaryngolHead Neck Surg. 2014)

DFS for pT1 by DOI (<5 mm vs ≥ 5 mm)P=0.01

DFS for pT2 by DOI (<10 mm vs ≥ 10 mm)p<0.001

DFS for pT3 by DOI (<10 mm vs ≥ 10 mm)P=0.004

DFS for pT4 by DOI (<10 mm vs ≥ 10 mm)P=0.11

• Retrospective analysis of 3149 OSCC from 11 cancer centers

• 1990 to 2011

• Surgery adjuvant

• Median follow-up: 40 mos

• Different models explored

Depth of invasion

TNM oral cancer, 8th edition

Rationale for Revising a Stage Classification

Better management

(treatment / assessments)

25

Revised clinical staging (T and N) for NPC

(Hong Kong, Mainland China and Canada)

NPC Stage Classification

▪ NPC management has evolved substantially

• More accurate imaging allows better delineation of tumor extent

and early detection of occult metastases

• Advances in radiotherapy with increasing conformity of tumor

coverage and sparing of non-involved structures

• Combination chemotherapy has improved tumor control and

cure rates especially for advanced locoregional disease

Contribution of imaging to

NPC Management

• Intracranial disease within

cavernous sinus (dashed

arrow)

➢ Perineural tumor through

foramen ovale (curved arrow)

➢ The solid arrow shows the

normal cavernous sinus

CORONAL

From O’Sullivan and Yu, 2010, Springer Verlag,Berlin

Heidelberg (Editors Lu, Cooper and Lee)

MRI of Skull Base

Adjacent soft tissue involvement → T2

OS for Adjacent vs Extensive Soft tissue Involvement

Extensive soft tissue involvement → T4

Change of NPC TNM from 7th to 8th Edition

2017

√

√

• The definition of lower neck lymph nodes

➢ Lymph node below “caudal border of cricoid cartilage” (replaces “below supraclavicular fossa”)

• No subdivision of N3a and N3b:

➢ T4 and N3 M0 merged as stage IVA while M1 disease is IVB

Take Home Messages Regarding HNC TNM▪ TNM is important for many elements of research, management, and surveillance

• Counselling, prognostic estimation, surveillance, research and clinical trials

• But TNM classification is NOT a treatment guideline:

➢ Treatments should not be altered based on TNM

− Numerous other factors are operational and change requires “best evidence”

▪ Important changes in TNM 8th edition:

• New disease recognised with a new clinical and pTNM (HPV+ OPC)

• Revision due to the successes in management (NPC)

• Modifications for factors used clinically (ENE and DOI)

AJCC Head and Neck Expert Panel

Robert Baatenburg deJongMargaret Brandwein-GenslerDavid BrizelJoseph CalifanoAmy ChenDimitrios ColevasStephen Edge (Editorial Representative)Matthew FuryRonald GhosseinChristine GlastonburyRobert HaddadBruce HaugheyDennis KrausQuynh LeAnne LeeWilliam Lydiatt (Vice Chair)Suresh MukherjiKishwer NehalBrian O’Sullivan (UICC)Snehal PatelJohn RidgeSimon RogersChrysaline SchmultzRaja Seethala (CAP representative)Jatin Shah (Chair)Erich SturgisRandal WeberBruce Wenig

Acknowledgement: UICC and AJCC HN Expert Panel

Erratum in one of the Manuals

or any single contralateral node with ENE+

Erratum needed

Derivation cTNM for HPV+ OPC/CUP

PMH 2000-2010• HPV+ OPC: 573• HPV(-) OPC: 237

All definitive RT

Huang, Xu, O’Sullivan, et al. JCO. 2015

DiscoveryPMH Study

- Feasibility- Statistical models - Evaluation criteria

DerivationICON-S Study

- Training-validation- Derivation of a cTNM

7 Centers 1907 HPV+ Patients• Training (PMH): n=661• Validation: n=1246

RT: 98%; Surgery: 2%

O’Sullivan, Huang, Xuet al. Lancet Oncol 2016

External Validation

Various Datasets

1.Porceddu Oral Oncol 20172.Husain Cancer 20173.Malm, Fakhry Cancer 20174.Wurdemann Front Oncol 2017

1.Brisbane: n=2792.NCDB Data: n=56263.Johns Hopkins: n=4354.Giessen (Germany): n=150

Discovery

- LN No. (≤4 vs ≥5) was prognostic

Derivation

A multicenter study (incorporating LN # pragmatically)

External Validation

Pathologic (post-surgical) pTNM for HPV+ OPC

Washington University• HPV+ OPC: n=220• TLM +/- adjuvant RT

Sinha et al Oral Oncol 51: 154-520, 2015

5 Centers (USA & UK) 704 Patients• TORS/TLM: 100%• pT1-2: 81%; pN0-2b: 87%

Haughey et al Oral Oncol 62:11-19, 2016

Zhan, et al, Oral Oncol73:152-159, 2017

Zhan: NCDB Database• N=3745• Surgery 2010-2014

• For refinement of post-surgical reporting and framework to facilitate post-surgical management • Cases first need to be classified by cTNM