Developing, Validating, or Optimizing the Staging

Classifications of OPC and NPC:

the viral induced pharyngeal cancers

Brian O’Sullivan Professor, Department of Radiation Oncology

The Princess Margaret Cancer Centre / University of Toronto

Radiation Oncology Chair United States NCI Head and Neck Steering Committee

Member, TNM Committee, UICC Chair, Prognostic Factors Committee, UICC

3:30-4:10 PM, Sunday, Sept 9, 2018

Hong Kong

Disclosure

None

Overview

Roles of different Professionals and the Different

Purposes involving Cancer Stage Classification (TNM)

How to create/validate a new TNM, or how to improve

an existing TNM classification

Use exampler of the two viral pharyngeal cancers

(NPC and HPV-related)

Challenges for the future and the incorporation of

factors beyond anatomic disease extent

Roles and Needs in TNM Classification

Numerous stakeholders:

IARC, WHO “blue books”

US NCI, CDC etc

Each group needs to be

aware of the needs and

purposes of the others

EBV:

• Responsible for majority of NPC in southern China and east Asia

HPV:

• Responsible for most OPC in western countries

EBV+ NPC and HPV+ OPC share similarity in:

• Multiple overlapping oncogenesis pathways

• Highly radio- and chemo-sensitive

• More immunogenic

• Circulating blood DNA with opportunities

to refine management and enhance

precision medicine

Viral Related Pharyngeal Cancer

Mesri 2014

EBV HPV

OS by 7th edition TNM Stage Groups [PMH Data 2000-2010]

Huang,

O’Sullivan, et

al. JCO,

March, 2015

HPV– OPC

(n=237) Inseparable OS between

stage I-IV (P=0.56)

Acceptable OS

performance (p=0.004)

HPV+ OPC

(n=573)

HPV(+) Stage IV disease does not have the ominous

outcome of smoking-related OPC

80.4%

Why Do We Need a New TNM for HPV+ OPC

HPV+ OPC is a new disease

7th Edition TNM was unable to adequately depict prognosis

Why HPV+ OPC Needs Its Own TNM

Necessary

• Consultation: relevant to discussion with patient / family

• Clinical trial eligibility and design (e.g. stratification)

• Framework for future clinical practice guidelines

Applicable

• For cancer surveillance

High HPV prevalence jurisdictions need an HPV+ TNM

Low HPV prevalence regions could theoretically continue to use HPV─ TNM

Brizel JCO 2015 Gillison JCO 2016

Developing and Validating A New Staging for

HPV+ OPC (cTNM and pTNM)

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

RT: 98%; Surgery: 2%

O’Sullivan, Huang, Yu, Xu et al. Lancet Oncol 2016

cTNM

5 Centers 704 Patients • TORS/TLM: 100% • pT1-2: 81%; pN0-2b: 87%

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

pTNM

5

Derivation cTNM for HPV+ OPC

PMH 2000-2010

• HPV+ OPC: 573

• HPV(-) OPC: 237

All definitive RT

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

Discovery PMH Study

- Feasibility - Statistical models - Evaluation criteria

Derivation ICON-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, Xu et al Lancet Oncol 2016

External Validation

Independent Datasets

1.Porceddu et al. Oral Oncol 2017 2.Husain et al Cancer 2017 3.Malm, Fakhry et al Cancer 2017 4.Wurdemann et al Front Oncol 2017 5.Cramer et al Head Neck 2018

1.Brisbane: n=279 2.NCDB Data: n=5626 3.Johns Hopkins: n=435 4.Giessen (Germany): n=150 5.NCDB Data: n=15116

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

T: T1, T2, T3, and T4 separate well; T4a and T4b behave similarly

N: inferior OS in N2c and N3; Similar OS between N0 / N1-N2a and N2b

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

Total 395 / 1907 80% (78-82) <0.001 Total 395 / 1907 80% (78-82) <0.001

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

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

Lancet Oncol,

2016

N3

N2c

T4b

T4a

Unilateral Neck

LNs

Bi-/contra-lat Neck LNs

Re-termed

ICON-S N

AHR: adjusted HR (adjusting for age, smoking, & chemo)

AHR Grid

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%

AHR Grid

External Validation of ICON-S Staging Study Sample

Size

Primary

Tx

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%

90% (3-yr)

(n=3631)

82%

(n=1242)

72%

(n=753)

NA

US NCDB

(Cramer)

N=15116 Sx: 44%

RT: 54%

90% (3-yr)

(n=8895)

81%

(n=3012)

68%

(n=1847)

31%

(n=320)

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

The 8th edition HPV+ cTNM reflects prognosis under current

treatment paradigms • But many had received intensified treatment

Stage I disease fares very well • Unknown if all stage I is suitable for less intensified treatment

• Uncertainty also about the optimal deintensification strategies

Stage I can be considered candidates for de-intensification

trials • Pre-mature to change treatment without trial data

Derivation of pTNM for HPV+ OPC Especially driven by the introduction of robotic surgery

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 Oncol 73:152-159, 2017

1. Zhan: NCDB (2010-2014) 2. Cramer: NCDB (2010-2013)

• For refinement of post-surgical reporting and framework to facilitate post-surgical management

• Cases first need to be classified by cTNM

Derivation of HPV+ pTNM

OS (UVA) N (%) HR p

pT1 (7th)

pT2

pT3

pT4

279 (40)

290 (41)

92 (13)

43 (6)

1.00

1.8 (1.08-3.05)

2.7 (1.38-5.16)

5.7 (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

0.9 (0.23-3.47)

1.2 (0.35-4.40)

1.9 (0.59-6.08)

3.6 (1.01-12.65)

2.7 (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

MVA: adjusting for

age, treating center,

and treatment

8th Edition: cTNM vs pTNM Methodological Comparison

cTNM (O’Sullivan, TLO 2016) pTNM (Haughey, OO, 2017)

Study Cohort All M0 disease Resectable disease only

Study Period 7 centers, treated in 1998-2011 5 centers, treated in 1985-2015

HPV/p16 testing rate 50-81% unknown

Sample Size N=1907 N=704

7th T and N Category cT and cN

• cT3: 412 (22%); cT4: 275 (14%)

• cN2c: 436 (23%); cN3: 7%

pT and pN

• pT3: 92 (13%); pT4: 43 (6%)

• pN2c: 52 (7%); N3: 39 (6%)

Methodology • Training-validation

• Using models and evaluation

criteria from the “Discovery Study”

• Pooled dataset

• Adoption of “LN number” parameter

directly from the “Discovery Study”

Time point Assigned at the initial diagnosis After resection of both primary and neck

Application For multiple purposes For risk stratification

7th Edition cTNM 8th Edition cTNM

7th Edition pTNM 8th Edition pTNM

(M1)

(M1)

(M1)

(M1)

Uniqueness of HPV+ OPC TNM

(8th edition) - the 1st time in HNC:

• T4 or N3 M0 is no longer

Stage IV

• Different cN and pN

classification, and stage

groupings

Treatment guidelines should not

change in the absence of trials

--- TNM is not a Guideline

Optimizing the Stage Classification for

Nasopharyngeal Cancer:

Refined T- and N- Classification

19

Rationale for Refining 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:

Increases conformity of tumor coverage and sparing of non-involved

structures

• Combination chemotherapy:

Improved tumor control and cure rates especially for advanced loco-regional

disease

Based on data from 1609 NPC patients from Fujian and HK

Recommended changes as follows:

– Changing MP/LP involvement from T4 to T2

– Adding Prevertebral muscle involvement as T2

– Replacing SCF with lower neck and merging this with a maximum nodal

diameter > 6 cm as N3

– Merging T4 and N3 as stage IVA (formerly IVA and IVB)

Cancer 2015

Changes of T and N category (7th vs 8th Edition)

T2

T4

T-Category:

Extent of soft tissue involvement

• Adjacent - T2: including

Medial & lateral pterygoid muscle

Pre-vertebral muscle

• Extensive - T4

Beyond the lateral surface of the

lateral pterygoid muscle, parotid

Eliminated inconsistent terms:

• “masticator space”

• “infratemporal fossa”

N-Category:

Replacing s/c fossa (blue) with

lower neck LN

Merge N3a and N3b as N3

s/c

T2

Postero-lateral

infiltration

Incl. medial and

lateral pterygoid

invasion

Cancer 2015

lower neck LN: below

caudal border of cricoid

cartilage (Pink)

T4

7th T 8th T

OS for Adjacent vs Extensive Soft Tissue Involvement

Adjacent soft tissue involvement

T2

Extensive soft tissue involvement

T4

Validation of 8th Edition NPC Staging

Guangxi, China

7th edition T 8th edition T LRC

7th edition Stage 8th edition Stage

OS

DC

OS

7th edition N 8th edition N

OPC T1 T2 T3 T4

N0 I I II III

N1 I I II III

N2 II II II III

N3 III III III III

NPC T1 T2 T3 T4

N0 I II III IVA

N1 II II III IVA

N2 III III III IVA

N3 IVA IVA IVA IVA

8th Edition: Similar cTNM Grid for NPC vs HPV+ OPC

IVB: T any _ N any _ M1 IV: T any _ N any _ M1

8th Edition Stage Classification for HPV+ OPC and EBV+ NPC:

• Similar N classification (except lower neck LN parameter)

• Similar stage grid, except “arbitrary” numerical stage designation (i.e. I and II)

Viral Related NPC and OPC: RFS by Stage RFS: NPC I-II vs OPC I

OS after DM RFS: NPC IVA vs OPC III

RFS: NPC III vs OPC II

Huang,

O’Sullivan,

et al ESTRO

2017

Practicalities about TNM Cancer Staging

Anatomic TNM Classification

Advantages:

– Relatively versatile globally (world wide), including resource-limited regions

– Applicable to individual (used in clinic) and in groups of patients

(administrative and research)

Limitations:

– Variable assessment methods to determine anatomic extent

– Does not fully predict response to chemotherapy and targeted therapy

– Limited response to emerging information in a timely fashion

– Inability to describe tumor biology and other non-anatomic factors

T4bN2c HPV(+) SCC Oropharynx

Case 1:anatomic Stage predominant Case 2: tumour Profile predominant

T2N2c HPV(+) SCC Oropharynx

2 HPV + OPC cases with identical treatments: 70 Gy in 35 f with concurrent cisplatin:

“different” distant metastasis outcomes

HPV+ metastasis resected -disease free 7 years later

(potentially cured with very advanced stage)

Rapid fatal DM at

2-years, with less

advanced stage

lung, brain, bone,

liver, spleen,

mediastinum,

pleura Cystic brain

metastasis

18

months

later

18 months

later

Prognostic Grouping and Incorporating

Biomarkers

T N M

Categories

T N M

Stage Groups *

Prognostic

Groups

Anatomic

T1-4, N0-N3 Anatomic

Groups I-IV

Combines “stage” with:

• Profile (tumor)

• Patient (host)

• Social determinants of

Health (management)

• TNM needs to incorporate non-anatomic factors in addition to “Staging”

• Combines anatomic (“Staging”) with non-anatomic factors

• Example: EBV DNA for NPC; smoking pack-year for HPV+ OPC

UICC definition:

“Staging” components

UICC definition:

The “Stage”

Profile candidates in Head and Neck in Past 10 yrs:

EGFR, VEGF, HPV, EBV, “smoking”, now PD1, PDL1 etc

Prognostic Groups including Smoking

Pack-years

HPV(+) OPC (n=661)

5-year OS: 75% (72-78)

Stage III (T4 or N3) (n=163) 5-year OS: 53% (46-62)

Stage I-II (T1-3N0-N2) (n=498) 5-year OS: 82% (79-86)

Smoking >20 PY (n=170) 5-year OS: 67% (60-75)

Smoking <=20 PY (n=328) 5-year OS: 90% (86-93)

Prognostic Model of HPV(+)

OPC by 8th Edition Stage

Group I (n=328) Stage I-II, ≤20 PY

5-year OS: 90% (86-93)

Group III (n=163)

Stage III (T4 or N3M0) 5-year OS: 53% (46-62)

Group II (n=170)

Stage I-II, >20 PY 5-year OS: 67% (60-75)

OS by 3 Prognostic Groups (unadjusted) OS by 3 Prognostic Groups (adjusted*)

Group IV: metastatic (M1) HPV(+) OPC)

Prognostic Grouping

Group I T1-3 N0-N2 M0 Smoking: ≤ 20 PY

Group II T1-3 N0-N2 M0 Smoking: > 20 PY

Group III T4 Any N M0 Any smoking PY

Any T N3 M0 Any smoking PY

Group IV Any T Any N M1 Any smoking PY

Huang, O’Sullivan et al JCO 2015

* Adjusted for chemo

Issues About Smoking PY on HPV(+) OPC

Influence of smoking pack-years on OS may not directly

reflect altered tumor biology

May reflect:

• Competing mortality risk from smoking (late toxicity, second

primary, COPD, social problems, etc)

• Treatment tolerance due to comorbidities

• Radiotherapy efficacy (hypoxia) in current smokers

• Modified biology with p53 mutations and “hybrid” tumours

Incorporation of Circulating DNA into “Staging”

Technical Requirement: • Subject to testing conditions

• Large variation between laboratories

• Requires stringent harmonization

Some patients have undetectable copies • What to do for those undetectable EBV NPC vs non-EBV NPC?

Uncertainty concerning optimal cutoff

Same principles apply to circulating EBV and HPV DNA

Plasma EBV DNA is prognostic in patients

with NPC

Challenges of incorporating plasma EBV DNA in future TNM Staging System

• Various copy # cutoffs (1500-4000) have been used

• Likely reflected inter-laboratory variability

– Importance of testing standardization and harmonization

• Not elevated in some patients

Wang et. al. Cancer 2013

Potential Prognostic Value of

Pre- vs Post-RT HPV DNA

Plasma HPV DNA

52 HPV+ tumor

35 Pre-tx Plasma

HPV DNA+

17 Pre-tx Plasma

HPV DNA-

5 Post-tx

HPV DNA+

30 Post-tx

HPV DNA-

Recurrence:

4/5

Recurrence:

2/30

1 Post-tx

HPV DNA+

16 Post-tx

HPV DNA-

Recurrence:

1/1

Recurrence:

1/16

Ahn et al JAMA OHNS 2014 140;846-54

Challenges:

• Small sample size, unproven prognostication

• Low sensitivity

• Not available for others

• Test harmonization

Total M0 NPC (n=518)

• 5-yr PFS: 81% (77-85)

• 5-yr OS 82% (77-86)

N0-N2 (n=388)

• 5-yr PFS: 87% (83-91)

• 5-yr OS 85% (81-90)

N3 (n=130)

• 5-yr PFS: 63% (54-74)

• 5-yr OS 70% (60-81)

T1-4N0-2 EBV<500 (n=211)

5-yr PFS: 94% (91-98)

5-yr OS 89% (84-94)

N-Category

T1-4N0-2 EBV≥500 (n=177)

5-yr PFS: 80% (73-87)

5-yr OS 83% (77-90)

T1-2N3 (n=54)

5-yr PFS: 64% (51-81)

5-yr OS 83% (71-96)

T3-4N3 (n=76)

5-yr PFS: 63% (51-78)

5-yr OS: 60% (47-77)

EBV DNA T-category

PFS OS

RPA 4 Group Prognostic Model of NPC by 8th Edition Stage Classification

Adjusted for age, sex,

smoking, ACE-27 scores,

LDH and treatment modality

The addition of pretreatment plasma EBV DNA into the 8th Edition NPC TNM stage classification

Lee V, Kwong D, Leung TW, Choi CW, O’Sullivan B, Lam KO, Lai V, Khong PL, Chan SK, Ng CY, Tong

CC, Ying PP, Chan WL, Wong LS, Leung D, Chan SY, So TH, Luk MY, Lee A. IJC, accepted 2018

Group I Group II Group III Group IVA

N0-N2

partitioned by

EBV for PFS

N3 disease

trumps

EBV (PFS

& OS)

Evolution of NPC and HPV Stage classifications

HPV+ OPC and EBV+ NPC have similar N classification and

grid in the 8th edition TNM

• Developing or refining T & N classification is evidence-based

reflecting current knowledge

Different challenges in incorporating non-anatomic factors for

prognostic grouping

• Smoking for HPV+ OPC: unknown underline mechanisms and may

be trumped at more advanced stage (T4 and N3)

• EBV DNA for NPC: testing harmonization and may be trumped at

the advanced anatomic stage (N3)

• Blood HPV testing is more nascent

Global Consultation No 1 on Cancer classification

Addressed the challenges to a common understanding of

cancer staging and the needs of the different constituents

Reaffirmed the purpose of staging classification,

recognized the scope of TNM, and provided guidance for

its appropriate use

Consultation among UICC, AJCC, NCI, CDC, FIGO, IACR (International Association of

Cancer Registries), IARC (International Agency for Research in Cancer), and the ICCR

(International Collaboration on Cancer Reporting)

O’Sullivan, et al. July 2017

Next phase (Consultation No. 2 - April 2018)

Strategies and systems to develop sound prognostic classifications:

• May include non-anatomic factors sensitive to the state of the science and

availability of new treatments

• Will not replace descriptions of anatomic disease extent

May not be in the form of a classification:

• Systems to capture and analyze multiple relevant variables comprehensively

Respect personalized approaches:

• Deploy the most robust technologies

artificial intelligence, machine learning, and neural networks

to predict outcomes in individual cancer patients by using a more

comprehensive set of information than is used currently

Continued Challenges

Develop an agreed framework to include: • Non-anatomic factors:

Biology / predictive markers, molecular and genomic profiling, and imaging

• New technologies and strategies Address “Big Data” approaches

“Project based” if simple classifications not suited

Maintain world-wide cancer staging purposes: • Cancer control

specifically surveillance at the population level

• Research activities clinical trials eligibility and stratification, translational research

• Clinical guidance clinical care and decision-making in addition to communicating prognosis

Ongoing initiative in 2018 from UICC, AJCC, NCI, CDC, NCI, CDC, AJCC, IARC, IACR,

WHO, ICCR, to:

Acknowledgements

UICC TNM Project Committee

• Mary Gospodarowiz, Jim Brierley, Malcolm Mason, Anne Lee

• Shao Hui Huang, UICC Volunteer and Research colleague

• Julie Torode and Staff at the UICC Office, Geneva

AJCC and its Disease Site Commitees

• Carolyn Compton, Mahul Amin, Jatin Shah

• AJCC Office (at American College of Surgeons) especially Laura Meyer and Donna Gress

Hong Kong and Chinese colleagues

IARC, CDC, US NCI, numerous others

Our patients throughout the world