Head & Neck Cancer

1.
2.
3.
4.

1.
2.
3.
4.
Anatomy of the Head and Neck Cancer
more than 90% is squamous cell carcinoma
 Head Neck Tumor Sub-sites and
Treatments
3500 CCRT
Non-OP First treatment
OP Subsites n
3000 Non-OP OP

350 3120
2500 oral cavity 3470
(10.1%) (89.9%)
328 156
oropharynx 484
2000 (67.8%) (32.2%)
hypopharyn 416 86
502
1500 x (82.9%) (17.1%)
233 95
larynx 328
(71.0%) (29.0%)
1000
31 39
(para)nasal 70
(44.3%) (55.7%)
500
16 121
salivary 137
(11.7%) (88.3%)
0 Total 1374 3617 4991
oral cavity oropharynx hypopharynx larynx (para)nasal salivary
 5 (2004-2009)
: vs.

Liao CT, et al. J Cancer Res Pract. 2015;2:103-116.

 - (3 5 )-

602

39% 45% 0.1

34% 40% 0.1
58% 0%
• 60 %

Pignon JP et al. Lancet 2000;355:949-55 Pignon JP et al. Lancet 2000;355:949-55

Tumor Sub-sites and 5-year Overall
Survivals

salivary 65.1%

oral cavity 56.6%

larynx 50.3%

(para)nasal 48.5%

oropharynx 38.7%

hypopharynx 20.8%

Pre-Tx *Oral **Oral **Hypo-

cavity pharynx pharynx
DM 1% 5% 10%
2nd 4% 4% 12%
*Liao CT, **Ng SH
DM, distant metastases; 2nd, 2nd primary
1996-2018

Cancer Registration in Each Hospital (1996-2018)

%

85%
OCSCC: Pre-OP Evaluation and Staging

• All had pre-surgical evaluation

– clinical examination
– head and neck CT/MRI
• MRI: tongue, retromolar, hard palate/upper gum
– FDG-PET (standard) Anatomic mapping:
– chest X-ray
– bone scan
– liver echography
{ -- Non-surgical approach
(1) 1%: distant metastases
(2) <5%: high risk
-- liver cirrhosis (>child B)
– (panendoscopy) -- poor heat function
(3) 1-2%: insufficient surgical margins
• Staging -- supra-notch T4b

– AJCC 1997(5th), 2002(6th), 2010(7th), 2017-8(8th)

 Oral Cavity Squamous Cell
Carcinoma (OCSCC) Sugery and
Adjuvant Theray
• Surgery
– Tumor: ≥1 cm margins
全世界
• (NCCN 的guideline 是 根據頭頸癌
guidelines: 2 cm 1.5-2cm  1.0-1.5 cm [2020])
– Neck: level dissection
• cN0
– level I-III (supra-omohyoid)
– T2-T4, T1 (tongue: all, buccal ≥5 mm tumor depth)
• cN+
– Level I-IV or level I-V (modified/radical)
• tumor reached or crossed the midline
– bilateral
– Reconstruction (>80%): free or local flap
• Post-operative adjuvant therapy (50%)
– head and neck team consensus
• pathological risk factors
 NCCN Oral Cavity Cancer
Guidelines
• T4b,N0-3
– Clinical trial
– Non-surgical approach
– Q: T4b

• Adverse features
– CCRT: extra-nodal extension, positive margins
– RT/CCRT: close margins (2020), pT3, pT4, pN2, pN3,
pN1(level IV/V), perineural invasion, vascular invasion,
lymphatic invasion.
– Q: NCCN
– Q: pT3 ( )
– Q:
 Linkou CGMH

NTUH

)
Kaohsiung
CGMH

CCH

2018
CMUH

KMUH

TVGH

TVTH
pT3

E-DAH

KFSYSCC

CMH
2017-2018

MMH

DMFCYCH

(
HTCH

KVGH

FEMH

2021
NCKUH

2
3
CMH

Chiayi CGMH

TSGH

TTMH

SMDPH

LCMH

DTCH

SKWHMH

SHH
pT3

Keelung CGMH

NTUHHCB
pT3

YGH

NTUHYLB

TTCH
Untreated: ≥1 cm surgical margins Recurrence: ≥1.5-2 cm margins
Level I-III(30 nodes) vs. I-V(50 nodes) Neck
Dissection

--- Cricoid cartilage

--- Transverse cervical vessel ---
* (+5.5 nodes, gain 2% neck control)
*
--- Clacvicle
Lymph node ratio: pN+ number/LNs-dissected number
: 2/30 versus 2/35 (better outcome)
 Salvage Surgery of Head and Neck Tumor

Laryngeal Cancer Hypopharyngeal Cancer

(post-concurrent chemoradiation) (post-concurrent chemoradiation)
Neck Lymph Node Metastases:
Clinical vs. Pathological
• Clinical staging (subjective)
– image for cN+
• short axis ≥10 mm (long axis for N1 or N2a or N3)
• central necrosis
• extra-nodal extension (ENE)
– PE (physical examination)

• Pathological staging (golden standard)

– 35% nodal metastases (pN+)
• 60% extra-nodal extension (ENE)
– micro vs. macro
– total 22% ENE
FDG-PET Detection: ≥5 mm Tumor
Size

PET: score 0 (cN0), pN+: 3mm tumor/4mm node

Clinical vs. Pathological Staging

cN1(stage III) pN3b(pN+ 7, ENE 2, stage IV): level I(6+/10), level II(1+/15)
Free Tissue Transfer at Lin-Kou
CGMH
 Goal of Flap Reconstruction
• Ablative cure
• Restoration of function
• Reconstruction of form
Facilitate Swallowing
Revision of External Skin Lining
Double Free-flap
Reconstructions
4th Primary oral cavity SCC S/P
-- Central tongue, L’t retromolar, hard palate, R’t upper gum

·s¼W Microsoft PowerPoint ²³ø.pptx

Adel M, Liao CT et al. Medicine 2016;95:e2950.

One Thigh, Second-Time Flap
Sup. Thyroid Artery Facial Artery
:Second-Time :First-Time
Vessel Vessel

Recip. al: (lt)_Facial artery, diameter 2mm; Superior thyroid artery preserved.
― 1996
Pathological Depth vs. Thickness

厚度

深度

Thickness
Depth
Rt Buccal SCC, pT4aN3b, ENE (n = 121)/ pN+ (n = 130)
 Margin Status and Outcome
≥1cm (radical)
surgical margins

>4mm vs. ≤4mm

≤4mm margins ≤4mm margins
pathological margins
10% 30-60%
(clear,close/positive)
Ebrahimi 2011
Nason 2009
Cheng 2008
More destruction of Woolgar 1999, 2005
bone, skin, and Brandwein-Gensler 2005
oral function Good / Poor McMahon/O’Brien 2003
? local control,
Sutton 2003
Parsons 1997
survivals Loree 1990
Reconstructive (functional and cosmetic
capabilities concerns?)

Free-flap based Good outcome

Hanasono 2009 (positive margin:18% change to 7%)
Thomas 2010 (QOL)
Taiwan Free flaps vs. local flaps
(2011-2017: n = 7297 vs. n = 1349)
Margin ≤4 mm: 44% vs. 55%

5-year disease-specific survival: free 82%/ local 77% 5-year Overall survival: free 73%/ local 68%

Liao CT. Ann Surg Oncol. 2021, accepted

 AJCC TNM Staging (OCSCC)
1997(5th) vs. 2002(6th)/2010(7th)
• Tumor status
– T1: ≤2 cm
– T2: 2.1- 4cm
– T3: >4 cm
– T4 (AJCC 1997), T4a/T4b (AJCC 2002, 2010)
• 2002 (6th):
– T4a (resectable): tumor involved skin, bone marrow, extrinsic
muscle of tongue, maxillary sinus
– T4b (unresectable): tumor involved masticator space, pterygoid
palate, internal carotid artery, skull base
• 2010 (7th):
– T4a: moderately advanced local disease
– T4b: very advanced local disease
 T4a tumor

AJCC 2017
Bone
marrow

Maxillary
Skin
sinus
 T4b tumor

Masticator Pterygoid
space plate

Internal
Skull
carotid
base
artery
 AJCC 2010 TNM Staging
(OCSCC)
• Lymph node status
– N1: single node ≤ 3cm
– N2a: single node, > 3cm, ≤ 6cm
– N2b: multiple nodes in single ipsilateral neck, ≤ 6cm
– N2c: bilateral or contralateral neck nodes, ≤ 6cm
– N3: single node >6 cm (very very rare)
• Stage
– I: T1 N0 M0 ( )
– II: T2 N0 M0 ( )
– III: T3 N0 M0, T1-3 N1 M0 ( )
– IVA: T4a N0-1 M0, T1-4a N2 M0 ( )
– IVB: AnyT N3 M0, T4b Any N M0 ( )
– IVC: Any T Any N M1 (best supportive care: pain, chemotherapy, etc.)
 AJCC 2017 8th edition OCSCC T-
Classification
T classification up-staged by depth of invasion (DOI):
T1: Tumor <= 2cm, <= 5mm depth of invasion (DOI)
T2: tumor <= 2cm, DOI > 5mm and <= 10mm
or tumor >2 cm but <=4 cm, and <= 10mm DOI
T3: tumor >4 cm or any tumor > 10mm DOI
  Old pT1 Old pT2 Old pT3 Total
 
Depth <=5mm 286 262 59 (18.0%) 607 (38.9%)
(74.5%) (30.9%)  
New pT2 92 (24.0%) 327 68 (20.7%) 487 (31.2%)
Depth >5, (38.6%)
<=10mm
New pT3 6 (1.6%) 259 201 466 (29.9%)
Depth >10mm (30.5%) (61.3%)
Total 384 848 (100%) 328 (100%) 1560
(100%) (100%)
 
T4: Extrinsic muscle infiltration is no longer a
staging
criterion for T4 designation in oral cavity, because
depth of invasion supersedes it and extrinsic
muscle invasion is difficult to assess (both clinically
and pathologically) Ebrahimi A, Gil Z, Amit M, Yen TC, Liao CT, Chaturvedi P,
68 pT4 tongue SCC (2010 AJCC 7th ed.) et al. Primary tumor staging for oral cancer and a
-- 63 extrinsic muscle alone (93%) proposed modification incorporating depth of invasion:
An International Multicenter Retrospective Study. JAMA
-- 4 extrinsic muscle + through cortex (6%) Otolaryngol Head Neck Surg. 2014 Dec;140:1138-48.
-- 1 extrinsic muscle + skin (1%)
Macroscopi Microscopi
c c
Clinical Outcomes in pT4
Tongue Carcinoma are Worse
than in pT3 Disease: How
Extrinsic Muscle Invasion
Should be Considered
Table 3. Multivariate Analyses of 5-year Loco-regional Control, Distant
Metastases, and Disease-free Survival in T3-T4 Tongue SCC Patients.
Risk factors (n) Loco-regional Distant Disease-free
control metastases survival
P; HR (95% CI) P; HR (95% CI) P; HR (95% CI)
pT4 tumor (68) 0.005; 2.064 ns 0.007; 1.884
(1.241-3.432) (1.187-2.989)
Pre-operative betel 0.015; 2.879 ns 0.004; 2.972
quid chewing (161) (1.230-6.742) (1.423-6.207)
Level IV/V 0.010; 2.500 ns ns
metastases (17) (1.247-5.011)
Perineural invasion 0.028; 1.856 ns ns
(114) (1.071-3.217)
Pathologic N2c (24) ns 0.001; 4.033 ns
(1.806-9.009)
Poor differentiation ns <0.001; 9.243 0.010; 2.132
(23) (4.311-19.817) (1.198-3.794)
Tumor depth > 10mm ns 0.024; 5.473 ns
(167) (1.246-24.038)
Margin status <= ns 0.047; 2.202 ns
4mm (29) (1.009-4.804)
Extra-nodal extension ns ns 0.001; 2.232
(78) (1.393-3.574)
Liao CT et al. Ann Surg Oncol. 2017 Sep;24:2570-2579.
AJCC 8th, 2017, T-status upstaged by DOI
T1: Tumor ≤2 cm, DOI ≤5 mm Reference of DOI for pT1-T3
T2: Tumor ≤2 cm, DOI >5 mm and ≤10 mm Ebrahimi A et.al JAMA Otolaryngol
or tumor >2 cm but ≤4 cm and DOI ≤10 Head Neck Surg 2014;140:1138-48
mm (international Consortium for
T3: Tumor >4 cm Outcome Research of OCSCC)
or DOI >10 mm
T4a: Through cortex/Skin invasion
AJCC 8th, 2018 (1st revision)
T1: Tumor ≤2 cm, DOI ≤5 mm
T2: Tumor ≤2 cm, DOI >5 mm and ≤10 mm
or tumor >2 cm, ≤4 cm, DOI ≤10 mm No reference for pT4a (DOI >20 mm)
T3: Tumor >4 cm
or DOI >10 mm but ≤20 mm
T4a: Through cortex/Skin invasion
or DOI >20 mm

AJCC 8th, 2018 (2nd revision)

T1: Tumor ≤2 cm, DOI ≤5 mm
T2: Tumor >2 cm but ≤4 cm
or tumor ≤2 cm, DOI >5 mm No reference for pT4a (tumor >4
T3: Tumor >4 cm cm and DOI >10 mm)
or tumor >2 cm but ≤4 cm and DOI >
10mm
T4a: Through cortex/Skin invasion
or tumor >4 cm and DOI >10 mm
pT3-4 tumor (n = 667) outcome analyses
Buccal/Gum/Hard palate/Retromolar
SCC Tumor >4 cm and DOI >10 mm vs. Figure 1
DOI >20 mm vs. Through cortex/Skin
invasion
 AJCC 8th edition Oral Cavity
Cancer zomm區分的能⼒最好
T4a-Classification
Tumor >4 cm/Depth >10 mm
AJCC 2018 2nd revision
Depth of invasion >20 mm
AJCC 2018 1st revision (X)
Skin/through cortex invasion
AJCC 3-8th edition

Liao CT et al. Ann Surg Oncol 2019;11:

3663-3672.
 AJCC 8th edition OCSCC N-Classification and
Staging
*N classification (both ENEma and
ENEmi are used to define
pathological ENE [+] nodal status)
ENEn (none)
ENEmi (microscopic ENE <=2mm)
ENEma (ENE > 2mm or gross ENE)

  Old pN1 Old Old Old Total

(Stage pN2a pN2b pN2c  
pN1: ENE (-) III/IVA) (Stage (Stage (Stage
IVA) IVA) IVA)
pN2a: old-pN1, ENE(+) ENE (-) 179 2 107 9 297
(69.6%) (22.2%) (27.4%) (11.8%) (40.5%)
pN3b: old-pN2a, ENE(+) ENE (+) 78 7 284 67 436
(30.4%) (77.8%) (72.6%) (88.2%) (59.5%)
pN3b: old-pN2b-pN2c, ENE(+) New New New New
pN2a pN3b pN3b pN3b
(Stage (Stage (Stage (Stage
pN3a: old-pN3 (single node >6 cm) IVA) IVB) IVB) IVB)
Total 257 9 391 76 733
 
 ⼆
⼝咽 的 staging
和其他有什麼不同

AJCC 2017 8th

N-classification
i 考慮35個 lymphnode
 AJCC 8 th
edition Oral Cavity
Cancer
N3-Classification
The pN3a classification currently in use is exceedingly rare,
accounting for 0%-0.10% of all OCSCC patients in large cohort
studies
AJCC
pN3-staging
: pN3a (n = 0)
pN3b (purple)

CG proposed
pN3-staging
: pN3a (red)
(pN+ ≤7/ENE ≤4)
pN3b (purple)
(pN+ ≥8/ENE ≥5)

Liao CT, Kang CJ, et al. Oral Oncol. 2018 Nov;86:188-94.

 Survival Analysis
(Surgery date to event/sensor)
• Local control (tumor relapse-free survival)
• Neck control (regional relapse-free survival)
• Loco-regional control
• Distant metastases
• Disease-free survival (DFS)
• Disease-specific survival (DSS)
• Overall survival (OS)
– 2nd/multiple primary
– other causes
 Statistics Applied (SPSS)
• Survivals
– Kaplan-Meier method (UVA)
• Significance (P value <0.05)
– log-rank test
– Cox logistic regression method (MVA)
• Significance (P value <0.05)
• HR (hazard ratio), 95% CI (confidence interval)
• Independent risk factors (MVA)
– The multivariate Cox models included all factors
that were identified in the univariate analyses.
– Forward/Backward selection(Stepwise), Enter(x),
– Scoring (grouping)
 (SPSS), > 200 /

Secondary Primary Overall Survival

Local Control Disease-free Survival
Neck Control Disease-specific Survival
Distant Metastases

19%/5-yr 85%/5-yr 85%/5-yr 10%/5-yr

66%/5-yr 71%/5-yr 79%/5-yr
 ― 1996
• :

( ) 6

• :
( ) ( 1 5 )

(T4b)
(T4b)

( )

48
 Taiwan OCSCC (n = 13750, 2011-2017)
vs. Liao’s OCSCC (n = 2263, 1996-2019)
Local Control Neck Control Distant
Metastases
90%/5-yr 95%/5-yr

3.4%/5-yr

Taiwan: Positive and close margins

50%

86%/5-yr 87%/5-yr

11%/5-yr

Liao: Positive and close margins

12%
Risk Stratifications
in
Oral Cavity Cancer
 /

30%-35% 5-6% 2-3%

10

(3 4 ) 70% 50% 40%

63%/4 60%/4 (SEER)

India: pan Taiwan

51
2018
Ten Leading Cancer in Taiwan (2018)
 Environmental Risk Factors of
OCSCCPotential risk exposure
Patient habits (Linkou CGMH)
Alcohol (A): ~ 60%
Betel quid (B): ~ 80%
Cigarette (C): ~ 85%
B + C: ~ 75%
A + B: ~ 55%
A + C: ~ 65%
A + B + C: ~ 50%
None: ~ 7%
(Liao CT et al., 2003-2017)
J Oral Pathol Med Ko YC et al., 1995
 OCSCC sub-sites and oral habit
1400

Subsites n %
1200
Tongue 1178 38.3
1000 Mouth floor 103 3.4

800
Lip 142 4.6

Buccal 1096 35.7

600

Gum 280 9.1

400
Hard palate 100 3.3
Frequency

200
Retromolar 173 5.6

Total 3072 100

0
to n g u e m o u th flo o r lip b ucca l g um h a rd p a la te re tro m o la r
Alcohol drinking: pre-OP (60%), post OP (15%)
Betel quid chewing: pre-OP (80%), post OP (1%)
Cigarette smoking: pre-OP (85%), post OP (25%)
Oral Cavity Cancer: Incidence, Survival, and
Treatment
1998 200
1 2003
Alcohol (liter)
Betel (Kg)
Cigarette (PC)

6041

5408

2084

Death
633

18
20
Liao CT et al. Oral Oncol 2014;50:721-31.
Early Stage OCSCC increasing in
⼝篩i 抓stageITaiwan
的case
: Oral Screening Since 1999

56
 T-status: Treatment, QOL, and
Outcome
Tx
{
QOL
{
NG: nasogastric tube; PG: percutaneous gastrostomy

T1: 91%/5-yr (21/276) T1: 84%/5-yr (49/276)

T2: 85%/5-yr (87/602) T2: 73%/5-yr (176/602)
T3: 74%/5-yr (62/257) T3: 57%/5-yr (117/257)
T4: 62%/5-yr (116/350) T4: 62%/5-yr (191/350)
P < 0.0001 P < 0.0001
Both survived, QOL different
 ) (

19
96

2.
1.
19
97
19
98
19
99

105
20
00
20
01
20
02
20
03
20
04
20
05
20
06
20
07
20
08
20

ICD-9-CM
09
20
10
20
11

ICD-10-CM
20
12
20
13
20
14
20
15
20
16
1995-2016

1,107
3,922
4,252

121
755
2,035

1,525
4,041
4,904

2,555
 Treatment Goals for OCSCC
• Increase controls and survivals
– Curative surgery

• Quality of life
– Functional preservation or restoration
• facilitate speech, swallowing, and chewing
• considerable cosmesis

– Minimize sequelae
 Clinico-Pathologic
data validation Problems-oriented Risk Stratification
&
organization Targeting Therapy
Genome-wide Association
Clinical Information Studies
•Microarray (Exon array)
•Risk factors analysis for (Image biomarkers) •Tissue array (IHC)
disease control
•Array CGH (SNP 6.0)
•Cosmetic and functional •Digital array (rt-PCR)
preservation •DNA sequencing-NHRI
•Quality of life •Tumor signaling pathways-
•Psychosocial support NHRI
•Lead compounds optimization-
NHRI
•Cytokine, Chemokine, Tumor
adhension molecules
•HPV
Back up
(Bio-Informatics)
Back up

• Genomic studies
• Pharmacogeneti
c studies • Tumor signaling
pathway
• Drug library
Hypothesis
Validation PI Initiated

National Institutes of MD Anderson

Health (US)
MSKCC, United
Stanford University States
Petach Tikva, Israel Tata Memorial
Hospital, India
Southern Illinois,
United States Tel Aviv, Israel
Cologne, Germany SHNCI, Australia
Sao Paulo, Brazil Camargo, Sao Paulo
Brescia, Italy Brazil
2 6
 2021 (1) margins ≤4 mm (2) ≤15

( )
30

0.27%

66
 :
1.3
(1 0.3 )
-- Liao CT et al. Ann Surg Oncol 2008;15:2187-94

: 14.30mm : 6.98mm
 AJCC T4b
• Definition of T4b tumor Surgical Outcome of T4a and Resected T4b
1 .0

OCSCC 1 .0

– AJCC 2002 6th edition

.9 .9

.8 .8

.7 T4a: 66%/5-yr .7

• unresectable tumor .6 .6
T4b: 49%/5-yr
DFS .5
T4b: 57%/5-yr .5 OS
– AJCC 2010 7th edition

D isease- free su rv iv al
.4 .4

.3 T4a: 45%/5-yr

O v erall su rv iv al
.3

• very advanced local disease

.2 .2

.1

P = 0.348 P = 0.776
.1

0 .0 0 .0
0 20 40 60 80 100 120 0 20 40 60 80 100 120

• Treatment of T4b tumor

M on th s M on th s

– NCCN 2019 Ver. II T4b Oral Cavity Cancer below the Mandibular
Notch
• clinical trial 1 .0
is Resectable with a Favorable Outcome
• non-surgical approach D isease- free Surv iv al Probability
.8

Infra-notch: 64.7%/5-yr
Supra-
(15% pt)

– Linkou CGMH Infra-

.6

(85% pt)
.4 P = 0.0004
• Initial surgery (>85%)
.2
Supra-notch: 14.3%/5-yr
0 .0
0 20 40 60 80 100 120

M onths

Liao CT et al. Cancer 2006;107:337-44. (cT4b)

Liao CT et al. Oral Oncol 2007;43:570-9. (supra-notch
T4b)
Liao CT et al. Oral Oncol 2013;20:230-6. (pT4b)
Liao CT er al. Ann Surg Oncol 2017;24:785-93. (Taiwan
69 T4b)
 Taiwan Cancer Registry
Database 1. Liao CT et al. Association between the
• diagnosis-to-treatment interval and overall
survival in Taiwanese patients with oral cavity
squamous cell carcinoma. Eur J Cancer. 2017;72:
226-34.
• 2004- long-form (Stage,
2. Liao CT et al. Clinical outcomes of Taiwanese
Treatment, Relapse) patients with cT4 oral cavity squamous cell
• Covering >98% of all Taiwanese crcinoma: Toward the identification of the optimal
initial treatment approach for cT4b patients. Ann
patients Surg Oncol. 2017;24:785-93.
• 2011- SS factors (depth, margin,
3. Liao CT et al. Comparative clinical outcomes of
extracapsular spread) Taiwanese patients with resected buccal and
• 2011- pre-treatment oral habit tongue squamous cell carcinomas. Oral Oncol.
2017;67:95-102.
(alcohol, betel, cigarette)
• OS, DSS ( ): OK 4. Tsai CY et al. Clinical outcomes of Taiwanese
patients with resected squamous cell carcinoma
• DFS: poor reliability of the upper and lower gum. Oral Oncol. 2021;118:
105334.
• Local/Neck control, distant
metastases: poor reliability 5. Liao CT et al. Clinical outcomes of Taiwanese
patients with resected oral cavity squamous cell
carcinoma who underwent reconstruction with
free versus local flaps. Ann Surg Oncol. 2021
accepted
Taiwan pT4a and pT4b tumors: 5-year DSS and
OSDisease-specific Survival: pT1-pT4b Overall Survival: pT1-pT4b
Original cohort:
-- pT4a: n = 4031
-- pT4b: n = 355
-- Depth ≥10 mm
(86%/pT4a; 93%/pT4b)
-- Positive margin
(10%/pT4a; 21%/pT4b)

C
Disease-specific Survival: pT4a- D
Overall Survival: pT4a-pT4b
pT4b Propensity
score
matching:
-- pT4a: n =
351
-- pT4b: n =
351
 AJCC

AJCC 8th Edition Oral Cavity Cancer T-

T classification:* Classification
T1: Tumor <= 2cm, <= 5mm depth of invasion (DOI)
T2: tumor <= 2cm, DOI > 5mm and <= 10mm
or tumor >2 cm but <=4 cm, and <= 10mm DOI
T3: tumor >4cm or any tumor > 10mm DOI
*Ebrahimi A, Gil Z, Amit M, Yen TC, Liao CT, et al JAMA
Otolaryngol Head Neck Surg. 2014 Dec;140:1138-48.

1 ” ” 2017 AJCC (T)

2012

International Consortium for

Outcomes Research of
OCSCC
(2013-2019:
2019 Head Neck. 11 publications)
2018 Cancer.
2016 Head Neck. (p.77, ref. 11; p.101, ref. 5; p.135, ref. 5)
2015 Ann Surg Oncol.
2014 JAMA Otolaryngol Head Neck Surg. (p.65, ref. 14;
p.94, ref. 5)
2014 JAMA Otolaryngol Head Neck Surg.
2014 Ann Surg Oncol. (p.94, ref. 6)
2014 Cancer. (p.77, ref. 10)
2013 Cancer.
2013 Br J Cancer. (p.77, ref. 20)
2013 Ann Surg Oncol. 2012 9 11
11
5 AJCC 2017 8 1/3
Ultra-deep Targeted Sequencing of Advanced Oral Squamous
Cell Carcinoma Identifies a Mutation-based Prognostic Gene
Signature
Genetic variants identified by NGS technology in FFPE samples are
clinically useful to predict prognosis in advanced OSCC patients.

A mutation-based signature affecting

ten genes (HRAS, BRAF, FGFR3, SMAD4,
KIT, PTEN, NOTCH1, AKT1, CTNNB1,
and PTPN11) was devised to predict
DFS.

Chen SJ, Liao CT et al. Oncotarget 2015;6:18066-80.

 An Ultra-deep Targeted Sequencing Gene Panel
Improves the Prognostic Stratification of Patients
with Advanced Oral Cavity Squamous Cell
ECS (-)
Carcinoma
ECS (-)

ECS (+) ECS (+)

pN+ grouping: score 0-3 (gene, pT3-4, ECS, n = 345)

Liao CT et al. Medicine. 2016; 95:e2751
 Oral Cavity Cancer Data (CG)
• Treatment of T4b oral cavity cancer AJCC 2002, AJCC 2010
– Cancer 2006;107:337-44
– Oral Oncol 2007;43:570-9
• Survival and skin preservation of buccal cancer
– Oral Oncol 2006;42:800-9
– Ann Surg Oncol 2008;15:2187-94
• Post-operative adjuvant therapy in p-stage III-IV, perineural invasion alone or pT1-2N0
– Cancer 2007;110:564-71
– Int J Radiat Oncol Biol Phys 2008;71:371-6
• Incidence and survival of second primaryOther
tumors in oral cavity cancer
– Oral Oncol 2007;43:811-9
than clinicopathological risk factors,
• Is (Are)
Prognosticator of local tumor control in oral there
cavity any prognosticators could
cancer
– Ann Surg Oncol 2008;15:915-22 predict outcome of OCSCC ?
• Post-operative treatment planning in different risk group of oral cavity cancer
– Cancer 2007;110:1501-8 -- Roles of molecular image
– Ann Surg Oncol 2009;16:159-70
• Timing of salvage therapy in relapsed oral cavity cancer
– Cancer 2008;112:94-103
• FDG PET in predicting survival of oral cavity cancer
– J Nucl Med 2005;46:775-81
– J Nucl Med 2005;46:1136-43
– J Clin Oncol 2006;24:4371-6
– Int J Radiat Oncol Biol Phys 2009;73:764-71
– Int J Radiat Oncol Biol Phys 2009;74:1054-61
– Eur J Nucl Med Mol I 2009;36:1783-93
– Int J Radiat Oncol Biol Phys 2010;77:421-9
– Clin Nucl Med 2011;36:963-4
– Oral Oncol 2011;47:288-95
– J Nucl Med 2011;52:180-7
– Eur J Nucl Med Mol I 2012;39:944-55
– Oral Oncol 2013;49:261-268
– PloS One 2013;8:e79766
– J Nucl Med 2015;56:22-30
 Radical Surgery

< 2 week s/p Operation 6 weeks Adjuvant RT/CCRT

Pre-RT/CCRT
Pre-OP 2nd PET/CT
1st PET/CT
for staging 1 .0
6.5% events
.9

.8

2nd FDG-PET findings: .7

24% events
D isease- free Su rv iv al

Neck recurrence/residual: 4/29 .6

-- change RT dose and fields .5

Distant metastases: 3/29 .4

-- palliation
.3

.2 With 2nd PET (29): 76%/2m, 59%/24m

NO 2nd PET(154): 93%/2m, 51%/24m
Change treatment P = 0.8044 (= 0.0013 at 2m)
.1

0 .0

: 24% (7/29) 0 2 4 6 8 10 12 14 16 18 20 22 24

M on th s
Liao CT et al. Eur J Nucl Med Mol I 2012;39:944-55.
 Pre-OP PET Pre-CCRT PET Post-RT 3m PET

35 y/o male, Right tongue SCC, pT2N2bM0. (a)(e)Pre-operative PET. (b)(f) Pre-
radiotherapy PET showed Left level I and level III node metastases (FNA cytology
proven). (c & g) RT dose escalation to these gross nodes with minimum 79.2Gy using
simultaneous-boost intensity-modulated RT. (d & h) Post-radiotherapy PET 3 months
Pre-adjuvant Therapy FDG-PET
for OCSCC Patients with ECS

Pre-OP PET: M0 Pre-CCRT PET: M1

 A combined analysis of
maximum standardized uptake
value on FDG-PET, genetic
markers, and clinicopathological
risk factors in the prognostic
stratification of patients with
resected oral cavity squamous
cell carcinoma
Liao CT et al. Eur J Nuc Med Mol Imaging. 2020;47:84-93.

MVA
*SUV_tumor ≥22.8/SUV_nodal ≥9.7
*ultra-deep targeted sequencing
(UDTS)/whole-exome sequencing
(WES)
* pN3b (ENE)
Close margins (2020)
 Association between Multidisciplinary Team Care
Approach and Survival Rates in Patients with Oral Cavity
Cancer Chang Gung
Team consensus
Case manager Guideline

1996 2001 2002 2004 2006 2008 2010 2015

LN clearance
Cisplatin
IMRT Dose painting Proton

Free flap,
FDG-PET PET-CT Pre-adjuvant PET PET-MRI
Margin

2004-2011

1996-2003
2008-2011: 74%/5-yr
2004-2007: 67%/5-yr, 61%/10-yr
2000-2003: 65%/5-yr, 51%/10-yr
1996-1999: 61%/5-yr, 51%/10-yr
p = 0.0246 (2008-2011 vs. 2004-2007)
p = 0.0510 (2004-2007 vs. 2000-2003)
p = 0.4097 (2000-2003 vs. 1996-1999)
p = 0.0002

Liao CT et al. Head Neck 2016;38 Suppl 1:E1544-53.

 Establish Oral Cavity Cancer
International Treatment
Guidelines

83
 • 10

2016 6000 (5817)

2000 (2042)

84
 :1996
• 1996 :
– ( 10 )
• (4 )+ (6 )
– ( 14 )
• (4 )+ (10 )
• 2
• 1996 :
–
– 2 ( 10 )
•
85
86
 ( )
•

– Hanasono MM, et al. Head Neck 2009;31:1289-96.

– Mucke T, et al. Ann Surg Oncol 2010;17:287-95.

87
88
89
 2004
Clinico-Pathologic
data validation Risk Stratification
Problems-oriented organization &
Targeting Therapy

Genome-wide Association
Clinical Information Studies
• Risk factors analysis for (Image biomarkers) •Microarray (Exon array)
disease control •Tissue array (IHC)
• Cosmetic and functional •Array CGH (SNP 6.0)
preservation •Digital array (rt-PCR)
• Quality of life •DNA sequencing-NHRI
• Psychosocial support •Tumor signaling pathways-NHRI
•Lead compounds optimization-
NHRI
•Cytokine, Chemokine, Tumor
adhension molecules
•HPV

Back up
(Bio-Informatics)
Back up

• Pharmacogeneti • Genomic studies

c studies • Tumor signaling pathway
• Drug library
Hypothesis
Validation PI Initiated

National Institutes MD Anderson

of Health (US)
MSKCC, United
Stanford University States
Petach Tikva,
Israel Tata Memorial
Southern Illinois, Hospital, India
United States Tel Aviv, Israel
Cologne,
Germany SHNCI, Australia
Sao Paulo, Brazil Camargo, Sao
Paulo
Brescia, Italy
5 Brazil
12 MD
Anderson Memorial Sloan
90 Kettering
91
 550

1996 2 550
92
93
Linkou CGMH

NTUH
Kaohsiung
CGMH

CCH

CMUH

KMUH

TVGH

TVTH

KFSYSCC
2015-2016

E-DAH

CMH

DMFCYCH

CMH

MMH

NCKUH

KVGH

Chiayi CGMH
OSCC

HTCH

LCMH

FEMH

TSGH

DTCH

TTMH

SMDPH

SKWHMH

NTUHYLB

Keelung CGMH

NTUHHCB

YGH

TTCH
Major Hospitals Specializing in Treating

SHH
 47%

26%

94
 5 (2012-2016)
: 3 10%

71.43%
60.66% 61.59%

3 10%
( / )
95
 5 (2004-2009)
: 30%

1
0.9
0.8
0.7 28%
0.6
0.5 35% 48%
0.4 31%
29%
0.3
0.2
19%
0.1
0
1 2 3 4 1-4

4 50%
20% 4 T4a, T4b
96 Liao CT et al. J Cancer Res Pract. 2015;2:103-16.
 : T4b
/
30%-35% 5-6% 2-3%
10
(T4b) (T4b)

(3 4 ) 70% 50% 40%

63%/4 60%/4 (SEER)

AJCC    
NCCN

97
 T4b :

98
 (1): NCCN T4b
• NCCN T4b

•
– : T4b

– :
– : T4b

99
 2003

Deep margin:
12mm
100
 T4b 5

T4b
101
 AJCC T4b
1 .0

2006 Cancer : .9

.8

T4b T4a .7

-- AJCC T4b .6
T4b: 49%/5-yr
.5

• Definition of T4b tumor .4

T4a: 45%/5-yr
– AJCC 2002 6th

O v erall su rv iv al
edition
.3

.2

• unresectable tumor .1

P = 0.776
– AJCC 2010 7th edition 0 .0

0 20 40 60 80 100 120

• very advanced local disease M on th s

• Treatment of T4b tumor

– NCCN 2019 Ver. III 4 T4b :
Liao CT et al. Cancer 2006;107:337-44. (cT4b)
• non-surgical approach Liao CT et al. Oral Oncol 2007;43:570-9. (supra-notch
• clinical trial T4b)
Liao CT et al. Oral Oncol 2013;20:230-6. (pT4b)
– Linkou CGMH Liao CT er al. Ann Surg Oncol 2017;24:785-93. (Taiwan
• Initial surgery (85%) T4b) 66%T4b
• 50%

102
 ( 1): T4b
•
•

103
 (2): NCCN
( )
• NCCN T3 (>4 >2
>1 )
( )
•
– :
1 ( ) ?
– : ( )
– : T3 2
( )

104
 • : 55%
• : 33%

105
 •
– 4-20%
•

106
 T3

( 72 )

T3

107
 ― 1996
• :

( ) 6

• :
( ) ( 1 5 )

(T4b)
(T4b)

( )

6
108
 “ ”

“
” Tata
Memorial MD
Anderson

2008

Liao CT et al. Int J Radiat Oncol Biol Phys. 2019 Sep. [Epub]

109
( 2) NCCN
Precision Adjuvant Therapy Based on Detailed  CGMH NCCN
Pathological Risk Factors for Resected Oral
Cavity Squamous Cell Carcinoma  CGMH – T3
: Long Term Outcome Comparison of CGMH
and NCCN Guidelines
 CGMH – 2 ( )

 CGMH VS. NCCN

 28% ( )
 ( )
 ( ) ( )
28%
(160/571)  ( )
 ( )
 2008~2016 6,772
3 3 6
 2016
Lin CY, Liao CT et al. Int J Radiat Oncol Biol Phys. 2019 Sep. [Epub]

110
 373
AJCC T4b pubmed
(ASTRO)
111
 / Tata Memorial MD
Memorial Sloan Anderson
(India) Kettering  
741 555 300 508 100 100

5 I/II/III/IV - - - - -
81/76/71/46%
1

pT4a 5 55% (pT4a)2 25%3 - - - -

 
T1-2 5 88%4 - 83%5 - - -
 
pT4 80%/5 - - 50%/3 - -
(T4b)2 (T4b)6
78%/5 41%/3
(T4a)2 (T4a)6
pT4 5 68% (pT4b)2 - - - 54%7 -
60% (pT4a)2
5 76%8 - - - - 63%9
1. 2012 2016 /
3 10% 2. Liao CT, et al. Oral Oncol. 2013;49:230-236. 3. Cheng SJ, et al. Head Neck. 2018;40:144-153. 4. Liao CT, et al.
Ann Surg Oncol. 2007;15:915-22. 5. Tai SK, et al. Ann Surg Oncol. 2012;19:1995-2002. 6. Mair MD, et al. Oral Oncol. 2018;82:17-22. 7. Zanoni DK, et al. Oral Oncol.
2019;90:115-121. 8. Liao CT, et al. Oral Oncol. 2006;42:800-809. 9. Diaz EM, et al. Head Neck. 2003;25:267–73.

5 10% Tata 30%

112
 • T4b
30% AJCC
T4b !
• NCCN
30% ( )
( )
(2008 1000
)
•

113
114
115