2. Anatomic Sites of Head and Neck
Cancer
• Heterogeneous group of cancers; varying primary sites
• Squamous histology in 95% of cases
• Anatomic sites
– Oral cavity
– Nasopharynx/oropharynx/hypopharynx
– Larynx
• Other anatomic sites
– Paranasal sinuses
– Lip
– Salivary glands
1. Adapted from: SEER training modules, head & neck cancer. National Institutes of Health, National Cancer Institute.
Oral Cavity
Lip
Buccal mucosa
Alveolar ridge
Retromolar
trigone
Floor of mouth
Hard palate
Oral tongue
(anterior two
thirds)
Larynx
Supraglottis
Glottis
Subglottis
Nasal Cavity
Tongue
Esophagus
Jaw
Nasopharynx
Oropharynx
Base of tongue
Soft palate
Tonsillar pillar
and fossa
Hypopharynx
Pharynx
4. HNSCC: Overview
• 2 different etiologies and corresponding tumor types
– Tobacco smoking and alcohol consumption (HPV-)
– Infection with high-risk HPV (HPV+); largely limited
to oropharyngeal cancers
• HPV+ tumors are distinct entity with better prognosis and may require differential
treatments
• Given recent genomic studies, etiology of differential biology of HPV+ and HPV- is
now increasingly evident[4,5]
2. Globocan Project. Geneva: World Health Organization; 2010. 3. Siegel R, et al. CA Cancer J Clin.
2013;63:11-30. 4. Wilting SM, et al. BMC Med Genomics. 2009;2:32. 5. Hayes DN, et al. ASCO 2013
Clinical Science Symposium. Abstract 6009.3. Siegel R, et al. CA Cancer J Clin. 2013;63:11-30. 4. Wilting SM, et al. BMC Med Genomics. 2009;2:32. 5. Hayes DN, et al. ASCO
2013 Clinical Science Symposium. Abstract 6009.
6. HNSCC: Etiology
HPV-Positive HNSCC HPV-Negative HNSCC
Anatomic site[7-9] Oropharynx (tonsil/base of tongue, soft palate) All sites/upper aerodigestive tract
Histology[10] Basaloid Keratinized
Age[9,11] Younger; healthier Older; higher rate of comorbidities
Sex[12] 3:1 men (unclear why) 3:1 men (due to tobacco use)
Socioeconomic status Tends to be high Tends to be low
Risk factors[9,11,13] Sexual behavior Tobacco
Cofactors[14,17,19] Marijuana/immune suppression (eg, HIV) Tobacco/alcohol
Incidence[11,12] Rising rapidly Declining
Survival[9,13] Improved Worse
2nd cancers[11] Uncommon Common (including lung cancer)
7. Smith EM, et al. J Natl Cancer Inst. 2004;96:449-455. 8. Herrero R. J Natl Cancer Inst Monogr. 2003;31:47-51.
9. Fakhry C, et al. J Clin Oncol. 2006;24:2606-2611. 10. Poetsch M, et al. Head Neck. 2003;25:904-910.11. Chaturvedi AK, et al. J Clin
Oncol. 2008;26:612-619. 12. Cole L, et al. PLoS One. 2012;7:e32657. 13. Ritchie JM, et al. Int J Cancer. 2003;104:336-344. 14. Gillison
ML, et al. J Natl Cancer Inst. 2008;100:407-420. 17. D’Souza G, et al. J Acquir Immune Defic Syndr. 2013. [ePub ahead of print] 19.
D’Souza G, et al. N Engl J Med. 2007;356:1944-1956.
7. Head & Neck Cancer
LIP CANCER
CANCER OF
BUCCAL
MUCOSA
TONSIL
CANCER
TONGUE CANCER
8. Staging overview
T and N stages vary by anatomic site
≥N2 or T4 tumours locoregionally advanced (Stage IV)
Typically T1: ≤2 cm, T2: 2-4 cm, T3: ≥4 cm, T4: invades adj. structures
N1: single LN ≤3 cm, N2: LN ≥2 cm or several LN, N3: >6 cm
TNM: tumour nodes metastases
Stage
Patel SG, et al. CA Cancer J Clin 2005;55;242-
258
TNM
Stage 0 TisN0M0
Stage I T1N0M0
Stage II T2N0M0
Stage III T3N0, T1-3N1, M0
Stage IVA T4a N0-2,M0, T1-3N2,M0
Stage IVB
Stage IVC
Any T, N3, M0, T4b, Any N, M0
M1, any T or N
9. HNSCC: Survival Rates by Stage of
Disease
• High cures rates are achieved for
localized and loco-regional disease
using:
– Surgery
– Radiation
– Chemoradiation
– ± Induction chemotherapy
• Survival rates for recurrent/
metastatic disease remain
very poor
• Better treatment options are
necessary
6. SEER. Stat fact sheets: oral cavity and pharynx cancer. 2003-2009.
5-Yr Relative Survival Rate
by Stage at Diagnosis[6]
Survival(%)
Localized Distant
83%
59%
Regional
36%
0
20
40
60
80
100
10. HNSCC: HPV Survival Advantage
• OS by HPV status in TAX 324[22]
• Risk classification according to most influential prognostic
factors to predict OS[23]
– 43% low risk: HPV+ with ≤ 10 pk-
yrs or > 10 pk-yrs and N0-N2a
cancer
– 30% intermediate risk: HPV+ with
> 10 pk-yrs or HPV‒ with ≤ 10 pk-
yrs and T2-T3 cancer
– 27% high risk: HPV‒ with ≤ 10 pk-
yrs and T4 cancer or > 10 pk-yrs
– 3-year OS: 93.0% low-risk group,
70.8% intermediate-risk group,
and 46.2% high-risk group
22. Posner MR, et al. Ann Oncol. 2011;22:1071-1077. 23. Ang KK, et al. N Engl J Med. 2010;363:24-35.
HPV+
HPV-
1.00
0.80
0.60
0.40
0.20
0
0 12 24 36 48 60 72 84 96 108 120
Survival Time, months
HPV+
HPV-
Pts at Risk, n
HPV+
HPV-
56 53 51 49 42 40 35 20 13 3
55 58 27 23 22 20 10 6 3 2
P = 6.63e-8
SurvivalDistributionFunction
11. DIAGNOSIS AND TUMOR STAGING
Histological examination – very important
Primary treatment -requires tissue diagnosis used to predict
distant metastasis
Radiologic imaging
MRI is generally more preferable and can obtain functional
imaging indicative of tumor grade.
PET combined with a CT scan using FDG has been
incorporated in the NCCN guideline as patients who
appear to have stage III and IV disease and as an
investigation for detection of occult primaries presenting
only with metastatic neck.
Gross anatomical and pathological descriptors are used for
TNM staging. Apollo Medicine 2012 JuneVolume 9, Number 2; pp.
14. Management
• SURGERY – early stages
• Radiotherapy – primarily – organ preservation+ ; or adjuvant after surgery
• Chemotherapy – Adjuvant along with RT ; palliative
• Targeted therapy – Along with primary RT / recurrent settings
15. Surgery
• First choice when possible, but often limited by disfigurement and
preservation of organ function such as speech and swallowing
Radiation
• Most head and neck cancer is sensitive to radiation while preserving organ
function
• Daily treatment lasts for 6-8 weeks
• Side effects can be severe; permanent dry mouth, oral ulcers,
osteoradionecrosis of the mandible, altered taste, weight loss, and tooth
decay.
Chemotherapy
• Can have dramatic response to treatment, but is often not a durable response
• Side effects can also be severe; decreased blood counts, anemia, infections,
weight loss, nausea, vomiting, and hair loss.
• Newer targeted therapies have lower side effects
TREATMENT STRATEGIES
16. CHEMOTHERAPY IN H&N CANCERS
• Used mainly in locally advanced setting
– Induction chemotherapy
– Concurrent CHEMO-RT
– Sequential INDUCTION ---- > CHEMO-RT
• Metastatic setting - palliation
20. CURATIVE SETTING
• Concurrent CT-RT – MACH NC Meta analysis / VALCSG trial
– 6.5% decrease in mortality ; HR of 0.81
• Induction chemotherapy --- Sequential CT/RT
– TAX 323/324 trials = superiority of DCF regimen followed weekly Carbo + RT
( earliest )
– DeCIDE / PARADIGM trials using DCF induction presented ASCO 2012
– All these trials showed superiority in CR rates but no stat sig PFS / OS
benefit
• Induction = more toxic
• Benefit not clearly seen in older patients
21. 5-FU, 5-fluorouracil; CI, confidence interval; HR, hazard ratio; RT, radiation therapy; SCCHN, squamous cell carcinoma of the
head and neck; TPF, docetaxel, cisplatin, 5-fluorouracil; Ctx: chemotherapy
1. Pignon JP, et al. Lancet 2000;355:949-955; 2. Bonner JA, et al. Lancet Oncol 2009;11:21-8;
3. Vermorken JB, et al. N Engl J Med. 2007;357:1695-1704; 4. Posner MR, et al. N Engl J Med 2007;357:1705-
1715.
Nonsurgical treatment options for
locally advanced HNSCC
22. HNC, head and neck cancer; MACH-NC, meta-analysis of chemotherapy in head and neck cancer; SCC, squamous cell
carcinoma; ORR, overall risk reduction; RR, relative risk.
Pignon JP, et al. Lancet 2000;355:949-955
63 randomised trials (1965-1993)
n = 10,717 pts with SCC of the oropharynx, oral cavity, larynx, or
hypopharynx
Comparison of locoregional treatment with and without
chemotherapy
Median follow-up: 6 years
Overall benefit4% at 5 years (32% vs. 36%)
Absolute benefit (5 Yrs), %
Meta-analysis of chemotherapy in HNC
(MACH-NC)
23. MACH-NC, meta-analysis of chemotherapy in head and neck cancer; IC: induction chemotherapy
Pignon JP, et al. Radiother Oncol 2009;92:4-
14
MACH-NC: An Update
24 added trials–87 studies, 16,485 patients
MACH-HN I: 8% absolute benefit concurrent-no significant effect of IC
No significant difference (p = 0.19) was seen between
mono-chemotherapy (HR 0.84) and poly-chemotherapy (HR 0.78)
In the mono-chemotherapy group, the effect of chemotherapy was
significantly higher (p = 0.006) with platin than with other types of mono-
chemotherapies
Age matters
Younger than 50 years of age: 24% increased survival
Older than 70 years of age: 3% increased survival
25. Trial Eligibility Target N*
Control
Tx
Exp Tx OS
DeCIDE
U Chicago
N2-3
400
285
DHFX
TPF x 2
DHFX
NS
Paradigm
DFCI
Stages III-IV
300
145
Cisplatin
CB-RT
TPF x 3
Carbo-RT or
D-CB-RT
NS
SWOG Oropharynx 400
Cisplatin
RT
TPF x 1-3
surgery or
cisplatin-RT
Carbo, carboplatin; CB, concomitant boost; chemoRT, chemoradiation therapy; DFCI, Dana-Farber Cancer Institute;
RT, radiation therapy; TPF, docetaxel, cisplatin, 5-fluorouracil. DHFX, docetaxel, fluorouracil, and hydroxyurea
*All powered to show survival difference of 10% to 15%.
Randomized trials of sequential therapy*:
Definitive chemo RT ± induction
26. RANDOMISE
Location
1. Glottic
2. Supraglottic
T Stage
1. T2
2. T3, fixed cord
3. T3, no cord fixation
4. T4, with base of tongue ≤ 1 cm
N Stage
1. N0, N1
2. N2, N3
STRATIFY
Chemotherapy
Arm 1: cisplatin 100 mg/m2/5-FU 1 gm/m2/24 hrs CVI x 120o q3wks x 3
Arm 2: cisplatin 100 mg/m2 Days 1, 22, 43 of RT
Arm 1:
Arm 2:
Arm 3:
CR, PR x 3 d cycle RT
CDDP/5-FU
x 2 cycles
NR surgery RT
Radiation therapy + CDDP
Radiation therapy
RTOG 9111: Larynx Preservation Trial-
concomitant therapy
Forastiere AA, et al. N Engl J Med 2003;349:2091-2098
Phase III larynx preservation trial: induction chemotherapy and radiation
therapy vs. concomitant chemotherapy and radiation therapy vs. radiation
therapy alone
27. Conclusions
RT/cDDP: stat signif in LFS (P = 0.01)
No SS diff in survival
5-FU, 5-fluorouracil; cDDP, cisplatin; DFS, disease-free survival; DMFS, distant metastasis-free survival; FS, free survival;
KPS, Karnofsky performance score; LFS, laryngectomy-free survival; OS, overall survival; RT, radiation therapy;
SGL, supraglottal larynx; SS, statistically significant.
Forastiere AA, et al. N Engl J Med 2003;349:2091-2098
RTOG 9111: Larynx Preservation Trial
The median follow-up among surviving patients, 3.8 years
Demographics: median age 59 years; 94% KPS 80; 50% N0; 68% SGL;
28% N2-3
30. Trial
3. Bachaud JM, et al. Int J Radiat Oncol Biol Phys. 1991;20:243-246.
RT (Gy)
F/U,
mos
LRC, % DFS, % OS, %
RTOG 9501[1]
≥ 2 LN, ECE, +
margins
n = 459
(60-66)
46
81 vs. 70
(P = 0.01)
33 vs. 25
(P = 0.04)
45 vs. 38
(P = 0.19)
EORTC 22931[2]
N2-3, ECE, +
margins
n = 350
(66)
60
82 vs. 69
(P = 0.007)
47 vs. 36
(P = 0.04)
53 vs. 40
(P = 0.002)
Bachaud[3]
+ ECE
n = 83
(> 60)
60
70 vs. 55
(P = 0.05)
45 vs. 23
(P < 0.02)
36 vs. 13
(P < 0.01)
DDP, cisplatin; CT, chemotherapy; DFS, disease-free survival; ECE, extracapsular extension; F/U, follow-up;
LN, lymph node; LRC, locoregional control; OS, overall survival; RT, radiation therapy;
HNSSC, head and neck squamous cell carcinoma
1. Cooper JS, et al. N Engl J Med. 2004;350:1937-1944; 2. Bernier J, et al. N Engl J Med. 2004;350:1945-1952;
Adjuvant Trials: HNSCC RT ± CT (DDP)
31. Cooper JS, et al. N Engl J Med 2004;350:1937-1944; Bernier J, et al. N Engl J Med 2004;350:1945-
1952;
Risk stratification
Category Standard of care
Favourable None
Ang KK, et al. Int J Radiat Oncol Biol Phys 2001;51:571-578
Low 56-60 Gy
Intermediate (ECE-/margin-) 60-66 Gy
High (ECE+/margin+) 60-66 Gy + cisplatin
Refining adjuvant therapy
35. Pluses and minuses of
chemo radiation
Improves locoregional control
Facilitates organ preservation
Beneficial impact on survival
Doubles the rate of severe acute mucositis
Use may be excessive based on stage
Long-term functional deficits in speech, swallowing, mobility
37. Psyrri A, Presented at ASCO 2013 Lecture: EGFR, new data and best use of inhibitors (adapted from
http://www.slideshare.net/melodyhsiao/scchn-cancer-report
1. Psyrri A, et al. Clin Can Res 2005;11:5856-62; 2. Baumann M, Krause M. Radiother Oncol 2004;72:257‒266;
3.Ang KK, et al. Cancer Res 2002;62:7350–7356
EGFR as a molecular target in HNSCC
EGFR expression linked to poorer outcome1 and reduced response to
radiotherapy2,3
38. Strategies to improve outcomes in
HNSCC utilizing EGFR inhibitors
CRT: chemoradiotherapy; OS: overall survival
Treatment intensification of locally advanced HNSCC to improve OS
Randomised trials: CRT+EGFR inhibitor versus CRT
EGFR inhibition in the post-induction setting to reduce toxicity in
sequential design
Randomised phase II studies of induction chemotherapy followed by
either chemoradiotherapy or cetuximab radiotherapy to reduce toxicity
without compromising efficacy
39. RANDOMISED
Primary endpoints: Overall survival, locoregional control
Arm 2 (RT + C)
Radiation therapy +
cetuximab wkly
n=211
Arm 1 (RT)
Radiation therapy
n=213
Patients with locoregionally
advanced squamous cell
carcinoma of either the
oropharynx, hypopharynx, or
larynx
N=424
Bonner JA, et al. N Engl J Med 2006;354:567-578
Radiotherapy plus Cetuximab for Squamous-Cell
Carcinoma of the Head and Neck
international phase 3 study
40. Results & Conclusion
Cetuximab plus radiotherapy
is superior to radiotherapy
alone in increasing both the
duration of locoregional
disease control and survival
in locoregionally advanced
head and neck cancer.
Bonner JA, et al. N Engl J Med 2006;354:567-578
41. TPF (153 patients)
3 cycles, 1 cycle q3w T = 75
mg/m² on day 1 P = 75 mg/m² on
day 1
F = 750 mg/m² on day 1 to 5
60 patients: RT 70 Gy
Cisplatin 100 mg/m² on days 1, 22 and 43
56 patients: RT 70 Gy ERBITUX 400 mg/m² 1
wk prior to RT then 250 mg/m² weekly on wks
1 to 7
R
Total laryngectomy
+ post-op RT< PR
23
≥ PR
116
P: cisplatin; F: 5-fluorouracil; T: docetaxel; TL: total laryngectomy; PR: partial response ; RT: radiotherapy;
CT: computed tomography; Tx: treatment
Lefebvre JL, et al. J Clin Oncol 2013;31:853-859
The randomized Phase II
Study:TREMPLIN
chemoradiotherapy vs bioradiotherapy
Previously untreated SCC larynx/hypopharynx suitable for TL
Primary endpoint: Larynx preservation 3 months after treatment
Secondary endpoints: Larynx function preservation and survival
18 months after treatment
42. Cisplatin
n = 58
ERBITUX
n = 56
p-value
Grade 3 mucositis
Grade 4 mucositis
25 (43%)
2
24 (43%)
1
NS
Grade 3 in field skin toxicity
Grade 4 in field skin toxicity
14 (24%)
1
29 (52%)
3
< 0.001
Other toxicities, any grade,
justifying a protocol
modification
Renal toxicity
Hematological toxicity Poor
general condition Infusion-
related reaction
9 (15.5%)
8 (14.0%)
7 (12.0%)
0
0
0
1 (1.7%)
3 (5.0%)
Protocol modification due to
acute toxicity
33 (57%) 19 (29%) 0.02
Acute toxicity during RT
*2 patients did not start the treatment in the cisplatin arm
Lefebvre JL, et al. J Clin Oncol 2013;31:853-859
43. Primary endpoint
(3 months after end of Tx)
Cisplatin
n = 60
ERBITUX
n = 56
p-value
Larynx preservation, n (%)
(larynx in place without tumour)
57 (95%) 52 (93%) 0.63
Secondary endpoints
(18 months after end of Tx)
NB: 1 pt lost to FU in the Cisplatin arm is considered as failure
Lefebvre JL, et al. J Clin Oncol 2013;31:853-
859
Cisplatin
n = 60
ERBITUX
n = 56
p-value
Larynx function preservation, n (%)
(larynx in place without
tumour/trach/feeding tube)
NB: At 18 months or at death
52 (87%) 46 (82%) 0.68
Overall survival
NB: Since randomisation
92 % 89 % Log-rank: 0.44
Endpoints (ITT)
There is no evidence that one treatment was superior to the other or could improve the
outcome reported with ICT followed by RT alone
44. Stratification factors: cN-stage (cN0-2a vs. cN2b- cN3), cT-stage (T1-2 vs.T3-4)
Zuprod Performance Status (0 vs. 1), smoking history (<10py vs. >10py)
Stage III/IV
Oropharynx
p16+
N= 849
RANDOMISED 1:1
II: Accelerated IMRT
70 Gy/6 weeks (cetuximabx8)
I: Accelerated IMRT 70 Gy/6 weeks
(cisplatin 100 mg/m², d1, 22)
Radiotherapy plus cetuximab or cisplatin in human
papillomavirus-positive oropharyngeal cancer (NRG
OncologyRTOG 1016): a randomised, multicentre,
non-inferiority trial
Gillison M et alwww.thelancet.com Published online November 15, 2018
45. Radiotherapy plus cetuximab did not meet the criterion for non-inferiority for overall
survival relative to radiotherapy plus cisplatin. In this randomised trial exclusive to
patients with HPV-positive oropharyngeal carcinoma.
Radiotherapy plus cisplatin is the standard of care.
Gillison M et alwww.thelancet.com Published online November 15, 2018
Results and Conclusion
46. Author
CRR: complete response rate
# pts Treatment Comparator
Primary
endpoint
Setting S vs. E
P
value
Giralt et al.
2012
150 C+EBRT+P C+ EBRT 2 yr LRC
Locally
advanced
68%
vs.
61%
0.3
Martins et al.
2013
204
C+RT+
Erlotinib
C+RT
CRR
Locally
advanced
40%
vs.
52%
0.08
Ang et al.
2011
895
C+RT+
cetuximab
C+RT PFS
Locally
advanced
64%
vs.
63%
NS
C: cisplatin; EBRT: external beam radiation therapy; RT: radiation therapy; S: standard, E: experimental arm; P: Panitumumab;
Randomized trials of EGFR inhibitor
plus chemo radiation in HNSCC
48. Nimotuzumab in combination with concurrent radiotherapy
and cisplatin versus radiotherapy and cisplatin alone, in
locally advanced squamous cell carcinoma of the head and
neck.
phase 3 randomized study to evaluate the efficacy and toxicity of addition of Nimotuzumab during
concurrent chemoradiation in locally advanced squamous head and neck cancer.
primary endpoint: progression free survival (PFS)
secondary endpoints: disease free survival (DFS), duration of locoregional control (LRC)
and overall survival (OS).
Clinical trial information:CTRI/2014/09/004980. J Clin Oncol 36, 2018 (suppl; abstr 6000)
Adult subjects (age ≥
18 years), with stage
III-IV, LASHNC,
Karnofsky
performance status of
≥ 70 and adequate
organ
function (N=536)
Radical radiotherapy (66-
70 Gy) with weekly
cisplatin (30 mg/m2)(CRT
arm)
Same schedule of
chemoradiation along with
weekly Nimotuzumab (200
mg) (NCRT arm)
Randomized 1:1
49. Results & Conclusion
The median follow up was 33.0 months (95%CI 30.7-35.2 months).
The PFS was significantly longer in the patients treated in the NCRT arm (2
year PFS 58.9% versus 49.5%, HR = 0.74; 95% CI 0.56-0.95; P = 0.022).
The median duration of PFS was 60.3 months (95% CI 29.4-NA) in the
NCRT arm (P = 0.023) and 21 months (95% CI 15.1-NA) in the CRT arm.
Addition of Nimotuzumab improved the LRC (HR = 0.75; 95% CI 0.57-
0.97, P = 0.030), DFS (HR = 0.75; 95% CI 0.57-0.97, P = 0.030) and had a
trend towards improvement in OS (HR = 0.85, 95% CI 0.65-1.10, p =
0.222).
Grade 3-5 adverse events (CTCAE version 4.03) were similar between the 2
arms except for the higher incidence mucositis in the NCRT arm (66.7%
versus 55.8%, p = 0.010).
Nimotuzumab in combination with cisplatin and radiotherapy was
superior to cisplatin and radiotherapy in improving the PFS, LRC and DFS.
This combination provides a new therapeutic option in the
armamentarium against LASHNC.
Clinical trial information:CTRI/2014/09/004980. J Clin Oncol 36, 2018 (suppl; abstr 6000)
50. Neck Dissection
Always: Patients who have any clinically apparent residual
disease after chemo radiotherapy
If surgical salvage is necessary for the primary tumor, a neck
dissection may be required to access the primary or for donor
vessels for free flap reconstruction
Observation is acceptable if: No lymph node or lymph node <1
cm at CT/MRI and negative PET/CT after chemo radiotherapy
51. Conclusions
Cisplatin chemo radiotherapy remains the standard of care for locally
advanced (LA) HNSCC
Cetuximab is approved with radiation for LA-HNSCC
TPF is the preferred induction regimen
Sequential therapy is not superior to chemo radiotherapy alone
HPV-positive patients constitute a separate prognostic and therapeutic
cohort
Weekly cisplatin is not non inferior to 3 weekly cisplatin
chemoradiation.
Nimotuzumab in combination with chemoradiation appears to be a
promising therapy.
Evolving understanding of genetic profiling in patients with HNSCC
may allow for development of additional targeted therapy: Promising
new targets include: PI3K, FGFR, CCND1, PD1/PD-L1
HNSCC is the 6th most common malignancy worldwide, and
treatment options remain an unmet needs for patients with this
disease