Head and Neck Squamous Cell Carcinoma (HNSCC) · 2020-06-15 · HNSCC, head and neck squamous cell...

Head and Neck Squamous Cell Carcinoma

(HNSCC)

Medical Education

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Procedure ID: 5955. Slides last updated: 31st March 2017.

HNSCC epidemiology

HNSCC, head and neck squamous cell carcinoma.

This information is from an international website which is intended for healthcare professionals not located in the United States of America (US) and the United

Kingdom (UK).

3

What is head and neck cancer?

1. Stewart BW and Wild CP. 2014 (eds). World Cancer Report. Lyon: WHO IARC Press, 2014. pp. 423; 2. Ferrarotto R, Gold K A. Expert Opin Investig Drugs 2014;23(1):135–

43; 3. Mountzio G, et al Ann Oncol 2014;25(10):1889–900; Image from: https://www.cancer.gov/types/head-and-neck/head-neck-fact-sheet.



Kingdom (UK).

Head and neck cancer is the term used to describe a wide range of tumours originating in the upper airway and swallowing tract (e.g. lip,

oral cavity, tongue, throat and voice box)1

Despite the variety in location of head and neck cancers, they are mostly of the same

cell type,1 with 90% being HNSCC2

HNSCC is a heterogeneous disease with multiple aetiologies, resulting in distinct

molecular subsets of tumours with different biological and clinical characteristics3

4

Global incidence of head and neck cancer

• Worldwide, head and neck cancer accounts for more than 550,000 cases annually1

1. Head and neck cancer. Union for International Cancer Control 2014 Review of Cancer Medicines on the WHO List of Essential Medicines.

http://www.who.int/selection_medicines/committees/expert/20/applications/HeadNeck.pdf (Accessed: March 2017); 2. Siegel RL, et al. Cancer Statistics, 2017. CA Cancer J

Clin 2017;67:7; 3. Gatta G, et al. Eur J Cancer 2015; 51:2130; 4. Bray F, et al. Int J Cancer 2013;132:1133; 5. Lambert R et al. Eur J Gastroenterol Hepatol 2011;23:633.



Kingdom (UK).

In the US, approximately

62,000 Americans develop

head and neck cancer

annually2

In Europe, there were

approximately 140,000

cases in 20123

Mouth and tongue cancers

are the most prevalent

cancer type in Indian men4

Nasopharyngeal cancer is

endemic in South East Asia5

5

Older males are more commonly affected by HNSCC

1. Head and neck cancer. Union for International Cancer Control 2014 Review of Cancer Medicines on the WHO List of Essential Medicines.

http://www.who.int/selection_medicines/committees/expert/20/applications/HeadNeck.pdf (Accessed: March 2017); 2. Forman et al 2014 ,Vol x, IARC Scientific Publications

164; 3. Vigneswaran et al Oral Maxillofac Surg Clin North Am 2014;26(2):123–41; 4. De Santis et al CA Cancer J Clin 2013;63:151–66.

Males are affected significantly more

than females with a ratio ranging from 2:1

to 4:11

The incidence in males exceeds 20 per 100,000

in regions of France, Hong Kong, the

Indian subcontinent, central and eastern Europe, Spain, Italy, Brazil, and among

African Americans in the US2

The risk of contracting HNSCC increases with age.

The majority of cases occur in people of

over 50 years of age, and it is more

common in men3

The incidence of laryngeal cancer, but not oral cavity and

pharyngeal cancer, is approximately 1.6

times higher in African American

men4



Kingdom (UK).

6

Global mortality caused by HNSCC

1. Machiels JP, et al. BMC Cancer 2014;14:473; 2. Head and neck cancer. Union for International Cancer Control 2014 Review of Cancer Medicines on the WHO List of

Essential Medicines. http://www.who.int/selection_medicines/committees/expert/20/applications/HeadNeck.pdf; 3. Siegel RL, et al. CA Cancer J Clin 2017;67(1):7;

4. Gatta G, et al. Eur J Cancer 2015;51:2130; 5. Settle K, et al. Cancer Prev Res 2009;2(9)776–81.

HNSCC, head and neck squamous cell carcinoma; HPV, human papillomavirus.


Kingdom (UK).

Prognosis for patients with

recurrent/metastatic HNSCC is very poor, and despite ongoing

efforts to develop new therapy options, treatment of this type

of cancer remains challenging1

300,000 deaths are caused by HNSCC

each year2

13,000 deaths in the US3 and 63,500

deaths in Europe in 20124

The mortality associated with both

laryngeal and oropharyngeal

cancer is significantly higher in African American men,

which may reflect the lower prevalence of HPV positivity in this

population5

7

5-year survival rates1 • 5-year survival has improved for head and neck cancer patients over the

past twenty years, and is currently around 66%

• The greatest improvement was seen in tonsillar and tongue cancers

1. Pulte D, Brunner, H. Oncologist 2010;15(9):994–1001.

*Difference between values in 1992–1996 and those in 2002-2006. p-value stated is for comparison of trend between1992–1996 and 2002–2006.

PE, point estimate; SE, standard error.


Kingdom (UK).

Location 1982–1986

PE (SE)

1987–1991

PE (SE)

1992–1996

PE (SE)

1997–2001

PE (SE)

2002-2006

PE (SE)

Difference* p-value

All 52.7 (0.5) 53.2 (0.5) 54.7 (0.5) 58.6 (0.5) 65.9 (0.5) +11.2 <0.0001

Lip 92.5 (1.3) 95.6 (1.4) 95.5 (1.4) 90.9 (1.5) 97.4 (1.7) +1.9 0.5

Tongue 45.2 (1.2) 48.1 (1.2) 50.5 (1.2) 55.6 (1.1) 64.9 (1.0) +14.4 <0.0001

Oral cavity 53.6 (1.0) 52.6 (1.0) 51.1 (1.0) 56.6 (1.1) 62.9 (1.2) +11.8 <0.0001

Nasopharynx 47.1 (2.2) 47.6 (2.1) 53.8 (2.1) 58.3 (1.9) 62.3 (1.9) +8.3 0.002

Tonsil 39.7 (1.7) 41.8 (1.7) 47.6 (1.7) 56.5 (1.5) 69.8 (1.3) +22.2 <0.0001

Oropharynx 26.2 (2.9) 23.4 (2.6) 33.3 (3.2) 37.8 (3.1) 42.2 (3.1) +8.9 0.2

Hypopharynx 24.2 (1.4) 26.2 (1.5) 29.8 (1.6) 29.7 (1.6) 33.8 (2.0) +4.0 0.3

Larynx 66.8 (0.8) 66.3 (0.8) 64.9 (0.9) 64.3 (0.9) 66.8 (0.9) +1.9 0.2

% patients surviving for 5 years:

8

Prognosis in HNSCC

• 5-year relative survival rate improved from 52.7% to 65.9% between 1982–1986 and 2002–2006 in all head and neck cancers1

– The exceptions to this trend were lip, oropharyngeal and hypopharyngeal cancer

• However, there has been little improvement since then: recent SEER statistics indicate that 5-year survival is 64% in patients with oral cavity and pharynx cancer, and 61% in patients with laryngeal cancer (data from period 2006–2012)2

• Better prognosis for HPV-associated HNSCC3

– HPV and p16 detection are established markers for HPV-related HNSCC

– Both are accepted as predictors of survival

– Survival of patients with HNSCC is prolonged if disease is HPV(+)/p16(+) or HPV(–)/p16(+)

1. Pulte D, Brunner, H. Oncologist 2010;15(9):994–1001; 2. SEER Cancer Statistics. https://seer.cancer.gov/statfacts/html/oralcav.html and

https://seer.cancer.gov/statfacts/html/laryn.html (Accessed: March 2017); 3. Coordes A, et al. Eur Arch Otorhinolaryngol 2016;273(8):2157-69.

HNSCC, head and neck squamous cell carcinoma, HPV, human papillomavirus; PE, point estimate; SE, standard error; SEER, Surveillance, Epidemiology, and End

Results Program.


Kingdom (UK).

HNSCC risk factors



Kingdom (UK).

10

• Lifestyle risk factors account for the development of approximately 80% of cases of head and neck cancer1

• HPV and EBV are also known risk factors2

• Variations in prevalence of these risk factors contribute to geographical differences in the observed distribution of head and neck cancer3

Main risk factors for head and neck cancers

Tobacco use Alcohol consumption HPV infection (for oropharyngeal

cancer)

EBV infection (for nasopharyngeal

cancer)

1. Stewart BW and Wild CP. 2014 (eds). World Cancer Report. Lyon: WHO IARC Press, 2014. pp. 423; 2. Deng Z, et al. PLoS One 2014;9(11):e113702; 3. Lubin JH, et al. Am J Epidemiol 2009;15;170(8):937–047.

EBV, Epstein-Barr virus; HVP, human papillomavirus.


Kingdom (UK).

11

Tobacco and alcohol are key risk factors for HNSCC

• Heavy smokers have an increased risk of HNSCC compared with nonsmokers1

• Cigar and pipe smoking are associated with an increased incidence of head and neck cancer that is independent of cigarette use1

• Smokeless tobacco (both chewing tobacco and snuff) is associated with an increased risk of cancer of the oral cavity and pharynx2

• Chewing betel nuts and paan are also considered risk factors3

Tobacco

• Alcohol consumption independently increases the risk of HNSCC4

• The risk may be multiplied by the interactive effects of alcohol intake and tobacco consumption5

• Genetic polymorphisms of alcohol dehydrogenase and aldehyde dehydrogenase may increase the risks associated with alcohol consumption6

Alcohol

1. Wyss A, et al. Am J Epidemiol 2013;178:679. 2. Proia NK, et al. Cancer Epidemiol Biomarkers Prev 2006;15:1061; 3. Dasgupta S, et al. J Cell Physiol. 2012;227:467–73;

4. Freedman ND, et al. Br J Cancer 2007;96,1469–74; 5. Znaor A, et al. Int J Cancer 2003;105:681; 6. Druesne-Pecollo N, et al. Lancet Oncol 2009;10:173.



Kingdom (UK).

12

HPV is a risk factor for HNSCC

Infection with HPV, a common, sexually transmitted virus, is

associated with oropharyngeal cancers1

At least one of two viral oncogenes (E6 and E7) are necessary to

maintain cell immortalisation and the malignant phenotype1

By 2030, over half of head and neck cancers will be related to HPV2

1. zur Hausen H. J Natl Cancer Inst 2000;92:690–8; 2. Pytynia et al Oral Oncol 2014;50(5):380–86; 3. D’Souza et al Prev Med 2011;53(Suppl. 1):S5–S11; 4. Spence T, et al

Cancers 2016;8:75; doi:10.3390/cancers8080075; 5.. Weinberger PM, et al. J Clin Oncol 2006;24:736.

HNSCC, head and neck squamous cell carcinoma; HVP, human papillomavirus.


Kingdom (UK).

An increased incidence of HPV-associated oropharyngeal

cancer has been observed in white middle-aged men2

The HPV-16 genotype has been identified as the causative agent in

approximately 45–90% of HNSCC cases3

Other high-risk HPV genotypes, such as HPV-18, -31, -33 or -35, are also

causative but are less common4

HPV-positive tumours are associated with better prognosis than HPV-negative HNSCC tumours and

so testing for HPV status may be useful as a prognostic marker5

HNSCC clinical staging



Kingdom (UK).

14

HNSCC categorisation by location

• Head and neck cancer is categorised by the area of the head or neck in which it occurs

• Sites include:

– Larynx

– Oral cavity, including the tongue

– Oropharynx, including the base of the tongue and tonsils

– Nasopharynx

1. Head and neck cancer fact sheet. http://www.cancerresearchuk.org/about-cancer/type/head-and-neck-cancer/ (Accessed: March 2017).



Kingdom (UK).

15

Staging of HNSCC (T)1

Stage Example (oral cavity)

TX Primary tumour cannot be assessed

T0 No evidence of primary tumour

Tis Carcinoma in situ

T1 ≤2 cm

T2 >2 cm to 4 cm

T3 >4 cm

T4a Through cortical bond, deep/extrinsic muscle of tongue,

maxillary sinus and skin

T4b Masticator space, pterygoid plates, skull base and

internal carotid artery

1. Deschler DG, Moore MG, Smith RV, eds. Quick Reference Guide to TNM Staging of Head and Neck Cancer and Neck Dissection Classification, 4th ed. Alexandria, VA:

American Academy of Otolaryngology–Head and Neck Surgery Foundation, 2014.

HNSCC, head and neck squamous cell carcinoma; T, tumour.


Kingdom (UK).

• Staging is essential to the proper and successful management of HNSCC

• HNSCC is staged according to the Tumour – Node – Metastasis (TNM) system

• T (Tumour) staging is described below

16

Staging of HNSCC (N and M)1

1. Deschler DG, Moore MG, Smith RV, eds. Quick Reference Guide to TNM Staging of Head and Neck Cancer and Neck Dissection Classification, 4th ed. Alexandria, VA:

American Academy of Otolaryngology–Head and Neck Surgery Foundation, 2014.

HNSCC, head and neck squamous cell carcinoma; M, metastases; N, nodes.


Kingdom (UK).

• Definitions of N (regional lymph nodes) and M (metastases) are shown below

NX Regional lymph nodes cannot be assessed

N0 No regional lymph nodes metastases

N1 Ipsilateral single ≤3 cm

N2 a. Ipsilateral single >3 up to 6 cm

b. Ipsilateral multiple ≤6 cm

c. Bilateral, contralateral ≤6 cm

N3 >6 cm

MX Distant metastasis cannot be assessed

M0 No distant metastasis

M1 Distant metastasis

17

Staging of HNSCC: Permutations of TNM staging1

1. Gregoire V, et al. Ann Oncol 2010;21(Suppl. 5):v184–v186.

HNSCC, head and neck squamous cell carcinoma; M, metastases; N, node; T, tumour.


Kingdom (UK).

Stage 0 T N M

Stage I T1 N0 M0

Stage II T2 N0 M0

Stage III T3 N0 M0

T1,T2,T3 N1 M0

Stage IVA T1, T2, T3 N2 M0

T4a N0, N1, N2 M0

Stage IVB Tb Any N M0

Any T N3 M0

Stage IVC Any T Any N M1

Diagnostic work-up of HNSCC



Kingdom (UK).

19

Common signs and symptoms of head and neck cancer

• Signs and symptoms vary depending on the location of the cancer

1. Cancer Research UK. http://www.cancerresearchuk.org/about-cancer/laryngeal-cancer/symptoms and http://www.cancerresearchuk.org/about-

cancer/type/nasopharyngeal-cancer/ (Accessed 13 March 2017); 2. Luryi AL, et al. JAMA Otolaryngol Head Neck Surg 2014;140(7):639–46.

Difficulty swallowing1

Chronic sore throat2

Hoarseness1

Lump in throat or neck area1

Cough1 Shortness of

breath1

Bleeding in the mouth2

Bleeding in the throat2

Halitosis1

Hearing loss/tinnitus/fluid collection in the

ear1

Red or white lesions2

Weight loss1


Kingdom (UK).

20

Diagnostic tests for HNSCC

1. Farah, et al. Chapter 2 in Contemporary Oral Oncology: Biology, Epidemiology, Etiology, and Prevention edited by Moni Abraham Kuriakose 2017; 2. Wemmert, et al

Oncol Lett 2016;11:1661–70; 3. Thariat, et al. Clin Cancer Res;2012;18(5):1313–32; 4. Gregoire V, et al Ann Oncol 2010;21(Suppl. 5):v184–v186.

CT, computed tomography; EGFR, epidermal growth factor receptor; HNSCC, head and neck squamous cell carcinoma; HVP, human papillomavirus; MRI, magnetic

resonance imaging.


Kingdom (UK).

Physical examination:¹

Feeling for lumps on the neck, lips, gums and cheeks, and physical inspection of the nose, mouth, throat and tongue

Biopsy:¹

Fine-needle aspiration is the preferred tissue sampling method for initial evaluation of neck masses or thyroid nodules

HPV testing:²

HPV has been linked to increased risk of some HNSCC; its presence has significant prognostic value

Molecular/biomarker testing:³

Biomarkers for HNSCC include EGFR

Endoscopy:¹

Including laryngoscopy, pharyngoscopy and nasopharyngoscopy

Imaging:1,4

Chest X-ray; head and neck CT scan or MRI (MRI preferable for all subsites except for laryngeal and hypopharyngeal cancers); thoracic CT scan to evaluate possible metastatic disease

21

Biomarkers

1. Wemmert S, et al. Oncology letters 2012;11:1661–70; 2. Marur S, et al. Mayo Clin Proc 2016;91(3):386–96.

HPV-positive tumours have increased expression of p16²

DCR, distant metastases control rate; F, female; HNSCC, head and neck squamous cell carcinoma; HPV, human papillomavirus; M, male; N, node; OPSCC,

oropharyngeal squamous cell carcinoma; T, tumour.

This information is from an international website which is intended for healthcare professionals not located in the United States of America (US) and the

United Kingdom (UK).

Variable HPV positive HPV negative

Race White > black White > black

Age (y) 40–60 >60

M:F 8:1 3:1

Socioeconomic status Higher Low-middle

Smoking/alcohol dependence Never or minimal Significant

Marijuana use Strong association Unknown

Early sexual experience Strong association Unknown

Multiple sexual partners Strong association Unknown

Tumour (T) stage Early T stage More advanced T

stage

Nodal (N) stage Advanced N stage Early N stage

Distant metastasis

DCR (%) 70–90 70–90

Second primary rate (%) 11 4.6

Overall response to treatment

2-Year OS (%) 94 (95% CI, 87–

100) 58 (95% CI, 49-74)

2-Year PFS (%) 85 (95% CI, 74-99) 53 (95% CI, 36-67)

Sec62 is a novel potential biomarker for HNSCC¹

Patients with high Sec62 and high nuclear survivin

demonstrated a poorer prognosis compared with patients

exhibiting low Sec62 and low nuclear survivin expression

(p=0.009)

There is a distinct biology and molecular phenotype among

HPV-positive OPSCCs when compared with HPV-negative

HNSCCs

22

Other genetic markers

• Chromosomal abnormalities

– Over 20 recurrent chromosomal alterations have been identified in invasive HNSCC¹

– Loss of heterozygosity near 9p21 is significantly more frequent in recurrent tumours than in non-recurrent tumours2

– Amplification of region 11q13 encoding the EGFR gene leads to high expression level of EGFR³

• Mutations in genes responsible for squamous differentiation (NOTCH1, IRF6, TP63)⁴

– Inactivation of TP53 in most cases⁴

– Inactivating mutations in NOTCH1⁴

– CDKN2A (p16) disruption is reported as a frequent event in HNSCC⁵

1. Wemmert S et al Oncol Lett 2016;11:1661–70; 2. Matsuura K et al Anticancer Res 1998;18(1A):453–8; 3. Rodrigo JP et al. Scientific Reports 2015;

Article number: 15698; 4. Stransky N et al. Science. 2011;26;333(6046):1157–60; 5. Lim AM et al Int. J. Cancer 2014;135:887–95.

CDKN2A, cyclin-dependent kinase Inhibitor 2A; EGFR, epidermal growth factor receptor; HNSCC, head and neck squamous cell carcinoma.


Kingdom (UK).

Treatment options in HNSCC



Kingdom (UK).

24

Primary systemic treatment of HNSCC: NCCN guidelines1

*Category 1 for oropharynx, hypopharynx or larnyx; 2B for lip, oral cavity, ethmoid sinus, maxillary sinus, occult primary.

**Category 1 for high risk non-oropharyngeal cancers.

5-FU, fluorouracil; HNSCC, head and neck squamous cell carcinoma; NCCN, National Comprehensive Cancer Network; RT, radiotherapy.


Kingdom (UK).

Treatment Category

High dose cisplatin (preferred) 1

Cetuximab 1,2B*

Carboplatin/infusional 5-FU 1

5-FU/hydroxurea 2A

Cisplatin/paclitaxel 2A

Cisplatin/infusional 5-FU 2A

Carboplatin/paclitaxel 2B

Weekly cisplatin 40mg/m² 2B

Post-operative chemoradiation

Cisplatin 1**

Treatment Category

Cisplatin + RT followed by

cisplatin/5-FU or carboplatin/5-FU

2B

(Carboplatin/5-FU)

Cisplatin + RT without adjuvant

chemotherapy

2B

1. NCCN Clinical Practice Guidelines in Oncology. Head and Neck Cancers, Version 1. Published: February 6th 2017.

Lip, oral cavity, oropharynx, glottic larynx,

supraglottic larynx, ethmoid sinus, maxillary sinus,

occult primary: primary systemic therapy and

concurrent RT

Nasopharynx: chemoradiation followed by adjuvant

chemotherapy

25

Treatment of recurrent, unresectable or metastatic HNSCC: NCCN guidelines1

*Surgery or radiotherapy not an option.

**Non-nasopharyngeal, if disease progression on or after platinum-containing chemotherapy.

HNSCC, head and neck squamous cell carcinoma; NCCN, National Comprehensive Cancer Network.


Kingdom (UK).

Treatment Category

Cisplatin or carboplatin/5-FU/cetuximab

(non-nasopharyngeal)

1

Cisplatin or carboplatin/docetaxel or

paclitaxel

2A

Cisplatin cetuximab (non-nasopharyngeal) 2A

Cisplatin/5-FU 2A

Cisplatin or carboplatin/docetaxel/cetuximab


2A

Cisplatin or carboplatin/paclitaxel/cetuximab


2A

Carboplatin/cetuximab (nasopharyngeal) 2A

Cisplatin/gemcitabine (nasopharyngeal) 2A

Gemcitabine/vinorelbine (nasopharyngeal) 2A

Combination therapy* Single agents*

Treatment Category

Cisplatin 2A

Carboplatin 2A

Paclitaxel 2A

Docetaxel 2A

5-FU 2A

Methotrexate 2A

Cetuximab (non-nasopharyngeal) 2A

Gemcitabine (nasopharyngeal) 2A

Capecitabine 2A

Afatinib** 2B

Pembrolizumab** 2A

Nivolumab** 1

1. NCCN Clinical Practice Guidelines in Oncology. Head and Neck Cancers, Version 1. Published: February 6th 2017.

26

Abbreviated EU SmPC

EGFR M+ NSCLC and sqNSCLC

GIOTRIF®: Irreversible ErbB family blocker. Active substance: Afatinib. Indications: GIOTRIF is indicated as monotherapy for (1) patients with locally advanced or metastatic NSCLC with activating EGFR mutations not previously treated with EGFR TKIs, (2) patients with NSCLC of squamous histology progressing on or after platinum-based chemotherapy. Posology: The recommended dose is 40 mg once daily, orally. Not recommended in patients with an eGFR <15ml/min and severe hepatic impairment. Contraindications: Hypersensitivity to afatinib or any of the excipients. Interactions: Potent P-gp inhibitors may lead to increased afatinib exposure, concomitant treatment with potent P-gp inducers may lead to a reduction in afatinib exposure. Afatinib is not an inhibitor or inducer of CYP enzymes. Undesirable effects: Paronychia, cystitis, decreased appetite, dehydration, hypokalaemia, dysgeusia, conjunctivitis, dry eye, epistaxis, rhinorrhoea, diarrhoea, stomatitis, nausea, vomiting, cheilitis, dyspepsia, alanine aminotransferase increased, aspartate aminotransferase increased, rash, acneiform dermatitis, pruritus, dry skin, palmar-plantar erythrodysaesthesia syndrome, nail disorders, Stevens-Johnson syndrome, toxic epidermal necrolysis, muscle spasms, renal impairment/renal failure, pyrexia, weight decreased, interstitial lung disease, keratitis, pancreatitis. Presentations: 20 mg, 30 mg, 40 mg, and 50 mg film-coated tablets. For detailed information, please refer to the published Prescribing Information.

Supply classification: POM.

This medicine is subject to additional monitoring.

Boehringer Ingelheim International GmbH, Binger Strasse 173, 55216 Ingelheim am Rhein, Germany

EGFR M+, epidermal growth factor receptor mutation positive; NSCLC, non-small cell lung cancer; TKI, tyrosine kinase inhibitor.

Date of text revision: July 2017

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