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Role of hpv in head and neck tumors
1. ROLE OF HPV IN
HEAD AND NECK
CANCER
Dr. Ayush Garg
Senior Resident
2. 1. Sparano JA et al. Springer New York 2010
2. Best SR et al. Otolaryngol Clin North Am 2012
3. Parkin DM Int J Cancer 2006
4. Kreimer AR et al. Cancer Epidemiol Biomarkers Prev 2005
Double-stranded DNA virus;
over 100 subtypes1,2
Cancer link;3
subtypes classified
as low- or high-risk according to
oncogenicity1,4
87% of HPV+ OPC caused by
HPV164
Primary transmission route: sexual contact1
Text Here
WHAT IS HPV?
3. x
x1. Best SR et al. Otolaryngol Clin North Am 2012
2. Sparano JA et al. Springer New York 2010
3. Smeets SJ et al. Int J Cancer 2011
E1
E4L2
7.9 kb dsDNA
E5
L1
HPV genome2
E2
E1
E7
E6
E6
E7
p53
pRb
E6 and E7 bind and
inactivate tumor
suppressor proteins3
HOW DOES HPV CAUSE
CANCER?
‣ HPV genome encodes six early (E) and two
late (L) proteins1
4. RADIOSENSITIVITY
▸ Suppression of p53 & pRb lead
to failure to delay cell cycle
progression & suppression of
downstream regulators by E6 &
E7 contribute to cellular
immortality.
▸ This leads to genetic instability
& may lead to tumor resistance
Wu et al, Oncology Letters 2016
5. Wounded Epithelia
HPV infected epithelia
• Selection of integrated cell clones
• Lower viral load
• Cell cycle dysfunction
• Genomic instability
Potentially malignant disorders with
dysplasia
Infection
HPV
• Episomal replication to high viral load
• High probability of integration
Progression
Squamous
Cell
CarcinomaINVASION
HPV
Particles
HPV INDUCED
CARCINOGENESIS
6. Variable HPV+
n=206
HPV‒
n=117
p16+ p16– p-value*
OS rate (%) 82.4 57.1 83.6 51.3 <0.001
Progression-free survival rate
(%)
73.7 43.4 74.4 38.4 <0.001
LRC failure rate (%) 13.6 35.1 <0.001
Distant metastases rate (%) 8.7 14.6 0.23
Second primary rate (%) 5.9 14.6 0.02
Ang KK et al. N Engl J Med 2010
Approximately 25% greater absolute survival in
HPV+ populations after 3 years
Approximately 25% greater absolute survival in
HPV+ populations after 3 years
In patients who had received CRT in the RTOG0129 study, 3-year outcomes
varied by HPV and p16 status
RTOG 0129: HIGHER 3-YEAR SURVIVAL
RATES OBSERVED IN PATIENTS WITH HPV+
VS HPV– TUMORS
7. WHY DE-ESCALATE TREATMENT?
▸ Reduction of long term
toxicities of CCRT
▸ Affects 21-43% of patients
(Non-IMRT data)
▸ Reduce economic & social
burden of toxicities
▸ Allow replacement of Cisplatin
with other agents
Machtay M et al, JCO 2008;26:3582–89
8. NOVEL TREATMENT STRATEGIES FOR HPV+ HNSCC
▸ Induction chemotherapy followed by reduced
dose/volume CCRT
▸ Rationale: Selection of good responders
▸ Replacement of cisplatin with cetuximab
▸ Rationale: Reduced toxicity of Cetuximab
▸ Surgery (TORS) followed by adjuvant RT (with
reduced dose)
▸ Rationale: Reduce morbidity by selecting patients based on
histopathological characteristics
▸ Modulating immune response & T-cell activation by
vaccination
9. INDUCTION CHEMO FOLLOWED BY REDUCED DOSE CCRT
▸ ECOG 1308
▸ Phase II RCT
▸ HPV positive oropharyngeal HNSCC
with Stage III/IV
▸ Utilised Induction Chemo
(TP+Cetuximab) for 3 cycles
▸ Complete responders received
reduced dose RT (54 Gy/ 27 Fr)
▸ Partial responders/stable disease
received standard dose RT (69.3 Gy/
33 Fr)
REGISTER
3c - TP+Cmab
ASSESS RESPONSE
CR PR/SD
Reduced dose RT
+ Cmab
Standard dose RT
+ Cmab
11. INDUCTION CHEMO FOLLOWED BY
REDUCED VOLUME CCRT
▸ NCT01133678 (U. Chicago)
▸ Phase II RCT
▸ No stratification by HPV positivity
and included Stage III/IV HNSCC
(all sites)
▸ Utilised Induction Chemo
(TP+Cetuximab) with or without
Everolimus
▸ Utilised hyperfractionated RT (75 Gy
with twice daily RT)
▸ Concurrent chemo was TFH (Taxane,
5-FU & Hydoxyurea)
REGISTER
ASSESS RESPONSE
Good Poor
RANDOMISE
2c - TP+Cmab 2c - TP+Cmab
+ Everolimus
Reduced field RT
+ TFH
Standard field RT
+ TFH
12. INDUCTION CHEMO FOLLOWED BY
REDUCED VOLUME CCRT
▸ NCT01133678 (U. Chicago)
▸ Response was judged by reduction of volume of disease by 50%
▸ Reduced field RT consisted of RT to primary disease site only
▸ Standard field RT consisted of RT to primary disease site & 1st
echelon nodes
▸ Primary endpoint - response rates
13. INDUCTION CHEMO FOLLOWED BY
REDUCED VOLUME CCRT
▸ NCT01133678 (U. Chicago)
▸ Results (N=94):
▸ 39% Good response rate, 91% LRC rate
▸ 14/15 LRF were in RT treatment volume
▸ Similar toxicity rates between good & poor responders
▸ Lower PEG dependency in good responders
14. REPLACEMENT OF CISPLATIN WITH
CETUXIMAB
▸ RTOG 1016
▸ Phase III RCT
▸ Includes Stage III-IV Oropharyngeal
Ca
▸ Utilises Accelerated RT (70 Gy/ 6
wks) in both arms
▸ Standard Cetuximab dosing
▸ Cisplatin 100mg/m2 D1, D22
▸ Primary outcome - 5yr OS
REGISTER
STRATIFY
T1-2N1-3 or T3-4N0, PS, Smoking
RANDOMISE
Acc RT +
Cetuximab
Acc RT +
Cisplatin
HPV p16 testing
15. REPLACEMENT OF CISPLATIN WITH
CETUXIMAB
▸ De-ESCALaTE
▸ Phase III RCT
▸ Includes Stage III-IV Oropharyngeal Ca
▸ Utilizes standard RT (70 Gy/ 7 wks) in
both arms
▸ Standard Cetuximab dosing
▸ Cisplatin 100mg/m2 D1, D22, D43
▸ Primary outcome - Acute & late toxicity
REGISTER
HPV-Positive
RT +
Cetuximab
RT +
Cisplatin
HPV p16 testing
HPV-Negative
RANDOMISE
RT +
Cisplatin
16. REPLACEMENT OF CISPLATIN WITH
CETUXIMAB
▸ TROG 12.01
▸ Phase III RCT
▸ Includes Stage III-IV Oropharyngeal Ca
(Excluding T4 & N3)
▸ Utilizes Standard RT (70 Gy/ 6 wks) in
both arms
▸ Standard Cetuximab dosing
▸ Cisplatin 40mg/m2 weekly
▸ Primary outcome - Acute toxicity
REGISTER
STRATIFY
T1-2N1-2 or T3N0, PS, Smoking<10y
RANDOMISE
RT +
Cetuximab
RT +
Cisplatin
HPV p16 testing
17. SURGERY FOLLOWED BY ADJUVANT
RADIOTHERAPY
▸ ADEPT
▸ Phase III RCT
▸ Includes HPV+, oropharyngeal Ca
▸ All patients undergo minimal access
surgery+Neck dissection
▸ RT is delivered by IMRT to dose of
60 Gy/30 Fr in both arms
▸ Primary endpoint: 2yr LRC, DFS
REGISTER
Minimal Access Surgery
R0 resection, ECE +
RT alone RT + Weekly
Cisplatin
HPV p16 testing
RANDOMISE
18. SURGERY FOLLOWED BY ADJUVANT
RADIOTHERAPY
▸ ECOG 3311
▸ Phase II RCT
▸ Includes HPV+, oropharyngeal Ca
▸ All patients undergo Trans-oral minimal access
surgery+Neck dissection
▸ RT is delivered by IMRT to dose of 50 Gy/25
Fr in low-dose arm & 60 Gy/30 Fr is standard
dose arm
▸ Chemo is delivered weekly, Cisplatin or
Carboplatin
▸ Primary endpoint: 2yr PFS, Complication rates
REGISTER
Trans-Oral Surgery
HPV p16 testing
Low-dose
RT
Observe Standard-
dose RT+
Chemo
RANDOMISE
Standard-dose
RT
Assess Risk
Low HighI/M
19. SURGERY FOLLOWED BY ADJUVANT
RADIOTHERAPY
▸ ECOG 3311
▸ Low Risk - T1-2, N0-1
▸ I/M Risk - Clear/close
margins, <1mm of ECE, LVI
or PNI+, 2-3 LN positive
▸ High risk - Margins positive,
4 or more LN positive, >1mm
of ECE
REGISTER
Trans-Oral Surgery
HPV p16 testing
Low-dose
RT
Observe Standard-
dose RT+
Chemo
RANDOMISE
Standard-dose
RT
Assess Risk
Low HighI/M
20. SURGERY FOLLOWED BY ADJUVANT
RADIOTHERAPY
▸ PATHOS
▸ Phase II/III RCT
▸ Includes HPV+, oropharyngeal Ca
▸ All patients undergo Trans-oral minimal
access surgery+Neck dissection
▸ RT is delivered by IMRT to dose of 50 Gy/25
Fr in low-dose arm & 60 Gy/30 Fr is standard
dose arm
▸ Chemo is delivered as weekly or q3week,
Cisplatin
▸ Primary endpoint: Swallowing function
REGISTER
Trans-Oral Surgery
HPV p16 testing
Low-dose
RT
Observe
Standard-
dose RT
RANDOMISE
Standard-dose
RT
Assess Risk
Low HighI/M
RANDOMISE
Standard-
dose RT+
Chemo
21. SURGERY FOLLOWED BY ADJUVANT
RADIOTHERAPY
▸ PATHOS
▸ Low Risk - No adverse
features
▸ I/M Risk - T1-3, N2a-2b,
Close margins, LVI or PNI
present
▸ High risk - Margins positive,
4 or more LN positive,
>1mm of ECE
REGISTER
Trans-Oral Surgery
HPV p16 testing
Low-dose
RT
Observe
Standard-
dose RT
RANDOMISE
Standard-dose
RT
Assess Risk
Low HighI/M
RANDOMISE
Standard-
dose RT+
Chemo
22. TIL - A NEW MOLECULAR MARKER FOR
GOOD-PROGNOSIS HNSCC
▸ CD8+ Tumor infiltrating lymphocytes
have recently been shown to influence
outcomes of HNSCC patients
irrespective of HPV status.
▸ Along with this, similar other molecular
markers can form a molecular signature
which can help to identify HPV positive
patients who are a potential candidate
for de-escalation or aggressive
approaches, which will further
strengthen risk models.
Balermpas P et al, Int J Cancer 2015
23. SUMMARY: CHARACTERISTICS
OF HPV+ SCCHN
1. Gillison ML et al, J Natl Cancer Inst 2008; 2. Chaturvedi AK et al, Head Neck Pathol 2012
3. Ragin CC et al, Int J Cancer 2007; 4. Chaturvedi AK et al, J Clin Oncol 2011
5. Licitra L et al, Hematol Oncol Clin N Am 2008
Growing incidence vs HPV–
tumors in Europe and US
High-risk sexual practices,
marijuana use
Lower mortality and risk of
progression than HPV–
(oropharyngeal SCCHN)
Younger age
(by 3–5 years) vs HPV–
Risk factors1,2
Prognosis3
HPV+
Patient profile2
Incidence4,5
Risk factors for HPV– SCCHN include smoking, alcohol, and poor oral hygiene1
24. CONCLUSIONS
▸ HPV positive oropharyngeal Ca has a different ethology and better prognosis than
other HNSCC.
▸ Its prevalence in India is expected to increase in the coming years.
▸ Due to its better prognosis, it gives us the opportunity to de-intensify treatment
protocols to reduce late toxicities associated with CCRT.
▸ Results of ongoing trials will further clarify which protocol is the most effective
in this setting.
▸ To avoid under treatment of patients, a new molecular marker, Tumor Infiltrating
Lymphocytes (TIL) may be used to better select patients with improved outcomes
irrespective of p16 status.
32. QUESTION 3
‣ LATENCY PERIOD FOR HPV TO CONVERT INTO
MALIGNANCY?
‣ 5 YEARS
‣ 10 YEARS
‣ 15 YEARS
‣ 20 YEARS
33. ‣ LATENCY PERIOD FOR HPV TO CONVERT INTO
MALIGNANCY?
‣ 5 YEARS
‣ 10 YEARS
‣ 15 YEARS
‣ 20 YEARS
34. QUESTION 4
‣ MOST COMMON SITE?
‣ LARYNX
‣ HYPOPHARYNX
‣ ORAL CAVITY
‣ OROPHARYNX
35. ‣ MOST COMMON SITE?
‣ LARYNX
‣ HYPOPHARYNX
‣ ORAL CAVITY
‣ OROPHARYNX
36. QUESTION 5
‣ HPV+ PATIENTS ARE 5-10 YEARS YOUNGER IN AGE AS
COMPARED TO HPV NEGATIVE PATIENTS?
‣ FACT OR MYTH?
37. ‣ HPV+ PATIENTS ARE 5-10 YEARS YOUNGER IN AGE AS
COMPARED TO HPV NEGATIVE PATIENTS?
‣ FACT OR MYTH?
38. QUESTION 6
‣ IN A PATIENT CLUP, FNAC FROM NODE IS SUGGESTIVE
OF HPV POSITIVITY. IT CAN BE TREATED ON THE LINES
OF OROPHARYNX?
‣ TRUE OR FALSE?
39. ‣ IN A PATIENT CLUP, FNAC FROM NODE IS SUGGESTIVE
OF HPV POSITIVITY. IT CAN BE TREATED ON THE LINES
OF OROPHARYNX?
TRUE
40. QUESTION 8
‣ A PATIENT PRESENTS WITH 2cm p16+ TONSIL CANCER
AND 2 POSITIVE LYMPH NODES IN THE SAME SIDE OF
THE NECK. WHAT IS THE STAGE OF THE PATIENT?
‣ STAGE I
‣ STAGE II
‣ STAGE III
‣ STAGE IV
41. ‣ A PATIENT PRESENTS WITH 2cm p16+ TONSIL CANCER
AND 2 POSITIVE LYMPH NODES IN THE SAME SIDE OF
THE NECK. WHAT IS THE STAGE OF THE PATIENT?
‣ STAGE I
‣ ACCORDING TO 7th
EDITION IT WILL BE STAGED AS
STAGE IV BUT IT BECOMES STAGE I IN 8th
EDITION
Key talking point: HPV is a virus linked to cancer
15 subtypes of HPV are considered to be high-risk: 16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, 68, 73, and 824
HPV 6 and 11 may also be implicated in SCCHN4
Key talking point: HPV enables the cell to produce two proteins which inactivate important ‘Tumor Suppressor’ proteins (like p53 and retinoblastoma protein) within the cell. The p53 protein prevents cell growth and stimulates apoptosis in the presence of DNA damage; tumor suppressor proteins protect the cell from progressing to cancer, which usually happens in combination with other genetic changes
Key talking point: A greater proportion of patients with HPV-positive SCCHN live longer than those with HPV-negative SCCHN
TUMOR INFILTRATING LYMPHOCYTES
Key talking point: HPV-positive SCCHN displays a number of characteristics that vary from HPV-negative tumors
