This document discusses a clinical trial comparing cisplatin-based chemoradiotherapy to cetuximab-based chemoradiotherapy for p16-positive oropharyngeal cancer. The trial found that while overall toxicity was similar between the two arms, serious adverse events were significantly more common with cisplatin treatment. However, patients receiving cisplatin chemoradiotherapy experienced significantly better 2-year overall survival and lower recurrence rates compared to those receiving cetuximab chemoradiotherapy. The findings suggest that for HPV-positive oropharyngeal cancer, cisplatin chemoradiotherapy provides excellent survival outcomes despite greater toxicity risks compared to cetuximab chemoradiotherapy.

1. Predictors of Locoregional &
Distant Failure in p16 positive
Oropharyngeal Cancer
Dr.RajibBhattacharjee
MD(Radiotherapy)
DNBPDT(MedicalOncology)
ApolloGleneaglesHospital,Kolkata

2. Biomarkers in Head & Neck Cancer
**Potential predictive factor for accelerated radiotherapy

3. 3
SCCHN: Biomarkers are limited, but efforts to personalize
therapy are ongoing
• 1. Kang H, et al. Nat Rev Clin Oncol 2015;12:11–26;
2. Feldman et al.; Molecular profiling of head and neck squamous cell carcinoma; HEAD & NECK—
DOI 10.1002/HED APRIL 2016
Prognostic and predictive
biomarkers are still being sought1
Biomarkers
under
investigation
HPV
PET
imaging
features
PIK3CA
EGFR
METFGFR
Cyclin
D1
TP53
PD-L1
Predictive biomarkers as
measured by IHC & ISH2

4. What is HPV?
1. Sparano JA, et al. Molecular Basis for Therapy of AIDS-Defining Cancers, Eds Dittmer DP, et al.
Springer New York 2010;211–234
2. Best SR, et al. Otolaryngol Clin North Am 2012;45:807–822
3. Parkin DM. Int J Cancer 2006;118:3030–3044
4. Kreimer AR, et al. Cancer Epidemiol Biomarkers Prev 2005;14:467–475
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
HPV, human papillomavirus;
OPC, oropharyngeal cancer

5. High-risk HPV and cancer: How clear is
the link?
1. Parkin DM. Int J Cancer 2006;118:3030–3044
2. Watson M, et al. Cancer 2008;113(10 Suppl.):2841–2854
3. Jayaprakash V, et al. Oral Oncol 2011;47:1048–1054
4. Mork L, et al. N Engl J Med 2001;344:1125–1131
High-risk HPV infection (e.g. HPV16, HPV18)
is linked to ~5% of all cancers worldwide1
More than half of HPV+
cancers attributable to
HPV16 and HPV181
Vaginal, vulvar, and
penile cancers*
~25% linked to HPV16
and HPV183OPC
~92% caused by HPV16
and HPV181Anal cancer
~70% caused by HPV16
and HPV181,2Cervical cancer
*40% of all these cancers are linked to HPV
The risk of OPC is
significantly
associated with
HPV/p16+ status
(odds ratio 14.4)4

7. HPV +ve SCCHN is a distinct disease with a
different patient profile to HPV -ve SCCHN

8. Two distinct subtypes of oropharyngeal
squamous cell carcinoma (OPSCC)

11. HPV+ and HPV– OPC undergo a different
sequence of molecular changes

12. p16 is elevated in HPV induced
cancers
Gillison ML, et al. Semin Oncol 2004;31:744–54.

13. How to Detect

14. >10 pack-years
(n=65)
≤10 pack-years
(n=23)
>10 pack-years
(n=90)
≤10 pack-years
(n=88)
N0-N2a
(n=26)
N2b-N3
(n=64)
T2-T3
(n=15)
T4
(n=8)
42.9% at low risk
3 year OS = 93.0%
27.4% at high risk
3 year OS = 46.2%
29.7% at intermediate risk
3 year OS = 70.8%
HPV-positive
(n=178)
HPV-negative
(n=88)
Oropharyngeal cancer (n=266)
Poor prognosis
More intensive
therapies may be
appropriate (requires
clinical evidence)
Good prognosis
Could patients receive
less intensive therapy
without compromising
survival?
Ang KK, et al. NEJM 2010;363:24–35
Patients with OPC can be divided into low,
intermediate and high risk-of-death categories based
partly on HPV status

15. Survival of patients with OPC based on risk
categories has been assessed in different regions*
0%
20%
40%
60%
80%
100%
0 5 10 15 20 25 30 35 40
Time (months)
0%
20%
40%
60%
80%
100%
0 1 2 3 4 5
Years since randomization
US and European studies show that a combination of factors, including HPV
status, smoking,‡ and T/N status, contribute to prognosis in SCCHN
US study (RTOG 0129)1† European study2
Low risk
Intermediate risk
High risk
*In both studies, patients were treated with CRT
† Based on RTOG 0129
‡Note: Some studies use 20 pack-years as a threshold value for
categorizing risk3
OPC, oropharyngeal cancer
HPV
status
Smoking
(pack-
years)
T/N
status
High
– ≤10 T4
– >10 Any
Interm
ediate
– ≤10 T2–T3
+ >10
N2b–
N3
Low
+ ≤10 Any
+ >10
N0–
N2a
Risk categories1
Overallsurvival
Low risk (Group 1)
Intermediate risk (Group 2)
High risk (Group 3)
1. Ang KK, et al. NEJM 2010;363:24–35;
2. Granata R, et al. Ann Oncol 2012;23:1832–1837;
3. O’Sullivan B, et al. Radiother Oncol 2015;114(Suppl 1):13

16. HPV16 DNA status is a significant prognostic
indicator of tumor recurrence

17. Prognostic Risk Groups In
HPV-positive OPC

18. Mirghani H, et al. Eur J Cancer 2014;50:1100–1111
Most studies have linked HPV and p16 to
lower EGFR expression in OPC
Author
No.
pts
Analysed
only
OPCC?
No. HPV+ (%)
EGFR
expression
assessment
Correlation: EGFR
and HPV
EGFR-
activating
mutation
HPV + EGFR:
outcomes
predictor
Kumar 50 Yes 27/42 (64) IHC Inverse (p=0.007) – Yes
Kong 99 No 36/82 (43) IHC Inverse (p=0.0002) – Yes
Hong 270 Yes 91 (33) IHC Inverse (p=0.0005) – Yes
Perrone 90 Yes 17 (19) FISH, IHC No No –
Romanitan 83 Yes 52 (63) IHC Inverse (p=0.01) – No
Kim 52 Yes 34 (65) FISH Inverse (p=0.04) – –
Reimers 106 Yes 30/96 (28) IHC Trend to inverse
(p=0.083)
– Yes
Young 212 No 75/131 (57) FISH, IHC Inverse – –
Al-Swiahb 220 Yes 33 (15) IHC Inverse (p<0.01) – Yes
Won 121 No 21 (17) IHC Inverse (p=0.003) – –
Hussain 101 No 29/87 (33) IHC Inverse (p=0.03) – No
EGFR, epidermal growth factor receptor;
FISH, fluorescence in situ hybridization;
IHC, immunohistochemistry

19. 1. Reimers N, et al. Int J Cancer 2007;120:1731–1738
2. Hong A, et al. Eur J Cancer 2010;46:2088–2096
3. Lassen P, et al. Radiother Oncol 2013;108:489–494
4. Wansom D, et al. Laryngoscope 2012;122:121–127
EGFR expression and HPV status act in
combination as prognostic markers
HPV and EGFR
status (n)
HR* (95% CI)
Time to LRC
failure
Time to event*
Time to all-cause
death*
HPV+/EGFR– (21) 1 1 1
HPV+/EGFR+ (69) 3.84 (0.48–30.84) 1.08 (0.41–2.85) 1.42 (0.39–5.19)
HPV–/EGFR– (11) 1.97 (0.12–33.40) 1.35 (0.31–5.79) 1.1 (0.17–7.04)
HPV–/EGFR+ (141)
12.79 (1.70–
96.26)
3.89 (1.61–9.37) 4.49 (1.34–15.03)
Association between EGFR and HPV status2
Prognosis1
–3
HPV
EGFR
–+
+–
EGFR expression
but not HPV
status inversely
linked to
T cell infiltration
in OPC4

20. Mechanism of radiosensitization by p16 overexpression
in HPV related OPC
Sano et al.; molecular mechanism of human papillomavirus-inducedcarcinogenesis in SCCHN; Int J Clin Oncol (2016) 21:819–826

21. HPV16 viral load and p16 expression are
associated with response to ICT and CRT

22. Improved survival outcomes with CRT vs surgery
followed by RT are most evident in
low/intermediate-risk patients

23. HPV and p16 status are prognostic factors in
locally advanced SCCHN

24. RTOG 1016: cisplatin + RT vs cetuximab + RT in
p16+ OPC1
Phase III, open-label, non-inferiority2
Efficacy
Cetuximab + RT
(n=394)
HD cisplatin + RT
(n=398)
p-value
5-year OS, % 78 85 0.02
5-year PFS, % 67 78 <0.001
5-year LRF, % 17 10 <0.001
OS
Cisplatin + IMRT (n=406)
Cetuximab + IMRT (n=399)
5-year OS, %
85
78
p=0.02
1. Trotti A, et al. ASTRO 2018 (Abstract No. A14737); 2. NCT01302834. Available at:
https://clinicaltrials.gov/ct2/show/NCT01302834. Accessed October 2018.
Primary endpoint:
5-year OS
p16+ OPC
(n=805)
R
Cisplatin 100 mg/m2 Q3W for 2 cycles
+ IMRT (AFX-C, 70 Gy in 6 weeks) (CRT)
Cetuximab 400 mg/m2 → 250 mg/m2
QW
+ IMRT (AFX-C, 70 Gy in 6 weeks) (ERT)
0
0
1 2 3 4 5
Years after randomization
406 372 349 314 222 100
399 367 334 305 207 106
10
20
30
40
50
60
70
80
90
10
0
Overallsurvival(%)

25. Acute toxicity burden was worse with cisplatin + RT
than cetuximab + RT
Safety endpoint
HD cisplatin + RT
(n=398)
Cetuximab + RT
(n=394)
p-value
Acute toxicity burden
(mean raw T-score)
3.19 2.35 <0.001
Grade 3–4 overall acute
toxicity, %
81.7 77.4 0.16
Late toxicity burden
(mean raw A-score)
0.38 0.27 0.12
Grade 3–4 overall late
toxicity, %
20.4 16.5 0.19
• Grade 3–4 anemia, hearing impairment (acute and late), nausea, vomiting, neutropenia, leukopenia, and acute
kidney injury were significantly worse with HD cisplatin + RT than cetuximab + RT*
• There were significantly fewer cases of grade 3–4 radiation dermatitis and acneiform rash with HD cisplatin + RT
than with cetuximab + RT*
Trotti A, et al. ASTRO 2018 (Abstract No. A14737).*Reported in abstract only.

26. De-ESCALaTE: CRT vs cetuximab +
RT in p16+ oropharyngeal SCCHN
www.clinicaltrials.gov/ct2/show/NC
T01874171
Primary
endpoint:
Severe acute and
late toxicity (2 yr)
Secondary
endpoints:
Toxicity, QoL, OS
N=304*
Cisplatin 100
mg/m²
RT
RT
R
A
N
D
O
M
I
Z
A
T
I
O
N
Cetuximab
Lead investigator: H Mehanna
Cancer Research UK/University
of Warwick
Oropharyngeal
SCCHN
p16+
Stage III–IVa, M0
Biological profiling
Details TBC
*Estimated number

27. De-ESCALaTE: Although overall toxicity was similar, serious
AEs were significantly more common with HD cisplatin + RT
vs cetuximab + RT
HD CRT
(n=166)
Cetuximab + RT
(n=168)
All-grade AEs,
events per patient
29.15 (95% CI 27.33–
30.97)
30.05 (95% CI 28.26–31.85)
p=0.49
Severe (grade 3–5) AEs,
events per patient
4.81 (95% CI 4.23–5.40) 4.82 (95% CI 4.22–5.43)
p=0.98
Serious AEs,
events per patient
1.00 0.58
p=0.001
Compliance
• Cisplatin: 84% of patients received ≥200 mg/m2 cisplatin
• Cetuximab: 79% of patients received 8 doses of cetuximab
• RT: Overall, 96% of patients received 70 Gy+ and 4% received 65–70 Gy (8% had
modifications)
QoL
• There was no difference in QoL and swallowing between arms
CI, confidence interval.
Mehanna H, et al. ESMO 2018
(Abstract No. LBA9_PR);
Mehanna H, et al. ICHNO 2019
(Abstract No. OC-011 – presentation).

28. De-ESCALaTE: Patients with HPV+ OPC benefit from
excellent survival outcomes with HD cisplatin + RT (3/7)
HD CRT
(n=166)
Cetuximab + RT
(n=168)
2-year OS rate, %*
97.5 89.4
HR 4.99 (95% CI 1.70–14.67), p=0.001
2-year
recurrence rate, %
6.0 16.1
HR 3.39 (95% CI 1.61–7.19), p=0.0007
Loco-regional
recurrence rate, %
3 12
p=0.003
Distant
recurrence rate, %
3 9
p=0.009
*Regarding OS, the number needed to treat for harm was 12:
if 12 patients were treated with cetuximab + RT, one would be harmed
HR, hazard ratio.
Time (years)
166 160 154 147 118
168 163 156 144 109
HD cisplatin + RT
Cetuximab + RT
Number at Risk
100
0
0
25
50
75
0.5 1.0 1.5 2.0
Probability(%)
HD cisplatin + RT= 6 deaths
Cetuximab + RT= 20 deaths
Overall Survival
Mehanna H, et al. ESMO 2018 (Abstract No. LBA9_PR);
Mehanna H, et al. ICHNO 2019 (Abstract No. OC-011 –
presentation).

29. TROG 12.01: CRT vs cetuximab + RT in HPV+
oropharyngeal SCCHN
www.clinicaltrials.gov/ct2/show/NC
T01855451
Primary endpoint:
Symptom severity (20 wks)
Secondary endpoints:
Symptom severity (2 yr), QoL
(3 yr), speech and dietary
function, toxicity, prognostic
markers
N=200*
Cisplatin 40
mg/m²
RT
RT
R
A
N
D
O
M
I
Z
A
T
I
O
N
RT: 70 Gy in
35 fractions,
5 d/wk over 7
wks
Cetuximab
Biological profiling
Prognostic markers (including
but not limited to EGFR protein
level, EGFR copy number, ERCC1,
plasma hepatocyte growth factor
level, and plasma IL-8)
Lead investigator: D Rischin
Trans-Tasman Radiation
Oncology Group
Oropharyngeal SCCHN
p16+
Stage III–IV
Excluding T4, N3, or distant
metastases for smokers
≤10 pack-years (otherwise
nodal disease must be
N0–N2a)
*Estimated number

33. Moral of the story

34. Thank
You
Bengal Cancer
Summit
2019