This ppt is providing detail of current status and future direction of treatment deintensification strategies of head and neck cancer in era of HPV positive sq cell carcinoma.

1. Treatment Deintensification in Human Papilloma
Virus-associated Oropharyngeal Squamous Cell
Carcinoma
Dr Rushi Panchal,
Consultant Radiation Oncologist,
M S Patel Cancer Hospital & Shree Krishna Hospital
Karamsad Anand Gujarat

2. Introduction
• From 1988 to 2004, the rates of human papillomavirus
(HPV)-associated OPSCC rose more than 200 percent.
Epidemic of HPV Positivity
• Proportion of oropharyngeal squamous cell carcinoma
associated with HPV has increased from 40.5% in studies
recruiting before the year 2000 to 72.2%.
• Prevalence in India : 15-25%.

3. Introduction
• It has various differences
in its clinicopathologic
features that have
potentially important
implications for staging,
prognosis, and therapy.
• More likely to present
with an T1/T2, & N2/N3
rather T3/4 & N0/1.
T1/T2 is 64% Vs 44% &
N2/N3 is 69% Vs 51%
compared with those
with HPV negative
tumours.
• Significantly less likely to
have a second

4. • HPV DNA integrates with the host DNA,
allowing for the production of viral
proteins E6 and E7. These proteins
interfere with the activation of host
tumour suppressor proteins p53 and Rb,
respectively. Inactivation of Rb by E7
results in the overexpression of p16, a
marker commonly used to identify HPV-
associated cases.
• In the typical HPV negative squamous cell
carcinomas, p53 mutations are very frequent, along
with decreased levels of p16 and increased levels of
pRb. By contrast, HPV positive carcinomas are
associated with wild-type p53, upregulation of p16
and down regulation of pRb.
Pathogenesis in HPV+ Oropharyngeal cancer

5. Management of Ca Oropharynx in pre HPV+ Era
• Early disease (T1 N0 and T2 N0) can be treated by a single modality (surgery or
radiotherapy) & Non-operative management was usually the preferred
approach.
• Loco-regional advanced disease ( T1-2, N2-3/ T3-4,N0-N+) often necessitates
multimodality therapy of either
a. primary concurrent chemoradiation (platinum based/Cetuximab)
or
b. altered fractionation (Hyper>accelerated)
or
c. primary surgical resection (+/- reconstruction) with postoperative RT or CT+RT
when indicated.

6. HPV TESTING FOR HPV-MEDIATED
OROPHARYNGEAL CANCER
• IHC for Expression of p16
is surrogate of HPV
(widely available).
• Other tests include HPV
detection through PCR
(provide additional
sensitivity )and in situ
hybridization-ISH
(provide additional
specificity) and are being
used in case of equivocal
p16 or unclear clinical
scenario.

7. Survival

8. The data reveal a significant
difference in overall survival HR
0.49 [95% CI 0.35–0.69] and
disease specific survival HR 0.41
[95% 0.3–0.56] in favour of the
HPV+ category.
The estimated risk of death for
HPV-positive OPSCC patients is
50 percent lower than for those
with HPV-negative disease.
Survival

9. Survival
5 year OS (AJCC 7th) HPV +Ve OPSCC HPV –Ve OPSCC
I 88 76
II 84 68
III 82 53
IVa 81 45
IVb 60 34

10. Nomogram for OS & DFS in oropharyngeal cancer, Fakhry et al 2017 JCO
35:4057-4065.

14. • HPV associated OPSCC patients are younger and have a
significantly better prognosis. The current standard of care for
OPSCC is derived from older trials with HPV-negative disease result
in excellent cancer control BUT they are also associated with
substantial long-term toxicity potentially representing
overtreatment of favourable-risk HPV patients. There is now great
interest in evaluating less intensive (i.e., de-intensified) treatment
regimens to improve the therapeutic ratio.
Aim of De-escalation

15. Aim of De-escalation
• Acute and late toxicities are both significant problems (grade ≥ 3 toxicity are
approximately 80% and 25%–60%, respectively ) and the possibility of de-escalating
treatment intensity provides an opportunity to reduce mucositis, gastric tube
dependence, osteoradionecrosis, chronic pain, scarring, fibrosis, swallowing
dysfunction, pharyngeal strictures, xerostomia, dental decay, hypothyroidism,
carotid stenosis and stroke, which negatively impact their quality of life. At 24
months after the receipt of radiotherapy (with or without chemotherapy) to the
head and neck, 15% of patients were found to have grade ≥ 2 swallowing
dysfunction, and 8% of patients had progressive dysphagia. Moreover, chronic
effects have been shown to occur in a radiation dose-dependent fashion. Increasing
dose to the supraglottic larynx is also associated with an increased likelihood of
swallowing dysfunction. Stricture and feeding tube dependence increase when the
volume of pharyngeal constrictors receiving 70Gy exceeds 50% and 30%,
respectively, and aspiration increases when >50% of the pharyngeal constrictors
receive 65Gy. Dysphagia increases with every 10Gy above 55Gy given to the superior
and middle pharyngeal constrictors. Therefore, a notable strategy for lessening
treatment morbidity is to reduce the dose and volume of normal tissue irradiated.

16. • The introduction of minimal invasive techniques (TORS/TLM) offers the ability to
reducing the extent of surgery could decrease the risk of surgical morbidity(e.g.
speech/swallow dysfunction, pain, loss of tissue and delayed recovery time).
• Modifying chemotherapy ameliorates haematological toxicity, neurotoxicity,
nephrotoxicity, ototoxicity and emetogenicity. The addition of chemotherapy to
radiation is known to increase rates of acute and chronic toxicity. Rate of grade ≥ 3
toxicity is 52% Vs. 89.5%in the RT alone Vs. CT+RT cohort. Trend for worsened
mucositis was observed by Adding chemotherapy. demonstrated a 10% increase in
the placement of a gastrostomy tube when compared to radiotherapy alone.
Disturbingly, 10-year results of RTOG 91-11 demonstrated increased non-cancer
mortality in the concomitant chemo-radiation arm (30.8%) compared to radiation-
alone arm (16.9%).
• Efforts should be made to reduce radiation related morbidity, and radiation dose
reduction below 55Gy may lead to improved functional outcomes regard to
dysphagia.
Aim of De-escalation

17. Tobacco usage and risk stratification
K. Kian Ang et Al, n engl j med,2010.
3-year OS of
93%
3-year OS of
70%
3-year OS of
46%

18. De-escalation treatment strategies
• Concern for treatment-induced morbidity has prompted the initiation of
multiple trials aiming to reduce treatment-related toxicity each with their own
“pros” and “cons.
• Exploring cetuximab as an alternative to cisplatin when given concurrently with
radiation.
• Reduction of radiation dose when given in combination with chemotherapy as
primary treatment (guided by induction chemotherapy response).
• Reduce total radiotherapy/concurrent chemotherapy dose.
• Reduction of adjuvant chemotherapy or radiotherapy dose following primary
treatment with surgery (guided by histopathological features in the resected
specimen.

19. cetuximab as an alternative to cisplatin when given
concurrently with radiation
Active but not recruiting

20. • Primary End Point: Over all Survival
It is a randomised clinical trial with a non-inferiority design to compare overall
survival when treated with radiotherapy plus cetuximab versus radiotherapy plus
cisplatin. Study group investigated the hypothesis that cetuximab would maintain
a high proportion of patient survival and reduce acute and late toxicity.

22. • In a post-hoc analysis of the
treatment effect, the one- sided 95%
upper CI for the HR was greater than
1·45 for all demographic and clinical
subgroups. Relative to treatment
with cisplatin, patients with a Zubrod
performance score of 1 did
significantly worse when treated with
cetuximab (HR 2·66, one- sided 95%
upper CI 4·32. due to lower mean
dose of cetuximab (1879 mg/m2 vs
1961 mg/m2), and a slightly higher
mean dose of cisplatin (192 mg/m2 vs
182 mg/m2).

23. Outcome at 5 years post treatment

24. Toxicity Profile
• An alternative measure of the overall acute toxicity burden for patients is provided by the T­­score—the mean number of grade 3–4 acute
adverse events per patient.13 Patients in the cetuximab group had a significantly lower T- -score than did those in the cisplatin group (raw T--score
2·35 vs 3·19; p<0·0001), corresponding to a 40% lower acute toxicity burden.
• With regard to late toxicity in the cetuximab versus cisplatin groups, neither overall number of one or more grade 3–4 adverse events (62 of
375 patients, 16·5%, 95% CI 12·9–20·7 vs 78 of 383 patients, 20·4%, 16·4–24·8, p=0·1904; table 2) or mean number of grade 3–4 adverse
events (raw A--score 0·27 vs 0·38; p=0·1189) were significantly different.

25. • Acneiform rash was significantly more
frequent in the cetuximab group,
whereas myelosuppression, anaemia,
nausea, vomiting, anorexia,
dehydration, hyponatraemia, kidney
injury, and hearing impairment were
significantly more frequent in the
cisplatin group.
Toxicity Profile

26. • There were no notable differences between
groups for treatment -related grade 3–4 adverse
events over time. At 1 year after treatment, 30
(8·5%, 95% CI 5·8–12·0) of 351 patients in the
cetuximab group and 36 (10·0%, 7·1–13·6) of 360
patients in the cisplatin group had grade 3–4
adverse events.
• At treatment completion, 225 (57·3%, 95% CI
52·2–62·2) of 393 patients in the cetuximab group
and 243 (61·5%, 56·5–66·3) of 395 patients in the
cisplatin group had a feeding tube. These
proportions dropped to 30 (8·4%, 5·8–11·8) of 356
patients in the cetuximab group and 34 (9·2%,
6·5–12·7) of 368 patients in the cisplatin group at
1 year after treatment (p=0·79).
• Patient- reported severity of swallowing problems
increased in both the cetuximab and cisplatin
groups from pre treatment to end of treatment,
but no difference was observed between groups
in change scores from baseline (mean 47·4 vs
48·0; p=0·86). At 1 year, the cetuximab group had
a statistically significant increase in symptoms from
pre treatment compared with the cisplatin group
(7·6 vs 2·5; p=0·0382), but this difference was
below the estimated clinically important

27. • After median follow-up duration of 4·5 years Radiotherapy plus cetuximab did not meet the criteria for
non-inferiority for overall survival when compared with radiotherapy plus cisplatin rather Radiotherapy
plus cetuximab treatment led to inferior overall survival when compared with radiotherapy plus cisplatin
treatment in locally advanced HPV + ( in both low- risk and intermediate -risk groups ) OPSCC. Cetuximab
was estimated to increase the risk of death by 45% (hazard ratio 1·45, 95% CI 1·03–2·05), the risk of cancer
progression or death by 72% (1·72, 1·29–2·29), and locoregional failure by 105% (2·05, 1·35–3·10).
• Profiles of moderate to severe acute and late toxicities were different for patients treated with cetuximab
versus cisplatin, but proportions of one or more such events were similar.
• RTOG 1016 Establishes the first standard of care( no prior phase III trial ) in HPV-positive oropharyngeal
carcinoma.
Accelerated IMRT 70Gy/6weeks + 100mg/m2 cisplatin x 2.
Outcome are very good (85%OS at 5 years),albeit with moderate to high toxicity burden.
• Cetuximab should not be substituted for cisplatin for patients with HPV-positive oropharyngeal cancer
who are platinum eligible. it might not be appropriate to extrapolate the results of RTOG 1016 to HPV-
negative head and neck squamous cell carcinoma.
Conclusion

28. • Setting: open label multicentric randomized controlled phase 3 trial (Ireland, the Netherland, and the UK) n=334, 2012-
2016.
• Inclusion Criteria: locally advanced – 7th
AJCC T3N0–T4N0, and T1N1–T4N3
Age: >18 Years
HPV+ Low risk OPC (Non smoker or <10PY)
ECOG:0/1
• Primary outcome: Overall severe (grade 3-5) toxicity events at 24 months from the end of treatment.
Secondary outcomes were overall survival, time to recurrence, quality of life, swallowing, and acute and late
severe toxicities reported separately; suspected recurrences were assessed by imaging and biopsy.

29. • We observed no notable imbalances in
baseline characteristics (age, tumour site,
tumour stage, smoking history, performance
status, and comorbidities) between the two
groups
• The mean age was 57 years. 80% of patients
were men, 65% had T1–T2 disease (TNM 7),
76% had N2–N3 disease (TNM 7), and 46%
were either current or past smokers, with a
median lifetime smoking history of 8 pack-
years

30. • Patients had a median follow up of 25·9 months (95% CI 25·5–26·0). The primary outcome of mean number of events per
patient of reported overall severe (grades 3–5) toxicity & rates of all grade toxicity & did not differ significantly between
treatment groups.
• Cisplatin also caused more haematological, metabolic, and renal toxicity than did cetuximab. For cetuximab, the most
common severe toxicities were also gastrointestinal (mean 1·9 acute and 0·2 late events per patient). Cetuximab also caused
more skin toxicity and infusion reactions in the acute phase than did cisplatin.

31. there was a significant
difference between
cisplatin and cetuximab
in 2-year overall survival
97·5% vs 89·4%, hazard
ratio 5·0 [95% CI 1·7–
14·7]; p=0·001 and 2-year
recurrence (6·0% vs
16·1%, HR 3·4 [1·6–7·2];
p=0·0007.
Conclusion:
•Compared with the standard cisplatin regimen,
cetuximab showed no benefit in terms of reduced
toxicity, but Instead showed significant
detriment in terms of tumor control in patients
with low-risk HPV-positive oropharyngeal
cancer.
•Cisplatin and radiotherapy should be used as
the standard of care for HPV-Positive low risk
patients who are able to tolerate cisplatin.
The mean global quality-of-life score
on EORTC QLQ-C30 did not differ
significantly between treatment groups
at any of the timepoints (mean
difference at 24 months of 1·51 points
in favour of cisplatin, p=0·9976

32. Induction chemotherapy followed by decreased chemo-
radiotherapy dose in good responders

33. IC ( Cisplatin + paclitaxel + Cetuximab ) x 3
cCR PR/SD
54Gy/27# with weekly Cetuximab 69.3Gy/33# with weekly Cetuximab
• Primary end point: 2 year PFS.
• Secondary end points included 2-year OS, clinical and radiologic
responses at the primary and nodal sites after IC and after overall
treatment, and safety and toxicity of treatment.
Patients with HPV16 and/or p16-positive,Resectable stage III-IV OPSCC received three cycles of IC with
cisplatin, paclitaxel, and cetuximab. Patients with primary-site cCR to IC received intensity- modulated
radiation therapy (IMRT) 54Gy(22% reduced dose of 70Gy) with weekly cetuximab(substituted for
Cisplatin); those with less than cCR to IC at the primary site or nodes received 69.3Gy and cetuximab to
those regions.

34. • The median age was 57 years (range,
35 to 73 years) and the majority had
stage T1-3 (89% of 80 eligible
patients), N0-N2b (69% of eligible
patients) OPSCC and were not
current smokers (84%). Ninety-six
percent were p16 positive.

36. ACUTE TOXICITY
The IC regimen of cisplatin, paclitaxel,
and cetuximab was well tolerated. 96%
of patients received all planned cycles,
without major delays or increase in
toxicity burden.
With 54 Gy of radiation and concur-
rent cetuximab vs 69.3 Gy of radiation
and cetuximab, the most frequent
grade 3 adverse events were mucositis
(30% vs 47%), dysphagia (15% vs 29%),
acneiform rash (12% vs 24%), radiation
dermatitis (7% vs 12%), and
lymphopenia (12% vs 29%). The
incidence of grade 4 toxicity was
less than 5% in both cohorts

37. Subset Analysis
• 2-year PFS estimate for patients with a primary-site
cCR treated to 54 Gy of radiation (n = 51) was 80%
(95% CI, 65% to 89%). The 2-year OS for these 51
patients was 94% (95% CI, 82% to 98%). For all 80
evaluable patients, 2-year PFS was 78% (95% CI, 67%
to 86%) and OS was 91% (95% CI, 82% to 96%).
• patients treated with IC and reduced-dose radiation
with low-volume disease T1-T3, N1-N2b and </= 10
pack-years of cigarette smoking to have high rate of
disease control, with a 2-year PFS of 96% (95% CI, 76%
to 99%) and OS of 96% (95% CI, 76% to 99%).
All recurrences
occurred in
patients with
>10 pack years
smoking
history.

38. Conclusion
• This prospective study of radiation de-intensification in patients with HPV-associated OPSCC
demonstrates that three cycles of IC with cisplatin, paclitaxel, and cetuximab result in an
excellent cCR of 70%, reducing tumour burden to subclinical disease. We hypothesized that IC
response would identify patients suitable for radiation dose reduction, and among the 51
patients with primary- site cCR treated with 54Gy of radiation, the 2-year PFS estimate was 80%.
• In this trial, baseline tumour and patient characteristics appeared more predictive of outcome
than radiation dose or IC response.
• The authors do not provide details on how many patients were able to receive reduced-dose RT
to both the primary and nodal sites. Complete response rates to neoadjuvant chemotherapy did
not correlate with smoking status (complete response rate was only 45% in never smokers). This
study does not answer the question whether neoadjuvant chemotherapy is needed to de-
intensify RT—is this trade-off necessary?

39. Reduce total radiotherapy/concurrent chemotherapy
dose

40. • Eligibility criteria :
• p16-positive squamous cell carcinoma of the oropharynx or MUO Neck.
• human papillomavirus or p16 positive;
• T0 to 3, N0 to N2c, M0
• <10 pack-years smoking history or >10 -30 pack-years and abstinent for the past 5 years
RADIOTHERAPY : 54-60Gy/30# (54Gy was delivered to anatomic regions at risk for subclinical disease)
CHEMOTHERAPY: Weekly Cisplatin 30mg/m2 once a week x 6
• Primary end point: The primary endpoint of this study was the pathologic complete response (pCR) rate. { biopsy of primary site or
minimally invasive resection (transoral surgery) if primary site partial response & dissection of pre-treatment nodal region - selective
nodal dissection regardless of radiological response Within 6 to 14 weeks after CRT }
• Secondary Endpoint: 2 year LC/RC/CSS/DMFS/OS & PRO-CTCAE & QOL
There are multiple ongoing clinical
trials that attempt to de-intensify
treatment; however, the decrease
in overall intensity is small or the
reduction in one treatment
modality is offset with an increase
of another.

41. The majority of patients were never
smokers or had </=10 pack years
95%. Sixty-four percent were
HPV+/p16+, and 36% were
HPV+/p16+.
All patients received the intended
de-intensified radiation dose of 60
Gy. 93% received 4 weekly doses of
cisplatin &70% received the
planned 6 doses. There were no
toxicity-related treatment delays.

42. Pathological Response
• With a median follow-up of 14.6
months (range, 4-31 months)
overall pCR rate was 86% (37 of
43).
• The pCR rate at the primary site
and in the neck was 98% (40 of
41; 2 patients were T0) and 84%
(33 of 39; 4 patients were N0),
respectively.

43. Toxicity Profile
No patient experienced grade 5 Toxicity. As expected,
chemotherapy-related hematologic toxicity was
minimal. 39% of patients (17 of 44) required a feeding
tube for a mean duration of 15 weeks (range, 5-22
weeks). No patient required a long-term feeding tube.
Rosenbek aspiration scores were similar before
treatment, 4 to 8 weeks after treatment, and 3 to 6
months after surgery for thin (1.3, 1.9, 1.4), pureed (1.0,
1.2, 1.1), and solid substances (1.0, 1.0, 1.1).
Grade 3/4 hematologic toxicities were 11%.
The rates of grade ≥3 toxicities compare favourably to
historical controls
There were no significant differences in modified barium
swallow studies before and after CRT.

44. • The pCR rate with decreased intensity of therapy with 60 Gy of IMRT and weekly
low-dose cisplatin is very high in favourable -risk oropharyngeal squamous cell
carcinoma, with evidence of decreased toxicity compared with standard
therapies.
• reasonable to expect a more favourable long-term toxicity profile with this de-
intensified regimen. Radiation dose was reduced by 16% (70 to 60 Gy), and the
cumulative chemotherapy dose was reduced by 60% (300 mg/m2 to 180
mg/m2).
• We believe the 10-Gy reduction in radiation dose is meaningful because cancer
control and long-term toxicity are predominately correlated to radiation dose.
The dose-response of normal tissue toxicity rises steeply in the high dose range,
so that modest decreases in total dose (in the range used in this study) can have
a major impact on long-term toxicity.
Conclusion

45. • Design: Single Arm, phase 2
• Eligibility: St III/IV Sq. cell P16+ve Oropharynx Carcinoma
2#NACT (n=44)
Paclitaxel (175mg/m2) + Carboplatin (AUC 6)
IMRT with daily IGRT + Conc Paclitaxel 30 mg/m2, Weekly
CR/PR
24(55%)
median follow up =
30mths
<PR/No response
20(45%)
54Gy/27#
43 Gy to uninvolved nodal
areas (SIB)
60Gy/30#
48 Gy to uninvolved areas
(SIB)
• Primary End point: PFS at 2 years
Radiation target volumes were defined
by the extent of disease before
chemotherapy, as assessed by imaging
and physical examination, including
endoscopy, and adjusted to conform to
anatomy after chemotherapy and
acknowledged anatomical boundaries
to tumour spread.

46. 2-year progression-free survival was 92% (95% CI 77–97). Adverse
events during induction chemotherapy were generally mild 26 (39%) of
44 patients had grade 3 adverse events, but no grade 4 events were
reported. The most common were leukopenia and neutropenia. and
during chemoradiotherapy were dysphagia (four [9%]) and mucositis
(four [9%]). One (2%) of 44 patients was dependent on a gastrostomy
tube at 3 months and none was dependent 6 months after treatment.
There were no cases of neutropenic fever. Three (7%) of 44 patients
required dose reductions of paclitaxel and carboplatin in cycle two of
induction chemotherapy because of neutropenia.

47. • Induction chemotherapy followed by chemoradiotherapy with the
radiation dose reduced by 15–20% from the standard yielded similar
2-year progression-free and overall survival to standard
radiotherapy regimens in patients with HPV-positive oropharyngeal
carcinoma, with an acceptable toxicity profile.
• Radiotherapy de-escalation has the potential to improve the
therapeutic ratio and long-term function for these patients.
Conclusion

48. Surgical treatment is the
only modality that
allows pathological
information about
adverse prognostic
factors (e.g.
ECE/LVSI/PNI) & that
influence adjuvant
treatment
recommendations.
Future research is
required to confirm
whether the traditional
risk stratification applies
equally to the HPV
positive cohort. If this is
not the case, equivalent
criteria will need to be
validated, and may be
potentially reliant on
novel markers.

49. TORS patients were less
likely to have positive
margins than were
patients who had
nonrobotic surgery (20.2%
vs 31.0%, P < .001). High-
volume TORS centres had
lower rates of positive
margins (15.8% vs 26.1%,
P < .001) and unplanned
readmissions (3.1% vs
6.1%, P < .03) than did
low-volume centres.
Transoral robotic surgery:
a population- level
analysis. Otolaryngol Head
Neck Surg. 2014
Minimal invasive surgery
is established as an
effective treatment for
early stage OPSCC.
Furthermore, similar to
CRT, HPV-associated
OPSCC is also associated
with a better prognosis
when treated with
primary surgery. The
deintensification of RT
and chemotherapy after
TLM or TORS has been
arbitrary, institution
specific, and has not been
studied in a controlled
manner.

50. Because of the use of
magnification the “host-
tumor” interface is better
visualized, allowing for
more precise negative
margin resections,
maximizing tumour
removal, and limiting
removal of normal
healthy tissue, resulting
in enbloc resection “
surgically targeted
therapy “
The major potential
benefits of primary TLM
and TORS are reduction
in surgical morbidity and
reduction in the intensity
of CRT without
compromising oncologic
outcomes

51. Surgical resection with or without adjuvant chemo-
radiotherapy (based on histopathology risk factors)
• The ADEPT, ECOG 3311 and PATHOS
trials will all randomise adjuvant
treatment strategies
(radiotherapy/chemotherapy) based
on objective histopathological
features from the resected
tumour/neck dissection addressing
the role of de-escalation of
chemoradiotherapy following initial
surgical management. ongoing trials
explore reducing the dose of
adjuvant radiotherapy or eliminating
adjuvant chemotherapy in patients
with pathologic evidence of
extracapsular extension (ECE)—a
departure from the standard of care
adjuvant chemoradiation established
for these patients based on the
combined analysis of EORTC 22931
and RTOG 9501.

52. • ECOG 3311 is a phase II trial in which 377 patients
with p16 +OPSCC are stratified into four arms
according to their surgical pathology. Patients with
intermediate histopathological risk factors will be
randomised to either low-dose (50 Gy) or standard-
dose IMRT (60 Gy).
• Patients deemed low-risk (margin-negative
resection, N0 or N1 disease, no ECE) after resection
are observed, intermediate-risk patients (negative
but ≤ 1 mm margin, +ECE, N2a, or 2–4 involved
lymph nodes) receive adjuvant radiotherapy alone
with 50 versus 60 Gy using standard daily
fractionation, and high-risk patients (>1 mm ECE,
positive margins, or ≥ 5 lymph nodes positive) are
treated with 66 Gy and weekly cisplatin.
• Results of this trial will determine if the combination
of minimally invasive surgical techniques with
reduced intensity adjuvant therapy proves to be less
toxic than current standard of care management,
and may justify a follow up phase III trial comparing
TORS and reduced dose post-operative radiation
therapy with standard chemoradiation.

53. • PATHOS is a UK based phase II trial that has just
received funding for 88 HPV+ Patients stratified
with intermediate or high-risk histopathological
features will be randomised respectively by RT
dose (low dose versus standard dose IMRT) or by
addition of chemotherapy to RT (standard dose
IMRT versus standard dose IMRT + cisplatin) and
the main outcome will be to assess early stage
swallow function.
• While the low-risk classification is the same as ECOG
3311, the other risk group criteria vary. The
intermediate-risk criteria are negative margin, ≥
pT3 disease, or pT1-2 disease with pN2a/b,
perineural invasion, lymphovascular invasion, or
negative but close margin (<5 mm). These patients
receive either 60 Gy in 2 Gy fractions over 6 weeks
or 50 Gy in 2 Gy fractions over 5 weeks. The high-
risk criteria include positive margin or ECE, and
these patients are assigned to receive 60 Gy with
or without concurrent cisplatin.

54. Trial Strength weakness HPV analysis*
RTOG-1016 Inferiority design of
trial
RT dose not reduced p16
De-ESCALaTE RT dose not reduced p16
TROG-12.01 RT dose not reduced p16
ECOG-1308 Small sample size (90
patients)
p16/HPV16
DNA ISH
University of Chicago Commercial sponsor (Novartis) +
Small sample size (80 patients)
p16
Quarterback trial Non-OPSCC cases
included in study
p16/HPV PCR
ADEPT Randomisation based
on histological analysis
p16
ECOG 3311 Randomisation based
on histological analysis
p16
PATHOS Randomisation based Small sample size (88 p16

55. Conclusion
• HPV status is strongly associated with positive therapeutic response and survival compared with HPV-
negative OPSCC, independent of the treatment modality chosen and even after adjustment for stage.
• Appropriate selection of patients for treatment de-intensification is critical in order to avoid jeopardizing
the excellent outcomes that are achieved with the current standard of care therapy in this patient
population.
• Therefore de-intensification is presently not recommended outside of a clinical trial. The approach to
treatment is currently the same for OPSCC of the same stage for AJCC 7 stage cancers. (For example, many
stage I and II HPV associated cancers in AJCC 8 will still be locoregionally advanced and require combined
modality treatment, whereas non-HPV associated stage I and II AJCC 8 cancers will be treated with single
modality surgery or radiation therapy), unless deintensification trials indicate it is safe to de- escalate
treatment. Additional data and longer follow-up will be required.
• A better understanding of the molecular alterations underlying HPV-associated disease should be elucidated
to provide further opportunities for targeted therapies with less toxicity. If these approaches prove
adequate, the quality of life of patients should be significantly improved.
• In the future, these patients will likely be managed with de-intensified therapies, whether it is through de-
intensification of surgery and adjuvant treatment, omission, substitution or reduction of the dose of
chemotherapy, and/or the reduction radiotherapy dose.

56. Thank you