A brief informative discussion on the treatment of squamous cell cancer of the oropharynx is presented to you. Thank you for reading my work.

1. Management of
oropharyngeal cancer
Woldemariam B.
(Clinical oncologist, AAU, TASH)

2. Outlines
• Introduction
• Workup
• Management principle and evidences
• Early stage
• Locally advanced
• HPV associated OPC
• surveillance

3. Introduction
• Oropharyngeal SCC arises in the soft palate, tonsils, base of
tongue, pharyngeal wall, or vallecula.
• OPSCC- consists of 10% of the scc of the HNC, and has M;F
ratio of 3:1.
• The traditional risk factors of smoking and alcohol are
decreasing, while HPV is rising.
• The management of HPV associated OPC is similar although
the prognosis is better.
• The 5-year survival rate of OPC is 68%.

4. Work-up
• Proper workup and staging is required to develop an optimal Rx plan.
• History
• Exposure alcohol, smoking,
• Sexual history
• Physical exam
• Visual examination and/or palpation of mucous membranes,
• Mirror examination or flexible laryngoscopy- tonsillar fossae and
tongue base, and synchronous dse
• Careful neck examination according to the LN levels- (P16+ OPC
asymptomatic neck mass)
• Examination under anesthesia;-
• To obtain a tissue dx, for surgical planning, and
• To search for CUP occult cervical LN (FDG PET-CT should be done 1st ).

5. Imaging
• CT scan
• Cortical bone destruction, skull base invasion & ENE
• MRI-
• Anterior extension of base of tongue tumors
• Assessment of pni and bone marrow signals.
• Evaluation the fat planes, RP nodes and soft tissue extent in the
parapharyngeal and pre-epiglottic spaces
• FDG-PET –
• Distance mets in LA dse, post Rx evaluation, in CUP

6. Biopsy
• Should be done after imaging study
• From the primary or
• FNAC of the neck mass has diagnostic accuracy of 89 - 98
percent.
• HPV Testing
• For all pts with Opc using p16 IHC, a surrogate for HPV asstd
OPC.
• p16 IHC positivity , (at least 70% nuclear and cytoplasmic
expression with at least moderate to strong intensity.)
• Other tests include HPV detection by PCR and ISH.

7. • Discrepancy rate of approximately 10 %, between HPV status and p16
status.
• In one meta-analysis patients with tumors that are both HPV+/p16+
had better 5-year OS and 5-year DFS.
• However, patients with tumors that are HPV-/p16+ had greater 5-year
OS, compared to patients with tumors that are p16-negative
(regardless of HPV status).

8. Treatment of OPC
• Goals
 Control of primary tumor
and regional LNs
 Preservation of anatomy
and function of the organ
 Minimal treatment
complications
• MDT involvement is vital
for treatment decision.
• Early stage; single modality
approach
• Surgery
• Radiotherapy
• For LA-OPC; Combined
modality
• Surgery +/- RT+/-concurrent CT
• RT with/out concurrent CT

9. Early stage OPC
• Non- HPV associated OPC
• primary surgery or
• definitive RT as a single modality.
• Have similar LC and survival, treatment related toxicity is
used in making treatment decisions.
• For early-stage HPV associated OPC,
• Surgery,
• Radiotherapy,
• Chemotherapy, either as single modalities or in
combination.

10. Surgery
• Minimally invasive techniques (TORS, and TOLM) preferably
TORS have;-
improved perioperative mortality
provide accurate staging and can lead to appropriate selection
of subsequent therapy.
• These approaches are most feasible for early (T1, T2)
tumors.
• Pts must be carefully selected to avoided post-op treatment
intensification and toxicity.

11. Management of the neck
• Early tonsil cancers without soft palate or base of tongue
involvement
• selective neck dissection (levels II to IV) in patients
undergoing primary surgery (transoral or open)
• ipsilateral neck RT in patients undergoing definitive RT.
• Tongue base, soft palate, and posterior pharyngeal wall
primary tumors-
• Bilateral neck irradiation or
• Bilateral SND including levels II to IV is recommended
based the treatment used for the primary.

12. Mgt of specific sub-sites
Soft palate
• Surgery; velopharyngeal
Tonsillar cancer
• Either primary surgery
or RT. & the
treatment-related
morbidity should be
weighed.

13. • Base of tongue
• RT is preferred in most patients
• Elective treatment to the bilateral neck. Surgery; for small
tumors, if negative margins can be obtained, and no other
adverse features

14. Adjuvant therapy for early stage OPC
• Salvage surgery; patients with residual disease after definitive
RT.
• Re-resection for positive margin after surgical resection.
• RT with concurrent, platinum-based chemotherapy for positive or
closely resected margins and/or ENE of LNs.
• Adjuvant RT alone for other high risk factors (LN positive, PNI, LVI,
pT3,pT4)

15. Surgery
• Smaller primary tumors with limited LN involvement
• where the primary tumor appears amenable to margin-negative resection
and good postoperative functional outcomes
• For patients with contraindications to RT
• For tumors with gross bony involvement

16. Adjuvant treatment ( post op)
• For patients with resected OPSCC who have the
adverse pathologic features of
ENE with or without a positive mucosal margin,
the recommended postoperative adjuvant
treatment is systemic therapy/RT (category 1).
• For other risk features—such as pT3 or pT4 primary,
pN2 or pN3 nodal disease, nodal disease in levels IV
or V, pni, vascular invasion, or lymphatic invasion, RT
alone is recommended, or systemic therapy/RT may
be considered

17. Adjuvant RT vs CRT

18. AcomparativeanalysisofPO-CRTvsPO-RT
EORTC(#22931)andRTOG(#9501)
• ECE and/or
microscopically involved
surgical margins were the
only risk factors for which
the impact of CERT was
significant in both trials.
• Patients with >/=2
pathologically involved
LNs without ECE didn’t
seem to benefit from PO-
CRT.
A comparative analysis of the selection
criteria, clinical and pathologic risk
factors, and treatment outcomes was
carried out using data pooled from
these two trials.

19. Nonsurgical approaches(RT, CRT)
Candidates
 Unresectable disease
 poor postoperative
functional outcomes
(significant soft palate or
base of tongue tumor
involvement)
 Ineligible for surgery due to
age, PS
options
• CCRT, (or RT alone if there is
a medical contraindication to
CRT),
• ICT followed by RT,
• ICT followed by CRT

20. Definitive RT
• RT- alone is a standard option for patients with stage I to II disease.
• For locally advanced disease, single-modality RT is an option for
selected patients.
Contraindication to platinum-based chemotherapy (eg, hearing loss,
renal insufficiency, neuropathy, bone marrow disease).
Refuse chemotherapy but still desire the locoregional control and
possible survival benefits of RT.
Relatively higher risk of chemotherapy-related complications (eg,
older age, poor social support, noncompliant).

21. Concurrent chemo-radiation
• Concurrent chemo radiotherapy is the preferred organ
preserving treatment aproach.
• The MACH-NC meta-analysis evaluated the efficacy of
chemotherapy administered as induction, concurrent, or
adjuvant therapy following definitive locoregional treatment
(surgery and/or RT).

22. MACH-NC:acomprehensiveanalysisbytumorsite
doi:10.1016/j.radonc.2011.05.036
• IPD of 16,192 pts from 87 studies were analyzed,
• And chemotherapy benefit calculated for each location of
HNCs in terms of OS, EFS and absolute benefit.
• Among the 5872 patients with OPC(both HPV and non-HPV
associated), CRT decreased the risk of death (HR 0.88, 95% CI
0.82-0.93), an absolute 5yr OS benefit of 8%.
• There was also no clear survival benefit with adjuvant or
induction chemotherapy.

23. FinalResultsofthe94-01FrenchHeadandNeckOncologyand
RadiotherapyGroupRandomizedTrial
At 5 years of follow-up
end point RT
alone
Concurr
ent CRT
P value
OS 22% 16% 0.05
SDFS 27% 15% 0.01
LRC 48% 25% 0.002
At 3-years
Concomitant CRT improved OS
and LRC of stage III or IV OPC.
• CRT improved OS and LRC rates and
does not statistically increase severe
late morbidity.
• Anemia was the most important
prognostic factor for survival in both
arms.

24. Radio-sensitizer
• High-dose cisplatin is the preferred CT in CRT.
• For patient-specific concerns about the toxicity of high-
dose cisplatin, weekly cisplatin 40 mg/m2 is non inferior.
• Weekly carboplatin (AUC of 1.5 to 2) is an acceptable agent
for CCRT in patients with a good performance status who
are ineligible for cisplatin.
• Carboplatin/5-FU is also category 1 preferred regimen used
in CRT
• Cetuximab is a less preferred sensitizing agent for CRT in
patients with a good PS who are not candidates
for cisplatin.

25. Wkly vs high dose cisplatinwith CRT
• A systematic review and
meta-analysis including
(https://doi.org/10.1016/j.critrevonc
.2021.103345)
• six randomized studies
involving 554 patients with
SCCHN showed that OS,
PFS, and toxicity did not
significantly differ between
weekly cisplatin and high-
dose cisplatin (both given
with RT).
• ConCERT trial
• noninferiority phase III RCT
• N=278 (60% OPC), stage iii-
iV, randomized to ciplatin
high dose or weekly with
RT.
• LRC rates at 2 years were
57.69% in C arm and
61.53% in T arm, with an
absolute difference of
3.84% and (one sided 95%
CI= -6.15, 13.80) which is
within the pre defined non
inferiority margin of -10%.

26. RadiotherapypluscetuximabforLA-HNC:5-yearsurvivaldatafrom
aphase3randomizedtrial
• N=424, stage III or IV non-
metastatic
• RT with or with out
concurrent Cetuximab
• RT(includes, CF, HF or
concomitant boost)
• median OS in cet/RT and
RT-alone was 49·0 vs 29·3
months respectively (HR
0·73, 95% CI 0·56–0·95;
p=0·018).
• But in an other randomized
Phase III Trial of Concurrent
Accelerated Radiation Plus
Cisplatin With or Without
Cetuximab for Stage III to IV
Head and Neck Carcinoma:
RTOG 0522,
• cetuximab fail to improve
outcome, rather increased
toxicity.
• RCTs also demonstrate the
inferiority of concurrent
cetuximab in P16+ OPC.

27. Docetaxel
• In an open-label phase III
trial conducted in India, doi:
10.1200/JCO.22.00980.
• 356 patients with LRA-HNC
who were ineligible
for cisplatin were randomly
assigned to either RT plus
weekly docetaxel at 15
mg/m2 or RT alone.
• weekly docetaxel plus RT
improved DFS (two-year DFS
42 versus 30 percent, HR
0.67, 95% CI 0.52-0.87) and
OS (two-year OS 51 versus
42 percent, HR 0.75, 95% CI
0.57-0.98).
The addition of docetaxel to RT demonstrated higher grade ≥3 acute
toxicity rates, but it did not worsen QOL at six-month follow-up.

28. ICT followed by locoregional therapy
• Patients who are not ideal candidates for initial CRT but may
tolerate ICT.
• Trials comparing induction CT vs initial CRT are limited.
• Induction CT followed by RT is not superior to CRT for OPSCC and
should not be regarded as a substitute.
• Systemic therapy prior to planned surgical resection for OPSCC is
also less common.
• The use of ICT is a category 3 NCCN recommendation in LA-
OPC(P16- & P16+).

29. Sequential therapy
• The rational behind combined effecacy
• CRT(alredy established benefit)
• ICT(decrease in distant metastases, in MACH-NC))
• ICT followed by CRT; in selected patients with
• advanced primary or nodal disease.
• bulky N2b, N2c low nodes or N3 nodal stage, and perhaps the T3 and T4
populations
• Pts with significant trismus, impaired swallowing and tongue function,
or airway obstruction requiring tracheostomy, to restore function prior
to definitive Rx.

30. InductionTPF+CRTvsCRTaloneinLAHNC.AphaseII-IIItrial
doi:10.1093/annonc/mdx299.
• 421 pts were with LAHNC randomized.
• Concomitant treatment alone [CCRT (Arm A1) or CET/RT (Arm
A2)]
• 3-Cycle of TPF followed by CCRT (Arm B1) or CET/RT (Arm B2).
• At a median follow-up of 44.8 months,
• Median OS was; 54.7 months vs. 31.7 months favoring ICT arm,
(HR 0.74; 95% CI 0.56-0.97; P = 0.031).
• Median PFS were also in favor of ICT: 30.5 months vs. 18.5
months.
• CR (P = 0.0028), PFS(P = 0.013) and the LRC(P = 0.036) were also
significantly higher in the ICT arm.

31. • However one Spanish trial, and others including the decide trial fail
to demonstrate similar efficacy of sequential treatment.
• The use of sequential therapy should be an individual
clinician/patient decision
• reserved for those very healthy patients at high risk for both distant
and LR recurrence.
• Intensification approaches are also most relevant for non-HPV
associated disease.
• Is an NCCN category III recommendation for OPC

32. RT principle
• Radiation dose prescription and schedule
• Depends on the primary tumor and neck node size, fractionation, and
clinical circumstances, including whether concurrent systemic therapy
will be used.
• Po-RT is recommended based on stage, histology, and surgical-
pathologic findings.
• RT uses a treatment plan based upon the tumor's initial size,
location, and relation to normal organs.
• IMRT or other conformal techniques are used,
• Proton therapy can be considered when normal tissue constraints
cannot be met by photon-based therapy.

33. Radiation fractionation
• No single fractionation schedule has proven to be best for all tumors.
• Data strongly indicate that SCCHN can grow rapidly and may
compensate for RT-induced cell loss through the mechanism of
accelerated repopulation.
• A number of trials done to test for different fractionation regimens to
overcome this.
• In the Definitive RT
• The EORTC protocol 22791
• The RTOG 90-03 trial
• Rtog 90-03

34. EORTC - 22791
• 325 pts with T2-T3, N0–1
OPC excluding base of
tongue primaries
• The end-point of the trial
was locoregional control
• At 5 years, a statistically
significant increase in LC
observed in the
hyperfractionation arm (38%
vs. 56%; P = .01) and
• The improvement in LRC
mostly observed in larger
tumors (T3)regardless of
nodal stage (No or N1).
• No increase in late
complications was observed.

35. EORTC 22851
• RCT
• N=512
• T2-4, any N, HNC, (hypo
pharynx excluded)
• Conventional RT vs AFX
RT(72GY/45#/5wks, 2wks
rest in b/n)
• AFX results in increased local
tumor control 13% benefit at
5yrs(46% vs 59%)
• Only a trend towards
improvement in survival
P=0.06.
• Unexpected increase in late
effects, some of which are
letal.
A less toxic scheme should, however, be investigated before using
accelerated RT as a standard regimen.

36. TheRTOG90-03hyperfractionationandtwovariantsof
acceleratedfractionationversusstandardfractionation
• HFX arm showed superior
LRC and survival at 5 years
compared with the SFX
arm (HR, 0.79; 95% CI,
0.62–1.00; P = .05).
• AFX-C was associated with
increased late toxicity
compared with SFX
• 1076 eligible patients with
stage III/IV squamous cell
cancer were randomized to
4 treatment arms

37. • Included IPD from 11,423 patients in 33 trials of RT as single modality
comparing altered fractionation with conventional fractionation.
• Median follow-up of years.
• Earlier MARCH(2006) study showed altered fractionation RT improved
OS and PFS compared with conventional RT, with hyperfractionated RT
showing the greatest benefit.
• This update aims to confirm ;
• ? the superiority of hyperfractionated RT over other altered fractionation
RT regimens
• ? the benefit of altered fractionation in the context of concomitant
chemotherapy.

39. Fractionation in CRT
• NCCN “conventionally fractionated radiation in combination with
most concurrent systemic therapies in the definitive treatment
setting.”
• Two randomized trials have not observed a benefit from altered RT
fractionation schedules when the RT is given in combination with
concurrent chemotherapy.
• RTOG 0129
• GORTEC90-02

40. GORTEC 99-02 RTOG 01-29
• In GORTEC 9902; ; conventional CRT improved PFS compared with
very accelerated radiotherapy (0·82, 0·67–0·99; p=0·041).
• In RTOG 0129; cisplatin, AFX-C neither improved outcome nor
increased late toxicity in patients with LA-HNC.

41. HPV associated OPC
• Given the excellent long-term prognoses of these patients, the
approach to treatment must take into consideration;
 oropharyngeal function preservation,
 the potential for late treatment-related toxicities, and
 avoidance of unnecessary intensification of therapy, if possible.
• Yet there are insufficient phase III data to alter therapy based
on HPV status .

42. • The treatment algorithms for p16-positive disease have been
divided by the NCCN panel into four staging categories and is
separate from HPV-ve OPC:
 cT1–2, cN0 – definitive RT Vs surgery
 cT0–2, cN1 (single node ≤3 cm) – definitive RT Vs CCRT(C-2B) Vs
surgery
 cT0–2, cN1 (single node >3 cm, or 2 or more ipsilateral nodes ≤6 cm);
or cT1–2, cN2; or cT3, cN0–2 – CCRT Vs surgery
 cT4 or cN3- CCRT

43. • T0-T2, N1- nonsmoking patients , single involved node ≤3 cm
without adverse features (eg, no radiographic evidence of
extranodal extension), single-agent IMRT.
• CCRT- For patients who are active smokers , heavy smokers (ie, >20
PYH), or
• have one involved node with certain high-risk features :
Endophytic, ulcerated primary tumor
Radiographic evidence of extranodal extension or nodal matting
Additional highly suspicious or clustered small lymph nodes
Retropharyngeal, level IV or V lymph node involvement

44. Treatment de-intensification?
Rx-De-intensification
• Treatment approach that aims to preserve superior oncologic
outcomes while minimizing treatment-related toxicity in P16+
OPC.
• Many different approaches have been or are being studied
• Surgical replacement of CRT/RT,
• A lower dose of adjuvant RT,
• ICT to de-escalate definitive RT dosing,
• Dose-reduced definitive RT alone, or
• substitution of a potentially less toxic drug than cisplatin.

45. Surgery vs RT
ORATOR trial
• N=68 OPC pts (T1-2 N0-2) 88%
P16+,
• between RT +/- (concomitant
cisplatin) Vs TORS with/out ND
+/- adjuvant RT or CRT,
• The RT arm show a better
swallowing quality outcome
• The OS and PFS are similar b/n
the two arms.
• This isn’t a deintensification
trial,
• so ORATOR-2 randomized HPV+
T1-2 N0-2 oropharyngeal
patients between two
deintensified treatments
ORATOR2; a phase II trial
The trial was closed early due to
unacceptable risk of grade 5 toxicity in the
SOT arm.
• At 17 months 3 OS events and 4 PFS
events all in the TOS.

46. Dose-reduced adjuvant RT
• ECOG 3311phase II,HPV +OPSCC
without matted nodes and treated with
transoral surgery,360 eligible
• low-risk disease -observed.
• intermediate-risk disease
low-dose (50 Gy) or
standard-dose (60 Gy) adjuvant RT.
• high-risk disease (eg, +VE margins, 5 or
more +nodes, one node >6 cm, or ENE
>1 mm), adjuvant CCRT(60 to 66 Gy of
RT).
• Among the patients with
intermediate-risk disease, patients
receiving either 50 Gy or 60 Gy of
RT demonstrated similar 3-yrs PFS
and OS.
• Compared with 60 Gy of RT,
treatment with 50 Gy of RT lowered
rates of grade ≥3 treatment-related
toxicity (15 Vs 25 %).
Intermediate-risk disease (ie, margins<3 mm, 2to 4 +ve nodes or a single
node >3 cm and ≤6 cm, ENE≤1 mm, or PN/LV invasion), randomly assigned
to receive either

47. Reduced-DoseRadiationTherapyforHPV-Associated
OropharyngealCarcinoma
NRG Oncology HN002
• N=306, pts p16+, T1-T2 N1-
N2b M0, or T3 N0-N2b M0
OPSCC (AJCC 7th ed,) with ≤
10 pack-years of smoking
• Arm1; 60GY/6wks with wky
cisplatin
• Arm2; 60GY/5wks alone
Ongoing
• Although both the arms in this study performed relatively
well, there is high confidence that the CRT arm did not
compromise PFS.
• Arm2 achieved prespecified end points to a phase III study.

48. Change Cisplatinto cetuximab
• In three randomized phase III trials, cetuximab and RT was compared
to cisplatin and RT as a de-intensification treatment strategy for HPV-
positive LA-OPC,
• but cetuximab and RT proved to be inferior to cisplatin and was not
better tolerated.
• RTOG 1016 non-inferiority trial
• the randomized phase III De-ESCALaTE HPV trial
• TROG 12.01 trial,

49. Inductionchemotherapy
• Induction chemotherapy treatment response guided de-
intensification has been studied in multiple phase ii trials
with heterogeneous design, and outcome.
• Data suggest that induction chemotherapy may allow for
the deintensification of RT.
• However, given the toxicities, it is unknown to what
extent induction chemotherapy constitutes deintensified
treatment.

50. HPV vaccine and OPC
• The effect of prophylactic HPV vaccines is well documented for
prevention cervical and anal cancer .
• In one review, the average relative prevention percentage (RPP), of
oral and Opx HPV infection amongst all the studies was 82.7% (CI
81.8–83.7%.), but the efficacy of prevention of HPV asstd OPC can’t
be estimated.
• CDC recommends HPV vaccination for 11- to 12-year-olds. And for
everyone upto 26 years, if not vaccinated already.
• Boys and older females are secondary targets for vaccination in the
WHO.

51. surveillance
• H&P exam (including a complete head and neck exam; and mirror and
fiberoptic examination):
• Year 1, every 1–3 mo
• Year 2, every 2–6 mo
• Years 3–5, every 4–8 mo
• >5 years, every 12 m
• Annual evaluation for panhypopituitarism following RT to the skull base.
(category 2B)
• There are no consensus guidelines on the frequency and modality of
routine post-treatment imaging in the asymptomatic patient.
• Obtain CT and/or MRI within 3–4 months after surgical treatment
• Thyroid-stimulating hormone (TSH) every 6–12 mo if neck irradiated.
• Dental evaluation.
• Supportive care and rehabilitation

52. References
• NCCN Guideline, Head and Neck Cancer, V2.2023
• UpToDate online
• DeVita, 12th ed.
• Perez & Brady’s Principles and Practice of Radiation Oncology, 7th
Edition,2018
• Target Volume Delineation for Conformal and IMRT,

53. Thank you!