Oropharyngeal cancer

1. MANAGEMENT OF
OROPHARYNGEAL CARCINOMA
Dr. Sachin S,
Junior Resident,
Dept. of Radiotherapy &Radiation Medicine,
SSH,IMS,BHU

2. Workup
Proper history and physical examination
Biopsy & p16 assay
MRI- face and neck / CECT face + neck
Endoscopy, laryngoscopy (FOL / IL)
Chest X-ray (CT thorax in advanced stages)
CBC, KFT, LFT, Viral markers
Dental prophylaxis
Swallowing and speech assessment

3. Why separation to HPV +ve and -ve groups?

4. Why better outcomes in HPV +ve OPSCC?
1. Harbour fewer different genetic alterations, which can be associated with better
response to therapy
2. The absence of field cancerisation (most are non-smokers)
3. Immunologic response play a role in improved response to CRT
4. Younger age, good performance status, fewer comorbidities of HPV-positive
oropharyngeal cancer patients may also contribute to improved survival
5. HPV-associated tumors may be less hypoxic - increase responsiveness to RT.

6. p16 + oropharyngeal cancers

7. Stage Clinical Pathological
I
T1-2 N0 M0
T0-2 N1 M0
T1-2 N0 M0
T0-2 N1 M0
II
T0-2 N2 M0
T3 N0-2 M0
T0-2 N2 M0
T3 N0-1 M0
T4 N0-1 M0
III
T0-3 N3 M0
T4 N0-3 M0
T3-4 N2 M0
IV Any T, any N, M1 Any T, any N, M1
Prognostic stage groups – p16+ OPSCC

8. p16 - oropharyngeal cancers

9. p16 - oropharyngeal cancers

10. p16 - oropharyngeal cancers

11. AJCC 7th vs 8th edition - Oropharynx
• Tis (in situ) not included in p16+ oropharyngeal cancer
• T0 only used in p16+ metastatic lymph nodes (unknown primary carcinoma)
primary tumor presumed to be oropharyngeal cancer
• In p16+ oropharyngeal cancer, T4a and T4b unified in a single category (T4)
• For p16- OPSCC, changes only in clinical N3 (ENE positivity)
• Different clinical and pathological node staging for p16+ OPSCC

12. AJCC
7th
AJCC
8th

13. Management goal
• Oropharynx is a site involved in speech, swallowing, airway conduit
• Maximize survival while minimizing morbidity

14. Definitive RT – Early stage
• Single modality: good outcomes and functional preservation.
• Randomized data and meta-analyses support an overall survival benefit with the use of accelerated
fractionation or hyper-fractionated RT.

16. • 1476 patients randomly assigned five (n=726) or six (n=750) fractions a week at the
same total dose and fraction number (66–68 Gy in 33–34 fractions to all tumor sites
except well-differentiated T1 glottic tumors treated with 62 Gy)
• Primary end point was LRC

17. 6 # 5 # P Value
LRC 70% 60% 0.0005
DFS 73% 66% 0.01
Acute
Reactions
53% 33% 0.0001

19. Fu et al IJROBP 32:577–588, 2000
•1113 patients entered , 1073 patients randomised

23. Conclusion
HFX and AFX-C decreased 5-year local-regional failure by 19% when compared with SFX
HFX, unlike AFX-C or accelerated therapy did so without increasing late toxicities

24. Definitive CCRT – Locally advanced stage
Radiotherapy with Concurrent Cisplatin is
the standard of care

25. CCRT RT p value
5 yr OS 22 % 16 % 0.05
5 yr
DFS
27 % 15 % 0.01
LRC 48 % 25 % 0.002

26. Conclusion
Concomitant chemo-radiotherapy improved OS and LRC and does not statistically increase severe
late morbidity

27. MACH NC Meta-analysis
Pignon, Lancet 2000; 355: 949–55
70 randomized trials – 3 comparisions
1. The effect of chemotherapy – LRT vs LRT plus chemotherapy.
2. The timing of chemotherapy — NACT plus RT vs concomitant or
alternating Radio-Chemotherapy with same drugs.
3. Larynx preservation with neoadjuvant chemotherapy —radical surgery
plus RT vs NACT + (RT in responders or radical surgery and RT in non-
responders)

28. Effect of Chemotherapy on survival
63
trial
s

29. Conclusion
Addition of CTH to LRT - small, but statistically significant, overall benefit in survival
(absolute benefit at 2 and 5 years was 4%)
No significant benefit of adjuvant or NACT but a significant benefit of CCRT
(absolute benefit at 2 and 5 years of 8%)

30. MACH-NC: Updates
• 87 trials - 16665 patients
• Median f/u 5.5 years
• Absolute benefit for chemotherapy of 4.4% at 5 yr.
• CCRT group: absolute survival benefit at 5 year is 8%
• Further updates consolidated the benefit of CCRT
IJROBP, Vol. 69, No. 2, Supplement, pp. S112–S114, 2007

31. MACH- NC-Conclusions
Addition of CT - Absolute benefit in survival-5% in 5 yrs.
Induction/adjuvant - 2% survival benefit
Concurrent CTRT 8% - 5yr survival benefit
Platinum based regimen more effective.
No significant difference in efficacy between mono and multiple drug platinum regimens
Small reduction in distant metastasis found in population of patients with CTRT
Inverse relation between age and impact of CT - disappears by around age of 70

32. Locally advanced SCCHN
Induction TPF→CRT vs CRT
Three cycles of TPF f/b CCRT (either Docetaxel or carboplatin) vs CCRT
alone with two cycles of bolus cisplatin
145 Patients
Stage III-IV (55% Oropharynx)
Median follow-up : 49 months
Primary end point - OS
Lancet Oncol 2013; 14: 257–64

33. No significant difference noted between those patients treated with IC f/b CCRT
vs CCRT alone
TPF→CRT CRT
p
value
OS 67% 83% 0.47
PFS 73% 83% 0.22

34. LAHNSCC
840 patients (66% oropharynx pts)
3 arms
1. Conventional CTRT (70 Gy/35# + 3 cycles concomitant carboplatin-fluorouracil)
2. Accelerated CTRT(70 Gy in 6 weeks +2 cycles of 5 days concomitant carboplatin-fluorouracil)
3. Very accelerated RT alone (64·8 Gy @ 1·8 Gy BD in 3·5 weeks)
Median FU - 5·2 years
Primary endpoint - PFS

35. Grade 3–4 acute mucosal toxicity
• very accelerated radiotherapy (84%)
• accelerated CT-RT(76%) or
• conventional CT-RT(69%; p=0·0001)
Acceleration of radiotherapy cannot compensate for the absence of chemotherapy

36. Vermorken JB et al N Engl J Med 2007;357(17):1695-1704
• 358 patients ( 46% oropharynx)
• Unresectable stage III–IV head and neck cancer
• TPF (docetaxel/cisplatin/5-FU) vs. PF (cisplatin/5-FU) IC f/b RT alone
• Primary end point - PFS
TPF PF p value
PFS 11 months 8.2 months 0.007
OS 18.8 months 14.5 months 0.02

37. Vermorken JB et al N Engl J Med 2007;357(17):1695-1704

38. • 501 patients ( 52% oropharynx)
• Unresectable stage III–IV head and neck cancer
• TPF (docetaxel/cisplatin/5-FU) vs PF (cisplatin/5-FU) IC f/b RT alone
• Primary end point - OS
Posner et al N Engl J Med 2007

39. TPF PF P value
3-yr OS 62% 48% 0.006
Median Survival 71 months 30 months 0.004
LRC 70% 62% 0.04
Posner et al N Engl J Med 2007

40. RT Simulation
• Supine position
• Thermoplastic cast for immobilization
• Neck neutral or slightly extended, shoulders pulled down to maximize
exposure
• Bite block – facilitate immobilization & ↓ amt of normal tissue in field
• For BOT – keeps primary tumor in field
• For soft palate - ↓ amt of unnecessary irradiated tongue
• CECT should be taken from above the calvarium to the carina

42. Conventional Field borders
• Upper margin – upto zygomatic arch
• Posteriorly – tip of mastoid
• Anteriorly – depending upon the clinical
extension(2 cm beyond the disease)
• Inferiorly – thyroid notch (3-field)

43. Conventional Field borders
LAN
• Superior: Lower border of throid notch and match with upper
neck lateral fields
• Inferior: inferior edge of the clavicular head
• Lateral: Two thirds of the clavicle or 2 cm lateral to
lymphadenopathy (which ever more lateral)

45. Conventional RT planning
Base of tongue:
• Risk of subclinical
nodal disease is
probably at least 50%
• Low neck is treated
with an anterior field
with a tapered midline
larynx block.

46. Tonsil
• T1-T2/N0 well-lateralized tonsil lesions
with no tongue invasion and no significant
extension onto the soft palate, I/L
treatment with wedge pair can preserve
C/L salivary flow
• Advanced disease - parallel-opposed
portals with either a 3:2 or 1:1 weighting

47. Conventional RT treatment
• The treatment is generally done in 2 or 3 phases.
• 2 phase:
Phase I : 44 Gy/22 # to B/L + LAN
Phase II : 22-26 Gy to the cone down volume after off-cord
• 3 phase:
Phase I : 44 Gy/22 # to B/L + LAN
Phase II : 16 Gy to the cone down volume after off-cord
Phase III : 10 Gy to the boost volume by further conforming to the GTV

48. RT technique
IMRT
Ability to minimize normal organ exposure to radiation.
This is particularly important for oropharyngeal cancer
Pharyngeal constrictor doses and parotid doses are associated with dysphagia and
xerostomia

49. RT volumes
GTV:
• GTV –P & GTV-N
CTV - HR: (66-70Gy)
• GTV + 5mm
CTV – IR: (60-63Gy)
• CTV-HR + 5mm, nodal - 1 level above and below involved level
CTV – LR: (54-60Gy)
• elective nodal volumes

51. Neck volumes
For oropharyngeal tumors – neck nodal volumes taken are B/L level II – IV and Retropharyngeal
node
Level IB - when node is + or large II node , that cannot rule out involvement of level IB , tumor
extension into oral cavity
Level V - positive node , large matted Level IV

52. Indication for ipsilateral radiotherapy
Well lateralised Tonsillar cancer cases not involving the base of tongue and with minimal
involvement of soft palate.
Patients with c/l cervical lymph node involvement usually seen in patients with tumor
approaching or crossing midline or have extensive I/L cervical lymph node involvement.

53. Study related with ipsilateral-only RT

54. • No c/l neck progression in patients with T1 tumors.
• Only 1-2 % c/l involvement occur in T2 tumors.
• C/L nodal progression in T3 tumor was 3 to 10 %.
• C/L nodal progression was associated with-
• Both base of tongue and soft palate involvement (13%)
• T3 stage (10%)
• Involvement of the midline of the soft palate (16.5%)
Rationale with ipsilateral-only RT

55. Treatment De-escalation – p16+ OPSCC
• Replace Cisplatin with Cetuximab - 3 Negative Phase III trials
• NACT Decreased RT doses - Positive Phase II, Phase III underway
• CTRT with decreased RT and chemo doses - Positive Phase II study
• Omitting Chemotherapy - HN002 Phase II Trial - Same OS, Phase III needed
• Protons instead of Photons - Phase II/III trial underway
• Less invasive surgery (TORS) - Phase III trials underway

56. N Engl J Med 2010; 363:1576

59. RT vs TORS + ND for OPSCC (ORATOR)
An Open-label, Phase 2 RCT

61. TORS for early OPSCC
From 2010 to 2022
Tors is investigational and struggling hard for ideal
case selection for single modality therapy to treat
opscc
Far away from reality in our country
Oropharynx - all subsites can be effectively treated by RT as
a single modality in early stage

62. Treatment De-escalation For HPV+ OPSCC:
A Systematic Review And Meta-analysis
• Primary outcome – OS, Secondary endpoints - PFS, LRC, and DM expressed as HR
• 55 studies (1393 references) - 38929 pts
• De-intensified t/t:
reduced OS in HPV+ OPCs (HR = 1.33,p < 0.01)
reduced PFS (HR = 2.11, p < 0.01)
reduced LRC (HR = 2.51, p < 0.01)
reduced DC (HR = 1.9, p < 0.01)
• CCRT improved survival in definitive setting compared with RT alone (HR = 1.42, p < 0.01)
• In adjuvant setting, standard and de-escalation strategies provided similar OS
• In conclusion, in pts with HPV+ OPC, de-escalation t/t should not be widely adopted in clinical
practice - risk of offering sub-optimal t/t
Review . 2022 May;44(5):1255-1266. doi: 10.1002/hed.27019. Epub 2022 Mar 3.

63. HPV mediated OPSCC - conclusion
• CCRT with Cisplatin remains the standard of care for locally advanced HPV-OPC, although it is
being challenged by de-escalation clinical trials.
• Multiple de-escalation strategies in pts with favorable-risk HPV-OPC have excellent short term
survival outcomes, but phase III data are needed
• Cetuximab + RT is inferior to cisplatin + RT for definitive t/t of pts with HPV-OPC

64. HPV mediated OPSCC – conclusion
• Novel predictors of pts at risk for recurrence (hypoxia, circulating tumor DNA, and genomic data
- PIK3CA, p53) are likely important for additional risk stratification in next-generation trials
• Other pt factors that might impact outcomes include neutrophil/lymphocyte ratio, microbiome,
body mass index, nutritional markers, and comorbidities
• Well-designed, large, randomized, multi-center clinical trials needed to refine, optimize, and
establish a treatment paradigm for HPV+ OPSCC that optimizes oncologic outcomes while
reducing acute and chronic toxicities - A way far away in India.

65. Surgery
• Very early tonsillar lesions:
• limited to anterior tonsillar fossa
• Not extending to base of tongue, soft palate or midline
• Exophytic base of tongue lesion that can be excised with negative margin

66. Role of Brachytherapy
• Historically played a role in boosting gross disease following EBRT.
• Developed in the pre-IMRT, preconcurrent chemotherapy era.
• Interstitial implants selectively used in
Accessible lesions
Small (preferably <3cm) tumors
Lesions away from bone
N0 nodal status
Superficial lesions

67. Brachytherapy guidelines
American Brachytherapy society (ABS)
• Recommend – EBRT doses of 45 to 60 Gy followed by an HDR boost of 3-4
Gy per fraction for 6 to 10 doses.
• With locoregional control of 82 % to 94 %.
• Prophylactic tracheostomy is often required.

68. Recurrent Locoregionally confined
squamous cell carcinoma of oropharynx
Options:
1. Surgical salvage
2. Re-irradiation
3. Palliative / metronomic chemotherapy
4. Supportive care

69. TAKE HOME MESSAGE
1. Upfront surgeries are difficult and morbid, TORS yet to develop in our country
2. NO role for IC/NACT at present
3. So the management – RT (early) / CCRT (locally advanced)
4. RT - hyperfractionation can be considered

70. TAKE HOME MESSAGE
1. PAROTID SPARING IMRT ALONG WITH HIGH DOSE CDDP IS
THE RECOMMENDATION
2. Unless for well lateralised early tonsil ca, B/L neck is irradiated
3. Though the epidemiology, staging, prognosis of HPV associated OPC are
different, the cause specific treatment is yet to come.
4. For Oropharynx cancer the toxicities which affects QOL patients - should be
kept in mind ,prevented and treated accordingly.

71. Thank
you