This document discusses the role of adjuvant radiation therapy in head and neck cancers. It begins by outlining the use of radical and palliative treatment for stage III and IV diseases. It then reviews several landmark studies that established the benefits of postoperative radiation therapy (PORT) over surgery alone in improving local control and survival. Key factors that determine the need for adjuvant therapy like extracapsular extension, positive margins, and T3/T4 stage are discussed. The document also addresses optimal radiation dose, timing, use of concurrent chemotherapy and altered fractionation schedules based on evidence from clinical trials. While targeted therapies in the adjuvant setting have not proven beneficial so far, ongoing studies are exploring their potential role.

1. Role of Adjuvant Radiation Therapy
in Head and Neck Cancers
Dr. Ashutosh Mukherji
Sr. Consultant Radiation Oncologist
and Academic Coordinator
Yashoda Cancer Institute, Hyderabad
CME: Head and Neck Oncology: Controversies and Consensus,
28th November 2018, Nizam’s Institute of Medical Sciences

2. Stage III and IV
Radical Treatment
Palliative Treatment

3. Advanced disease-Radical Rx - III&IVa
1.Ca oral cavity(Stage III,IVA)
2.Ca larynx -T4a (Cartilage)
3.T4a hypopharynx (Cartilage)
4.T3 Hypopharynx-Non responders
Surgery
Post op
XRT+/-chemo
NCCN Guidelines V1 2018

4. Evolution of Radiotherapy
 Fletcher and colleagues - (IJROBP 1984)
 MSKCC data - Vikram et al
(head and neck surgery 1984)
 Robertson et al-(clinic.oncology1998)

5. Oral Cavity Cancers treated
with Surgery first: higher chance of cure…

6. Questions to be answered
 Pre op or Post op?
 Dose?
 Duration of treatment?
 Indications for Adjuvant ChemoRT
 Role of Targeted therapy

7. Pre op Vs Post op RT
RTOG 73-03
277 PATIENTS - FOLLOW UP 10 yrs
PRE OP RT POST OP RT
[ 50.0 GY ] [ 60.0 GY ]
• Loco regional control better (p = 0.04)
• No difference in absolute survival (p = 0.15)
• Complications same (p - NS)
IJROBP 1991;20:21-28

8. • Phase 3 RTOG 73-03 trial
• 354 LAHNSCC randomized to pre- and post op RT.
• LRC (48% vs 63%, p=0.03) and survival (26% vs 38%,
p=0.04)
• In favour of PORT for LAHNSCC.

9. Why need adjuvant therapy
after major surgery?
• Stage III/IV a/b cancers have a 30-40% 5 year
survival
• A more than 15% risk of recurrence has
traditionally been used to recommend
adjuvant therapy
Management of Head and Neck Cancer A Multidisciplinary Approach.
2nd ed. Philadelphia: J. B. Lippincott; 1994

10. Advanced oral
cancer
SURGERY
follow-up
3YRSSURGERY+POST
OP RT(60Gy)
Disease free survival 38% v/s 68% ( p < 0.005)

11. Selecting patients?
Risk factors for recurrence
Primary
• positive or close (<5mm)
resection margin
• pT3/T4 tumours
• oral cavity site
• perineural invasion
• lymphovascular space
invasion
• Depth of invasion
• subglottic extension
Nodal
• Extra capsular extension
• 2 or more nodes or 2 or
more nodal stations
involved
• Node more than 3cm in size
Olsen KD et al Arch Otolaryngol Head Neck Surg 1994;120:1370-1374
Huang et al Int J Radiat Oncol Biol Phys 1992;23:737-742

12. Risk stratification of patients
Ang KK et al Int J Radiat Oncol Biol Phys 2001;51(3):571-8
Peters LJ et al. Int J Radiat Oncol Biol Phys 1993;26(1):3-11

13. Depth of invasion
Depth of invasion
(DOI)
Tumor thickness

17. PNI+ = Decrease in
DFS, LCFS, OS

18. Selecting patients
for intervention
MD Anderson Studies
• oral cavity, oropharynx,
hypopharynx. p T3 to T4 in
61%
• 58% had N2 to N3 neck
disease.
• 86% III/IV disease
Peters LJ et al. Int J Radiat Oncol Biol Phys 1993;26(1):3-11
Ang KK et al Int J Radiat Oncol Biol Phys 2001;51(3):571-8
• local–regional control
rate of 83%. = LOW
RISK, not for RT

20. Does RT help in the
adjuvant setting?
Huang et al
Int J Radiat Oncol Biol Phys 1992
1982-88, 441 cases
125 ECS or positive margins 71 Surgery, 54
PORT.
LC@ 3 years S vs PORT:
• ECS: 31% vs 6% (P =0.03)
• positive margins, 41% vs 49% (P =0.04),
respectively; and
• ECS and positive margins: 0% and 68%
(P =0.001), respectively.
• multivariate analysis of local control
• use of PORT (P =0.0001)
• macroscopic
• extracapsular extension (P =0.0001)
• margin status (P =0.09) significantly
impacted local control. DFS@ 3 years
was 25vs 45%
Lundahl et al / Kao et al
Int J Radiat Oncol Biol Phys 1998/2008
95 patients with
node-positive squamous cell
carcinoma who were treated with
S +/- PORT
• 56 matched pairs of patients
were identified
• recurrence in the dissected
neck (RR=5.82; P =0.0002)
• death from any cause higher
for Surgery only group
(RR=1.67; P =0.0182)
Mishra RC et al Eur J Surg Oncol. 1996 Oct;22(5):502-4: PORT improves outcomes

21. Which patients may
NOT benefit from RT?
RT proven to reduce risk:
• Extra capsular extension
• Node positivity
• positive or close (<5mm)
resection margin
• Advanced T stage
What about other risk factors?
• pT1-T2 N0 tumours?
• perineural invasion
• lymphovascular space
invasion
• Depth of invasion
• subglottic extension
• Oral Cavity site

22. Oral Cavity: 461 cases

23. SEER Data base – 8795pts (1988-2001)
5 yr OS
43.2% Vs 33.4%
Cancer 2008;112:535-543

24. 8/31
4/23
0/9
0/19
1/18
Total
0/3
0/4
0/2
4/25
6/109
Total RNDRND
XRT+XRT-
2/12
2/6
0/1
0/2
0/2
0/1
0/2
0
0/1
0/4
4/440/174/24N1ECS-
0/110/80/2N1ECS+
9.5%
23/243
8/34
4/27
7/127
Reg
Rec
13/10010/143
13%6.9%
Regional
Recurrence
6/190/2N2ECS+
2/170/2N2ECS-
1/166/105N0
SNDSND
pN Stage
Role of XRT
Single node ECS -Ve
M D Anderson Data

25. Management of Neck - Single node, NO ECS
Rec.
Surgery 11% 5/47
Surgery + port 0% 0/21
[Retrospective]
Barkley Am j Surg 1972

27. Dose of Adjuvant treatment
Int J. Radiation Oncology Biology Physics Volume 26. Number I. 1993

28. RT details: Dose
Median dose of at least 60Gy
Even lower risk patients for RT have higher
relapse if <57.6Gy
For ECS and positive margins higher dose may
benefit
RT cannot compensate for suboptimal
margins/surgery
Pfreundner L. Int J Radiat Oncol Biol Phys 2000;47:1287-1297

29. RT : Overall time from Surgery
Egyptian studies: Hypothesis
generating (Better LC in higher
risk adjuvant patients)
MD Anderson:
Higher risk arm – Conv RT versus
Altered Frac
• Trend to better LC and DFS for
Altered Frac
• Delay of starting RT >6weeks
=poorer outcome
Overall time from Surgery to Rt
completion>100days= poorer
outcome
Ang KK et al Int J Radiat Oncol Biol Phys 2001;51(3):571-8
Rosenthal et al Head Neck 2002;24:115-126

31. • Ang et al randomized post-operative high-risk HNSCC patients:
63 Gy delivered over 5 / 7 weeks. In the 7-week schedule,
prolonged interval between surgery and post-operative RT
associated with significantly lower local control and survival.
• 5yr LC: for an overall time of <11 weeks, LC 76%, compared to
62% for 11–13 weeks and 38% for >13 weeks (P = 0.002).
Hence post-operative RT should preferably
start within 6 weeks after surgery
Ang KK, Trotti A, Brown BW, et al. Randomized trial addressing risk features
and time factors of surgery plus radiotherapy in advanced head-and neck
cancer. Int J Radiat Oncol Biol Phys 2001;51:571–8.

32. Adjuvant ChemoRT

34. EORTC &RTOG

35. RTOG Study
I. Locoregional control 82% v/s 72% (p = 0.01)
II. Disease free survival better (p = 0.04)
III. Overall survival similar (p = 0.19)
IV. Acute toxicity [GR3] 77% v/s 34% (p < 0.001)
EORTC Study
I. Progression free survival 47% v/s 36% (p = 0.04)
II. Overall survival 53% v/s 40% (p = 0.02)
III. Locoregional recurrences 18% v/s 31% (p = 0.007)
IV. Toxicity [GR3] 41% v/s 21% (p = 0.001)

36. ECE
+ve margin

37. Adjuvant chemoRT
• Margin positive disease
• Extra capsular spread
Good Performance status is mandatory

38. Update 9501
IJROBP 2012

39. Concurrent Chemotherapy
• 3 Cisplatinum based studies
• Carboplatin concurrently may not produce similar
results as cisplatin

40. Combined Analyses:
Justifying Toxicity to Benefit
Eligibility Outcomes
Bernier et al, Head & Neck 2005

42. Summary recommendations
Type of
intervention
Level 1
evidence
(strong)
Level 2 evidence Level 3
evidence
(weak)
CTRT (cisplatin
+RT)
Positive margins,
ECS, fit for CTRT
(age <70)
Close
margins
RT T3.T4 disease; Node
positive without ECS
irrespective of nodal
stations
Positive margins, ECS,
and NOT fit for CTRT
LVI, Depth of
invasion

43. CDDP Weekly Vs 3Weekly?

44. Weekly Versus 3 Weekly
Better LC
with similar
PFS,OS

45. Neoadjuvant Chemotherapy has
No role
in the routine management of oral cancers

46. Chemotherapy Alone prior to RT

47. MD Anderson Data
• Site matched control
• Stage was lower in NACT group (Mainly Taxane based)
• Hypothesis generation: Intense Taxane based NACT can
improve outcomes for matched groups?

48. • Post hoc analysis N2 disease ?? Better with TPF?

50. TPF-CTRT versus CTRT

51. TPF-CTRT versus CTRT

52. Metaanalysis

54. Total Surgery= 29/84;11 responders to chemo
Total Surgery= 13/39; 5 responders to chemo

56. Unblinded assessor; Retrospective
study…

57. Regression post chemo is not
concentric and centripetal…

58. RT details: Target
• Use generous margins to prevent marginal failure
• Address contralateral neck when lymphatics could
communicate with contralateral side

59. Altered fractionation
Adjuvant studies:
• Trend to LC benefit
Increased acute toxicity
Opinion:
• To compensate for overall
treatment time, if needed
• Benefit may be in higher
risk patients, compared to
RT only
• Extra acute toxicity
• Logistically difficult
Sanguineti et al Int J Radiat Oncol Biol Phys 2005;61(3):762–71
Suwinski R et al Radiother Oncol 2008;87 (2):155–63

60. • Awwad et al, 46.2 Gy @ 1.2 Gy tid x 14 days vs td 60 Gy / 30#
• The 3-year locoregional control rate was significantly better in
the accelerated hyperfractionation (88+4%) than in the CF
(57+9%) group, P=0.01 (and this was confirmed by
multivariate analysis), but the difference in survival (60+10%
vs 46+9%) was not significant (P=0.29).

62. OCAT TRIAL - TMH
• Assess post-operative adjuvant CCRT or accelerated
radiotherapy (6 instead of 5 fractions / week), on LRC
and OS in LAHNSCC oral cavity.
• Arm A: PORT; Arm B: PO-CCRT; Arm C: PO-AccRT.
• 5 year LRC for arms A and B was 59.9% and 65.1%
(arm B vs arm A: p = 0.203, HR: 0.83, 95% CI: 0.63 –
1.10) and 58.2% for arm C (arm C vs arm A: p = 1.02,
HR: 1.02, 95%CI: 0.78 – 1.30).
• Advanced T & N stage, tongue involvement, and ECE
had poorer outcomes but no significant difference in
LRC or OS between the three arms even with these
high risk features.

63. ACC-RT OR CCRT?

64. Phase III – SCCHN – (IHN01 study)
“Phase III, double-blind, placebo-controlled study of post-operative
adjuvant concurrent chemo-radiotherapy with or without nimotuzumab for
stage III/IV head and neck squamous cell cancer.”
s# Country
1 Singapore
2 Korea
3 India
4 Saudi Arabia
5 Cuba
6 Thailand
7 Australia
8 Indonesia
9 Malaysia
10 Philippines

65. Phase III , multicentric , randomized, two arms, controlled study.
–Stratified according to tumor primary site, nodal status, presence/absence of
microscopic margins/adverse features and investigator center
– Patients pool: Post-curative surgery: stages III, IV SCCHN
Clinical trial design
Resected,
SCCHN
stages
III/IV
710
patients
RT:60-66 Gy/ 30-
33f over 6-6.5
weeks, 5 f / week;
Cisplatin at 100
mg/m2 given on
days 1, 22 and 43
of RT, or 7 weekly
30 mg/msq
RT:60-66 Gy/ 30-33f over 6-6.5 weeks,
5 f / week;
Cisplatin at 100 mg/m2 given on days
1, 22 and 43 of RT, or 7 weekly 30
mg/msq
Nimotuzumab 200 mg weekly for 8
weeks concurrent with standard
radiation
R
a
n
d
o
m
i
z
at
io
n
ENDPOINT
1) DFS AT 2
YEARS
2) OS, tox at
5 years
219 patients
recruited till date

66. Adjuvant Targeted therapy
 RTOG O234- Phase II- No benefit
 RTOG0920- Phase III -Completed
 EGF102988- Phase III – lapatinib- No benefit
 IHNO1- completed - Phase III - Nimozitumab

67. Adjuvant treatment- Advanced Disease:
Take Home Message
 Pre op vs post op- Post op better
 Minimum Dose- 57.6 Gy in intermediate risk, > 60 Gy
in high risk.
 Altered fractionation not proven benefit
 Over all treatment time- within 100 days
 Post op chemo RT- ECS or margin +Ve
 Neoadjuvant chemo: benefit not proven, developing
 Any targeted agent- No benefit

68. THANK YOU