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Role of Post-op Radiotherapy in Head and Neck Cancers
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)
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
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
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
19.
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
25. Management of Neck - Single node, NO ECS
Rec.
Surgery 11% 5/47
Surgery + port 0% 0/21
[Retrospective]
Barkley Am j Surg 1972
26.
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
30.
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.
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
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?
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).
61.
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.
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
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at
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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