The Management of Head and

Neck Cancers
Sue S. Yom, MD, PhD
University of California, San Francisco
 Disclosure

• Clinical trial research support: Genentech, Inc.

 Learning Objectives
• Defend the use of IMRT in head and neck cancer.
• Describe 2 current controversies in the radiotherapy
of oropharyngeal cancer.
• Evaluate the role of induction and concurrent
chemotherapy in nasopharynx and
larynx/hypopharynx cancers.
• State the common indications for postoperative
radiation and chemoradiation.
 Epidemiology of SCCHN
• Mucosally based squamous cell carcinomas of the
head and neck in the U.S. in 2015:
– 45,780 new cases (~3% of U.S. cancers)
– 9th most common cancer
– 8,650 deaths (<2%); rate is declining!!
• Globally, these cancers result in:
– 644,000 cases yearly, 2/3rds in developing world
– Endemic areas of nasopharyngeal cancer and oral
cavity cancer
– 4-5% of world cancer deaths
American Cancer Society, Cancer Facts and Figures, 2015.
 Survival
• The 5 year overall survival for mucosally based
head and neck cancers remains about 60% for
past few decades
– Very dependent on site and stage
Survival and stage at diagnosis by site
100
90
80
70
60
50 Overall Survival
40 Local
30 Regional
20 Distant
10
0

Carvalho et al. Trends in incidence and prognosis for head and neck cancer in
the United States: a site specific analysis of the SEER database. 2005.
Major etiology (smoking) is in decline in
the U.S.

Sturgis et al. Cancer. 2007. 110(7): 1429-35

Smoking is synergistic with alcohol

• The combined effect is multiplicative of

the individual effects
• ~75% of SCCHN can be attributed to
their combined use
• Synergism:
– EtOH acts as a solvent for tobacco
hydrocarbon carcinogens
– Smoking changes oral microflora
increasing acetaldehyde concentrations
 “New kid” on the block?
HPV & HNSCC
• Association was
difficult to establish
due to heterogeneity &
limited detection
methods
• Syrjanen et al. 1983:
some oral SCC
morphologically and
IHC features of HPV
 HPV epidemiology
 Gillison et al, 2000 reported PCR detection of HPV
DNA with oropharyngeal cancer
 Distinct clinical profile
Younger, Caucasian, non-tobacco smoking, male
Marijuana intake, multiple sex partners, oral sex
Tonsil and base of tongue with high predilection for
nodal spread
Exceptionally responsive to all treatments
 ~70% of oropharynx cancers and incidence is rising
unlike other HNSCC
Keratinizing SCC

Basaloid SCC

Courtesy of Richard Jordan

 HPV detection methods
• Polymerase chain reaction (PCR):
– Home made assays
– Roche Linear Array and Amplicor
• In situ hybridization (ISH):
– Dako GenPoint: HPV 16/18, 6/11
– Ventana Inform HPV: “cocktail” containing HPV 16
• Immunohistochemistry (IHC):
– HPV common antigens
– p16 surrogate
 p16 Immunohistochemistry
• Surrogate marker of HPV
• Correlates with HPV DNA integration into
host
– p16 inhibits CDK4 (which phosphorylates Rb,
preventing cell cycle progression at G1/S phase)
– Sensitivity 100%, specificity 80-100%
• ~7% of cases are p16+ but HPV16 –
• Differences due to non-HPV 16 strains,
impaired pRb
HPV 16 ISH p16 IHC

Courtesy of Richard Jordan

OPC survival differences by HPV-16 status
Study Year # Patients TX type Survival Survival
HPV + % HPV - %
(years) (years)

Lassen 2009 156 RT 62 (5) 26 (5)

Hafkamp 2008 77 NS 69 (5) 31 (5)
Reimers 2007 97 S, RT, CRT 73 (5) 63 (5)
Fakry 2008 62 CRT 78 (5) 50 (5)
Weinberger 2006 107 RT 79 (5) 20 (5)
Kumar 2008 50 CRT 80 (5) 40 (5)
Chung 2009 46 CRT 86 (5) 35 (5)
Nichols 2009 44 CRT 89 (3) 69 (3)
Ang 2010 323 CRT 82 (3) 57 (3)
Rischin 2010 185 CRT 91 (2) 74 (2)
Lassen 2011 794 RT, CRT 66 (5) 28 (5)
Posner 2011 111 CRT 82 (5) 35 (5)
 Survival after recurrence
Kaplan-Meier estimates of overall survival after disease progression for patients with p16-
positive and p16-negative oropharyngeal carcinoma (OPC) who had (A) locoregional
progression, (B) distant metastases, (C) salvage surgery, and (D) no salvage surgery.

Carole Fakhry et al. JCO 2014;32:3365-3373

©2014 by American Society of Clinical Oncology

 (Somewhat generally accepted)
oropharynx cancer treatment options
• T1-2 N0, select T1-2N1  single modality
– RT alone
– Surgery +/- postop RT
• T1-2 N1-2b, T3N0-N2b  double modality
– Altered fractionation RT
– Chemo-RT
– Chemo-RT + brachytherapy
– Surgery + postop RT +/- conc chemo
• T4a-b or N2c-N3  intensified therapy?
– Chemo-RT
– ?? Induction chemo  chemo-RT
 Tonsillectomy

• Aulus Cornelius Celsus

• 1st Century BC
• “the tonsils are loosened by
scraping around them [with
a blunt hook] and then torn
out” with a finger
• Vinegar and milk for
postoperative hemostasis
(Aetius de Amida
recommended frog fat)
10
From: Transoral Robotic-Assisted Lingual Tonsillectomy in the Pediatric Population

JAMA Otolaryngol Head Neck Surg. 2013;139(10):1032-1036. doi:10.1001/jamaoto.2013.4924

Figure Legend:
Robotic Equipment Positioning
Central position of the endoscope flanked by 2 robotic trocars is shown.

Copyright © 2015 American Medical

Date of download: 2/1/2015
Association. All rights reserved.
 TLM or TORS, +/- RT +/- chemo

Institution # T stage N stage # PORT LRC-5 OS-5

Mayo 69 T1-3 N0-2 None 70-90% 86%

* 25 refused
PORT

Wash U 84 T1-2 N0-3 50 94% 88%

74% N2 76%
T3-4
26%
Univ of 166 T1-3 N0-3 51 63-89% 82%
Paris 87 T2 85 N0
U Penn 47 T1-3 N0-2c 40 98% 82%
23 T2 24 N1 (2yrs) (2yrs)
 21
ECOG 3311 P16+ Trial – Low Risk OPSCC:
Personalized Adjuvant Therapy Based on Pathologic
Staging of Surgically Excised HPV+ Oropharynx Cancer
LOW RISK:
T1-T2N0-N1 Observation
Assess negative margins
Eligibility:
HPV (p16)+ Radiation Therapy
SCC IMRT 50Gy/25 Fx
oropharynx R
A
N INTERMEDIATE:
Stage III-IV: Evaluate for 2-yr PFS
Transoral Resection D Clear margins
cT1-3, N1-2b Local-Regional
(any approach) O ≤ 1 mm ECS
Recurrence, Functional
(no T1N1) with neck dissection M 2–3 metastatic LN
Outcomes/QOL
I PNI
Baseline Z LVI
Functional/ E
Radiation Therapy
QOL IMRT 60 Gy/30 Fx
Assessment HIGH RISK:
Positive Margins
> 1 mm ECS or Radiation Therapy
≥ 4 metastatic LN IMRT 66 Gy/33 Fx +
CDDP 40 mg/m2 wkly
Courtesy of Robert Ferris
Postoperative Radiation Therapy: Unique
Considerations after Surgery
• Postoperative status does not change the basic
anatomy of elective coverage, but should try to
reduce doses to avoid excessive fibrosis
• Risks of surgical intensification: palatal
insufficiency, trismus, nerve pain, shoulder
weakness, fibrosis
• Recently reported complication of nonhealing
soft tissue necrosis in primary tumor bed with
fraction size > 2Gy/day
Lukens JN et al. Late consequential surgical bed soft tissue necrosis in advanced
oropharyngeal squamous cell carcinomas treated with transoral robotic surgery and
postoperative radiation therapy. Int J Radiat Oncol Biol Phys. 2014 Aug 1;89(5):981-8.
RADIATION ALONE FOR SMALL PRIMARY

RTOG 0022
 Small, early trial of IMRT feasibility
 For oropharyngeal cancer T1-T2, N0-N1
 Prescribed to 66 Gy at 2.2 Gy/fraction over 6 weeks
with subclinical dose of 54-60 Gy
 Not selected for HPV or p16 status
2 year locoregional control 91% at 2 years
All cases of LRF, metastasis, or second
primary cancer occurred among patients who
were current/former smokers
NCCN T1-T2 N0-N1 ALGORITHM

 Codifies the attempt

to use single modality
if possible for T1-T2
N0
 Note that concurrent
systemic therapy is
advised only for T2 N1
at a lower level of
recommendation (2B)

Pfister et al. Head and neck cancers,

ver 2.2013 JNCCN 2013.
 IMRT for oropharynx - outcomes
UCSF Stanford Wash U Iowa

Pts 71 definitive 85 definitive 31 definitive 56 opx pts

22 post-op 43 post-op 151 total HNSCC
Chemo Concurrent Platinum 80%, 17 pts 68 pts, platinum
platinum cetuximab 7% platinum based
F/U 33 months 29 months 33 months 18 months
LC 3 yr 94% - - 2 yr 94% (all pts)

LRC 3 yr 90% 3 yr 92% 4 yr 87% 2 yr 98% (opx

only)
DFS 3 yr 81% 3 yr 81% 4 yr 81% -

OS 3 yr 83% 3 yr 83% 4 yr 87% 3 yr 82% (all pts)

Huang, Cancer 113(3):497, 2008
Daly, IJROBP 2009
Chao, IJROBP, 59(1):43, 2004
Yao, IJROBP, 63(2):410, 2005
Rapid adoption of IMRT in the U.S.

Mell, Cancer. 2005 Sep 15;104(6):1296-303

Sites treated with IMRT in the U.S.

Mell, Cancer. 2003 Jul 1;98(1):204-11.

Justification for IMRT: NPC studies

• Kam et al. randomized NPC chemoRT study:

observer-rated severe xerostomia was 82%
in IMRT patients vs 39% in 2D patients at 1
year

• Pow et al. randomized study in early-stage

NPC: improvements in stimulated saliva flow
and quality of life at 1 year for IMRT vs 3D
conformal radiation

Kam JCO 2007, Pow IJROBP 2006

 Justification for IMRT: PARSPORT
• Pharyngeal SCC, T1-4
N0-3 at six UK centers
• Up to 24 months,
benefits in recovery of
saliva with IMRT
• Improved dry-mouth-
specific and global
quality of life scores
• At 24 mo, no differences
in late toxicities,
locoregional control, or
overall survival

Nutting CM, Lancet Oncol. 2011 Feb;12(2):127-36.

 Justification for chemoradiation:
GORTEC : XRT +/- carbo/5FU
• 226 pts
• stage III-IV OPX cancers
– 86% had T3-T4 tumors
• RT 70 Gy in 35 fx +/- chemo
– Carbo (70mg/m2/d x 4d) & 5FU (600 mg/m2/d CI x 4d)
on days 1, 22, and 43 of RT

RX % G3-4 Muc % LRC % DFS-3 % OS-3

RT 39 42 20 31
CRT 71 66 42 51
P-value 0.04 0.02

Calais G, JNCI 91:2081-6, 1999

 Oropharynx/Mixed Chemoradiation
Intergroup : XRT +/- CDDP
• 295/462 pts, stopped for slow accrual
• stage III-IV, 85% had T4 or N3 tumors

• Radiation: 70Gy/30fx
• ChemoRT: 70Gy + CDDP 100 mg/m2 in wk 1,4 and 7
• Split course chemoRT: 30Gy, break, 30-40 Gy +
CDDP 75mg/m2 and 5-FU 1 g/m2 x 4 days q 3 wk
– At break evaluate for resectability

Adelstein, JCO, 21(1):92, 2003

 RT vs chemoRT
GORTEC GORTEC Intergroup Intergroup Intergroup
RT alone chemoRT RT alone chemoRT Split
Pts 113 109 95 87 89
70 Gy 70 Gy 70 Gy 70 Gy 30 Gy break
RT
35 fx 35 fx 35 fx 35 fx Surg v boost
Chemo Carbo 70 Cisplatin Cisplatin 75
none none
5FU 600 100 5FU 1000
F/U 5.5 years 5.5 years 41 months 41 months 41 months
LRC 5 yr 25% 5 yr 48% - - -
DSS 5 yr 15% 5 yr 27% 3 yr 33% 3 yr 51% 3 yr 41%
5 yr 5 yr
OS 3 yr 23% 3 yr 37% 3 yr 27%
16% 22%
Toxicity 30% late 56% late 52% acute 89% acute 77% acute
 Impact of Therapeutic Sequence:
MACH-NC Findings
Design
(No. of Studies/ Chemotherapy
No. of Hazard Ratio Effect Absolute Benefit
Subjects) (95% CI) (P Value) 2 Years 5 Years
Adjuvant1 0.98
0.74 1% 1%
(8/1854) (0.85-1.19)
Neoadjuvant1 0.95
0.10 2% 2%
(31/5269) (0.88-1.01)
Concomitant1 0.81
< 0.0001 7% 8%
(26/3727) (0.76-0.88)
Total1 0.90
< 0.0001 4% 4%
(65/10,850) (0.85-0.94)

MACH-NC = Meta-Analysis of Chemotherapy in Head and Neck Cancer; PF = cisplatin +

fluorouracil.
1. Pignon et al. Lancet. 2000;355:949.
2. Monnerat et al. Ann Oncol. 2002;13:995.
 MACH-NC – Type of Chemotherapy

Improvements driven by use of platinum

Bourhis, Curr Op Onc, 19:188-194, 2007

ACUTE TOXICIT Y BURDEN OF CURRENT
CHEMORADIATION APPROACH

Platinum based
Chemoradiotherapy
Estimated for
Bioradiotherapy

RT alone

Trotti A et al. Lancet Oncol 2007;

 Phase III study:
“Dealer’s choice” RT +/- Cetuximab
• RT alone (213 pts)
– 2 Gy qd to 70 Gy, 1.2 Gy bid to 72-76.8 Gy, or
concomitant boost to 72 Gy

• RT + cetuximab (211 pts)

– 400 mg/m2 one week prior to RT
– 250 mg/m2 each week during RT

• Stage III/IV SCC of opx, hpx, lx

• Definitive tx, post-op pts excluded

Bonner, NEJM, 354:567, 2006

 Kaplan–Meier Estimates of Locoregional Control and
Overall Survival among All Patients Randomly Assigned
to Radiotherapy plus Cetuximab or Radiotherapy Alone.

Toxicity and QOL outcomes very similar between arms

Bonner JA et al. N Engl J Med 2006;354:567-578.
 RTOG 1016: PHASE III TRIAL OF RADIOTHERAPY
PLUS CETUXIMAB VERSUS CHEMORADIOTHERAPY IN
HPV- ASSOCIATED OROPHARYNX CANCER

CLOSED, 5 YEAR RESULTS NOT YET MATURE

(noninferiority design based on OS hazard)
Enlarged to 1000 patients, for analyzable 834 patients
with 45 expected events
 CLINICAL SELECTION OF PATIENTS FOR
“DE-INTENSIFICATION” SCHEMAS

Profile that has achieved excellent outcomes

in retrospective series and prospective trials
 P16+
 Oropharyngeal cancer
 Minimal smoking history ≤10 pack-years
 Non bulky primary and non extensive pattern of
disease spread
 RTOG 0129 PHASE III TRIAL: CONCOMITANT
CRT WITH STANDARD VS ACCELERATED
FRACTIONATION RT IN ADVANCED SCCHN

CRT

Stage III/IV (T2, N2-3, M0 or

T3-4, any N, M0) SCCHN R Cisplatin
• Oral cavity, oropharynx, A (IV on d1, d22, d43)
hypopharynx, and larynx N Standard fractionation RT
• No prior RT to head and D (5 d/w for 7 wks)
neck except radioactive O
iodine therapy M
• No prior surgery to primary Cisplatin
I
(IV on d1 and d22)
tumor or nodes except for Z
Accelerated fractionation RT
diagnostic biopsy E
(5 d/wk for 3.5 wks; then bid,
Expected N=720 5 d/w for 2.5 wks)

 743 enrolled, 721 analyzable

 Primary endpoint = 25% increase in OS 20
 RTOG 0129 RESULTS

• 60% oropharynx cancers

• 80-86% male
• Primary endpoint of 5y OS: 59% vs. 56% (p=0.18)
• 1 vs 3 cycles of cisplatin had significantly inferior OS (HR
2.1) and PFS (HR 1.8)
• SFX with 2 vs 3 cycles of cisplatin more likely to
experience local-regional relapse (HR 1.7)
• RT given over 8-9 weeks vs. 6-7 weeks resulted in lower
OS (HR 2.2)
• As a continuous variable, each day of RT delay
decreased OS, PFS by 5%, 4% (p=0.001, 0.006)

Ang, JCO 28:15s, 2010 (suppl; abstr 5507); Ang NEJM 2010
RTOG 0129: HPV and p16 survival analyses

Ang K et al. N Engl J Med 2010;10.1056/NEJMoa0912217

RTOG 0129: DEFINITION OF LOW RISK
RTOG 0129: SURVIVAL BY RISK
CLASSIFICATION
 E 1 3 0 8 : A P H A SE I I T RI A L OF I N DUC T ION C H E M OTH ERAP Y
FOLLOW E D BY C E T UX IMAB W I T H LOW DOSE OR STA N DARD
DOS E I M RT I N PAT I ENT S W I T H H P V - A SSOCI ATE D RE SE C TABLE
SQUA M OUS C E LL CA RC I N OMA OF T H E OROP H A RY NX

Induction Chemotherapy Concurrent

Chemoradiation
N=90 patients, 80 analyzable

R* CLINICAL CR
E Low dose IMRT 54Gy/27fx** +
Key Eligibility Cisplatin 75mg/m2 D1
S Cetuximab weekly
1.OPSCC Paclitaxel 90mg/m2
2.HPV16 ISH + D1,8,15 P
and / or p16+ Cetuximab 250mg/m2 O
3.Resectable D1,8,15
stage III, IVA Q 21 days for 3 cycles
N CLINICAL PR /SD
S Full dose IMRT 69.3Gy/33fx** +
E Cetuximab weekly

*Response Assessment
: Direct visualization of primary **Uninvolved nodes get 51.3 Gy/27 fx
: Clinical exam of neck
: CT/MRI Courtesy of Barbara Burtness
RESULTS: PFS IN STANDARD AND LOW DOSE
RT ARMS

Progression-free Survival
1.0

1-yr PFS 91%

0.8

1-yf PFS 87% 1-yr PFS 89%

0.6
Probability
0.4

Low-dose (n=62)
Std-dose (n=15)
All evaluable pts (n=80)
0.2

# at risk
6 mo 9 mo 12 mo
All eval 72 69 61
Low dose 57 55 48
Std dose 14 13 12
0.0

0 5 10 15 20 25 30

Time in months
Presented by: Courtesy of Barbara Burtness
ASCO 2012
ECOG 1308: 2-YEAR PRIMARY ENDPOINT

For reduced-dose IMRT patients (78% of all

patients), at 23 mo followup, PFS was 84%
 overall survival 95%
 primary site LC 94%
 nodal control 95%
 distant control 92%
Patients with <10yrs smoking, T1-3 and N0-2b
disease achieved 96% PFS and OS

ASCO 2014
RESULTS IN INDUCTION CHEMOTHERAPY
+ CETUX-54 GY ARM AT 2 YEARS

ASCO 2014
PRINCESS MARGARET HOSPITAL:
RADIATION ALONE
PMH RADIOTHERAPY ALONE FOR P16+
AND <10 PY SMOKING: RT VS CRT
Eligibility R S R 60 Gy XRT (2Gy/fx)
OP SCCA
E T A
Central Declare in 6 weeks +
≤10 pack- G review R Intent N cisplatin 40 mg/m2
year I p16+ A Unilat
T1-T2 N1- S IHC
D weekly x 6 cycles
T vs
N2b T I Bilat O
T3 N0- E F Neck M
N2b XRT 60 Gy XRT (2 Gy/fx)
R Y I at 6 fractions/week
Z for 5 weeks
44% of RTOG 1016
population eligible E
 WHAT EVER HAPPENED TO INDUCTION
ANYWAY?

TAX 324: TPF vs PF

Did not include direct comparison to
concurrent CRT
PARADIGM
DeCIDE
TAX 324: Docetaxel/Cisplatin/5-FU vs Cisplatin/5-
FU Sequential Therapy in Advanced SCCHN
ICT CRT
Docetaxel (75 mg/m2)
Cisplatin (100 mg/m2)
R 5-FU (1000 mg/m2/day,
A 96-hr C-I)
Chemotherapy- and RT-naïve N every 3 weeks, 3 cycles Carboplatin
stage III/IV SCCHN D
• Oral cavity, oropharynx, O (AUC 1.5 weekly)
hypopharynx, larynx M Daily RT
I Cisplatin (100 mg/m2) (5 days/week)
N=501 5-FU (1000 mg/m2/day,
Z
E days 1-5)
every 3 weeks, C-I 3 cycles

TPF PF
Response P Value
N=255 (95% CI) N=246 (95% CI)
ORR (ICT) 72% (65.8-77.2) 64% (57.9-70.2) 0.07
CR (ICT) 17% (12.1-21.6) 15% (10.8-20.1) 0.66
ORR (ICT+CRT) 77% (70.8-81.5) 72% (65.5-77.1) 0.21
CR (ICT+CRT) 35% (29.4-41.5) 28% (22.5-34.1) 0.08

Posner, N Engl J Med. 2007;357:1705.

TAX 324: Docetaxel/Cisplatin/5-FU vs Cisplatin/5-FU
Sequential Therapy in Advanced SCCHN: Results
Survival PFS
100 100

90 90
Survival Probability (%)

Log-rank P=0.0058 Log-rank P=0.004

80 80

PFS Probability (%)

HR=0.70 HR=0.701
70 70

60 60

50 50

40
TPF 67% 40
PF 54% TPF 53%
30 TPF 62% 30
PF 42%
20 PF 48% 20 TPF 49%
TPF (N=255) TPF (N=255)
10
PF (N=246)
10
PF (N=246)
PF 37%
0 0

0 6 12 18 24 30 36 42 48 54 60 66 72 0 6 12 18 24 30 36 42 48 54 60 66 72

Months Months

• TPF significantly improves survival and PFS compared with PF in an ICT regimen
followed by CRT

Posner. N Engl J Med. 2007;357:1705. Copyright © [2007] Massachusetts Medical Society. All rights
reserved.
Paradigm: Phase III Sequential Therapy Trial
in North America

ICT CRT
Carboplatin (every week)
CR Daily RT (days 1-5)
Docetaxel
R 7 weeks
Cisplatin
Paradigm A
N 5-FU
Stage III/IV SCCHN every 3 weeks, 3 cycles Docetaxel (every week for 4 wks)
D
• Oral cavity, O PR Daily/twice-daily RT (days 1-5)
oropharynx, M 6 weeks
hypopharynx, larynx I
• Expected N=330 Z Cisplatin (weeks 1, 4)
E Daily/twice-daily RT (days 1-5)
6 weeks

US National Institutes of Health Web site. http://clinicaltrials.gov/ct/show/NCT00095875?order=1.

Accessed November 2, 2007.
 PARADIGM

• Arm 1: TPF x 3  weekly carboplatin or

docetaxel with accelerated RT
• Arm 2: Cisplatin x 2 with accelerated RT
• Enrolled 145 pts: oropharynx: 80, larynx: 24,
hypopharynx: 15, and oral cavity: 26
• Study terminated early due to low accrual
• 3y OS was 73% vs 78% (p=0.77)
Haddad et al., The PARADIGM trial: A phase III study comparing
sequential therapy (ST) to concurrent chemoradiotherapy (CRT) in
locally advanced head and neck cancer (LANHC). ASCO 2012.
Abstract #5501.
Decide: Phase III Sequential Therapy Trial in
North America

ICT CRT
R
A Docetaxel (day 1)
N Cisplatin (day 1)
DeCIDE
D 5-FU (days 1-5)
Chemotherapy and RT-
O every 3 weeks, 2 cycles Docetaxel (day 1)
naïve SCCHN
M 5-FU (days 0-4)
• Expected N=400 I Hydroxyurea (days 0-4)
Z Twice-daily RT (days 1-5)
E
every 2 weeks, 5 cycles

US National Institutes of Health Web site. http://clinicaltrials.gov/ct/show/NCT00117572?order=1.

Accessed November 2, 2007.
 DECIDE

Arm 1 (standard): 5 days of D 25 mg/m , F 2

600 mg/m , hydroxyurea 500 mg BID, and RT

2

150 cGy BID followed by a 9 day break

Arm 2 (induction): 2 induction cycles (D 75
mg/m , P 75 mg/m , F 750 mg/m day 1-5) 
2 2 2

same CRT
Enrolled 280 patients
3y OS 73% vs 75% (p=0.70)
Cohen et al., DeCIDE: A phase III randomized trial of docetaxel (D),
cisplatin (P), 5-fluorouracil (F) (TPF) induction chemotherapy (IC) in
patients with N2/N3 locally advanced squamous cell carcinoma of the
head and neck (SCCHN).). ASCO 2012. Abstract #5501.
Defensible Induction Chemotherapy
Scenarios
1. Need to optimize patient’s medical status
2. Very high potential for metastasis, or
oligometastasis with plan to consolidate
3. Unavoidable delay in starting radiation
4. Impending local issue (airway, CNS) that is not well
addressed with surgery
5. Markedly advanced neck disease (dermal
infiltration, truly massive N3)
6. Markedly advanced primary disease (T4b)
* Consider 1-4% risk of mortality and effect on compliance with
subsequent CRT
Adapted from: Haddad and Shin, NEJM 2008
 Basic IMRT Delineation for OPC
• GTV = All gross disease on imaging or exam
• CTV1 = “Microscopic margin”: GTV + 5-10 mm margin
(many use 7-8 mm)
• CTV2 = “High Risk” nodal volumes and mucosal sites
– Not defined consistently
– E.g. uninvolved level 3 nodes in base of tongue cancer with
involved level 2 nodes
• CTV3 = “Elective” uninvolved nodal regions at risk for
microscopic disease
– E.g. uninvolved level 4 nodes in base of tongue cancer with
involved level 2 nodes

• PTV = CTV + 2.5-5 mm (many use 3 mm) ICRU 50

– Accounts for tumor motion and setup error 30
Common standard dose schedules
• Chemo-RT • RT alone
–33 Fractions –30 Fractions
–CTV1 = 70 Gy –CTV1 = 66 Gy
–CTV2 = 59-63 Gy –CTV2 = 60 Gy
–CTV3 = 54-57 Gy –CTV3 = 54 Gy
 Tonsil cancer
start with CTV2 at pterygoid plates
include half of medial pterygoid
High coverage
Medial vs
not needed for
lateral
tongue base
pterygoid
cancers
muscle
 Tonsil cancer
start RP nodes above jugular foramen
(put in intermediate dose if N+ neck)
This is the
tonsil
 Tonsil cancer
CTV1 should cover maxillary tuberosity
 Tonsil cancer
cover retrostyloid nodes for N+ neck

styloid
 Tonsil cancer
include some tongue base/GP sulcus
CTV stay
outside
bone

Come out
into neck
at C2
transverse
process
 Tonsil cancer
CTV1 extends to just above hyoid
Make sure Follow
to cover lateral
vasculature pharyngeal
wall with
CTV1
 Tonsil cancer
CTV2 covers lateral pharyngeal wall to just
above AE fold
AE fold
Don’t go
outside
platysma

Can drop contralateral

level 5 if limited
adenopathy
 Dose constraints
• Cord: 45Gy max dose (<40Gy, if achievable)
• Cord Expanded 5mm: 50Gy max dose if possible
• Brainstem: 54Gy max dose (typically <40 Gy)(try
• for <30 Gy to posterior portion to reduce nausea)
• Brain: Tight 54Gy gradient
• Parotid (contralateral): <26Gy mean dose
• Cochlea: <35Gy max dose (<30Gy, if possible)
• Mandible: <70Gy max dose, no hot spots >105%
Monroe, A.T., Reddy, S.C., and Peddada, A.V. Dorsal vagal complex of the brainstem:
Conformal avoidance to reduce nausea. Pract Radiat Oncol. 2014; 4: 267–271
Where is/what is the DVC (area postrema)?
• Area postrema lies within DVC, in
the medulla oblongata between
caudal aspect of pons and cranial
aspect of the spinal cord
• Receives sympathetic and vagal
innervation from GI tract: may
serve as “vomiting relay” to CNS

Monroe, A.T., Reddy, S.C., and Peddada, A.V. Dorsal vagal complex of the brainstem:
Conformal avoidance to reduce nausea. Pract Radiat Oncol. 2014; 4: 267–271
 Dose constraints
• Optic Chiasm & Optic Nerves: <54Gy max dose
• Oral cavity: ALARA, mean dose <40Gy or <34Gy
• Larynx: mean <35Gy (<25-30Gy preferred)
– Strongly consider low neck split field approach which
reduces dose to approximately 10 Gy
• Cervical Esophagus: ALARA, minimize 60Gy
• Posterior Neck: <35Gy (try to control the 30Gy to
reduce hair loss and long term cramping)
• Lens <5Gy or <10Gy if close to the target
• Brachial plexus: <60 Gy max dose (LOW PRIORITY)
Rosenthal DI, Int J Radiat Oncol Biol Phys. 2008 Nov 1;72(3):747-55.
 Contouring the plexus
• You can recognize BP
on low-res CT
– MR fusion not usually
helpful
– Practice will help C2 C2
• How I do it
– Identify C5, C6, C7 nerve C4
roots above VB
– Identify C8, T1 nerve
roots below VB
– Contour between ant and
middle scalenes
– 3-4 mm brush on axial
cuts
– Confirm using sagittal
plane images
– For postop cases, confirm
using contralat neck
 “Dose Dump” into Hot Spots

Think about this in advance and plan subvolumes accordingly

 1. Submandibular sparing?
if contralateral level IIA uninvolved
submandibular
gland may be
bilobed and
look like a node
 Submandibular gland sparing
• Contribute 65-90% of unstimulated mucin-rich
saliva and 95% of salivary flow during a 24-
hour period
• Mean dose < 39 Gy improved salivary flow and
correlated with improved patient- and
observer-rated xerostomia
• Oral cavity and submandibular dose reduce
xerostomia independent of parotid sparing
Murdoch-Kinch et al., IJROBP 2008, 722:373-382.
Little et al., IJROBP 2012, 83:1007-1014.
SMG sparing IMRT for OPC * Recurrences in oral cavity cases
N Definitive Mean Disease control Late
RT SMG dose xerostomia
Gensheimer, U 76 86% 30.7 No peri-SMG 23% gr 2, no
Washington recurrence* gr 3
Collan, 50 49% 27.8 No peri-SMG No perm gr 3
Helsinski recurrence
Doornaert, VU 20 100% 34.1 No peri-SMG but --
Netherlands 3 primary recur
Little, U 17 100% 43 No level I No gr 3
Michigan recurrence
Wang, 17 12% 20 Two contralat --
Shanghai Jiao level 2 recur
Tong U
Chajon, Centre 8 100% 33.8 No peri-SMG No gr 3
Eugene recurrence
Marquis
Robin, MSKCC- 71 100% 33 One IIA --
U Colorado recurrence
 2. Reducing contralateral neck
volumes
• Likelihood of failure in neck levels I and V is
generally very low for OPC
• With high non-bulky jugulodigastric
adenopathy, it is reasonable to treat
contralateral levels II-IV only
– Based on surgical dissection series
– For limited-primary tonsil cancer, could also
consider treating this unilaterally

Lim YC et al. Distributions of cervical lymph node metastases

in oropharyngeal carcinoma: therapeutic implications for the
N0 neck. Laryngoscope. 2006 Jul;116(7):1148-52.
Where is Level IB?
Sub-mandibular
 Separation of levels IV and V
• Va/b upper posterior triangle  Vc lower posterior triangle
– Separated by plane at inferior cricoid Formerly “supraclav
– Posterior border at anterior trapezius fossa” or “Ho’s triangle”

• IVa lower jugular  IVb medial supraclavicular

– IVa ends 2 cm above sternoclavicular joint, IVb ends at manubrium
– Lateral aspect defined by plane of anterior scalene

Delineation of the neck node levels for head and neck tumors: a 2013
update. Radiotherapy and Oncology. 2014 Jan;110(1):172-81.
 3. Ipsilateral radiation therapy
for tonsil T1-2, N0-N2a ?maybe N2b?

The ultimate
form of salivary
gland sparing!
 Ipsilateral RT
N1 N2 N3 Total N Contralat failure

Rusthoven, U Colorado -- -- -- 20 0 (0%)

Al-Mamgani, 43 50 0 93 1 (1%)
Rotterdam
Jackson, British 54 7 16 77 3 (4%)
Columbia
Chronowski, MDACC 23 43 0 66 1 (2%)

Cramer, Duke 1 22 0 23 0 (0%)

Hwang, Wash U 6 35 0 41 0 (0%)

Kagei, Japan 5 4 1 10 0 (0%)

Koo, Korea 8 10 0 18 0 (0%)
Lu, Peter MacCallum 14 14 5 33 0 (0%)

O’Sullivan, PMH 56 36 3 95 8 (8%)

Mendenhall, Florida - - - 64 2 (3%)

Vergeer, Netherlands - - - 50 7 (14%)

*incl oral cavity
 Caveats
• For primary site in contiguity with posterior pharyngeal
wall or >1cm of soft palate or tongue base
involvement, unilateral therapy is NOT advised
• Unilateral therapy for well lateralized tongue base
tumors is extremely controversial – I would not
recommend it
• With large size nodal burden or extracapsular
extension in the neck, there is altered lymphatic flow
to the contralateral side, not established whether this
represents risk that will manifest but take this seriously
• Ipsilateral series with acceptable results represent
highly selected patients treated at high volume centers
4. Sparing the larynx with split field
• Whenever possible, we
match an upper IMRT plan
at a monoisocentric plane
set above the arytenoids
• Cheater block  cord
block for initial 40 Gy then
open up
• Generally this reduces
larynx dose to 10 Gy versus
25-35 Gy with IMRT
• We will not split through
any gross disease
40
4. Sparing the larynx with split field
• Whenever possible, we
match an upper IMRT plan
at a monoisocentric plane
set above the arytenoids
• Cheater block  cord
block for initial 40 Gy then
open up
• Generally this reduces
larynx dose to 10 Gy versus
25-35 Gy with IMRT
• We will not split through
any gross disease
4. Sparing the larynx with split field
• Whenever possible, we match
an upper IMRT plan at a
monoisocentric plane set
above the arytenoids
• Cheater block  cord block
for initial 40 Gy then open up
• Generally this reduces larynx
dose to 10 Gy versus 25-35 Gy
with IMRT
• We will not split through any
gross disease
• Can block off cord completely
if treating ipsilaterally
 WHAT COULD THE FUTURE LOOK LIKE FOR
“GOOD RISK” OPC? OPTIONS UNDER STUDY…

 Acclerated radiation (in its many artful forms)

 Radiation + systemic therapy (in its many artful forms)
 Surgery +/- radiation
 Surgery + radiation +/- systemic therapy
 Induction systemic therapy followed by radiation +
systemic therapy
 Induction systemic therapy followed by de -escalated
radiation-based treatment

 Decision making will balance treating center’s

expertise, therapeutic efficacy, long -term toxicity
 T2 parapharyngeal

T4 skull base
N2 neck nodes
 T2 parapharyngeal

The same treatment will be

recommended for all three

T4 skull base
N2 neck nodes
 The search for better selection
algorithms continues in NPC just
as in other sites
NPC is fairly uncommon in Europe and the U.S.
(2/100,000)
NPC is extremely common in southern China
and Hong Kong (20-25/100,000) and accounts
for up to 18% of all cancer diagnoses
NPC has been called "the Cantonese cancer”
NPC is also common in Taiwan, Singapore,
Malaysia, Thailand, and Vietnam
NPC is seen in Africa, the Mediterranean, and
among the Alaskan Inuit
Area Incidence*
Chinese White
Hong Kong 1965-1969 24.7 --
Singapore 1960-1964 20.2 --
San Francisco-Oakland 1969 17.9 0.9
Hawaii 1960-1964 10.4 1.1

* Incidence per 100,000 per year

Buell, Cancer Research 34:1189-1191, 1974
Nodal involvement is common,
prognostic, and relates to type
• Nodal mets at presentation
– 90% subclinically node +
– 70% clinically node +
– 50% bilateral node +
• Type of cancer impacts amount of lymph
node spread
– 73% node + if WHO type I (“keratinizing”)
– 92% node + if WHO type IIA/IIB (endemic
Chinese/Asian type)
• 40% of pts with N3 dz present with mets,
75% will ultimately have mets
EBV+

EBV+

HPV+
HPV+
EBV-HPV-
EBV-HPV-

HPV+

EBV+
EBV+
EBV-HPV-
HPV+

EBV-HPV-

Stenmark, IJROBP
 Intergroup 0099 (RTOG 88-17)

S R
AJCC A RT
T T stage
1992 N alone
R N stage
stage (70 Gy)
III-IV A Performance D
T status O
M0
I Histology M RT (70 Gy)
F I Cisplatin x3
Y Z
E Cisplatin + 5FU x3
N = early closure at 193  147
FU = 2.7 yrs
Al Sarraf, J Clin Oncol 1998; 16:1310-1317
 Intergroup 00-99
Results
RT only CRT + adj chemo
5 yr PFS 29% 58% p < 0.001

5 yr DFS 46% 74% p < 0.001

5 yr OS 37% 67% p < 0.001

Closed early at first interim analysis (N=193)

 Criticisms of Intergroup 00-99
• Possible overestimation of effects - due to early closure
• Ineligibility rate - high proportion (24%) not meeting
criteria or with missing data
• Applicability - high proportion (22%) of WHO I, which has
lower survival and may require more chemotherapy
• Low survival in RT-only arm compared to results in Asia.
Did chemotherapy compensate for poor quality RT? Were
RT results with the Western population worse than in Asia?
• Toxicity - only 63% completed concurrent chemo, 55%
completed adjuvant chemo
• Design - did not distinguish benefit of concurrent vs.
adjuvant vs. both
Taiwan – Taichung Veterans ph III:
RT vs CRT
• 284 patients, stage III to IV (M0) NPC

• Arm 1: RT alone (70-74 Gy)

vs
• Arm 2: RT (70-74 Gy)
+ Cisplatin 20 mg/m2/d and 5FU 400
mg/m2/d x 4 days, weeks 1 and 5
(NO ADJUVANT)
Lin et al, JCO, Vol 21, No 4 (February 15), 2003: pp 631-637
 Overall Survival
Radiation alone vs chemoRT
Intergroup 0099 Taichung Veterans Hospital

p=0.001

Al-Sarraff, JCO, 16(4):1310, 1998

Al-Sarraff, ASCO, Abs 905, 2001
Lin, JCO, 21(4):631, 2003
 RTOG 0225 phase II
IMRT feasibility study
R
AJCC 70 Gy to gross disease
E
2002 G 59.4 to microscopic disease
stage I-
IVB I All in 33 fractions with IMRT
S
All WHO T
types
N=68
E
R Lee et al, JCO 2008
• 68 NPC patients, all WHO types
• T2b or N+ had concurrent cisplatin and
adjuvant cisplatin-5FU

• 2-y local PFS 92.3%

• 2-y regional PFS 90.5%
• 2-y DM-free rate 85.7%

• Clinical outcomes improved compared to

Intergroup 0099 due to IMRT
• Xerostomia scores were improved compared
with previous RTOG trials
Individual patient data from 8 randomized trials
OS benefit: 4% at 2 years, 6% at 5 years
EFS benefit: 9% at 2 years, 10% at 5 years
Risk reduction from concurrent: 40%
No discernible OS risk reduction from
induction (1%) or adjuvant (3%)
NB: Intergroup 00-99 was classified in the
concurrent group

Baujat, IJROBP, 2006 Jan 1;64(1):47-56

Sun Yat Sen Univ, Guangzhou trial

R RT ( ≥ 66 Gy)
A Weekly cisplatin
AJCC 1997 40 mg/m2
N
stage III-IV
M0 D
O RT ( ≥ 66 Gy)
Excluded Weekly cisplatin
T3-T4N0 M 40 mg/m2
I
Z
N = 508 Cisplatin + 5FU x3
E Chen et al, Lancet Oncology 2011 50
Chen et al., Concurrent chemoradiotherapy plus adjuvant chemotherapy versus concurrent
chemoradiotherapy alone in patients with locoregionally advanced nasopharyngeal carcinoma: a
phase 3 multicentre randomised controlled trial, Lancet 2012
 category 2A
(previously category 1)

Pfister et al. Head and neck cancers,

ver 2.2013 JNCCN 2013.
This trial did not have a statistically
appropriate non-inferiority design.
Higher absolute number of failures in
the concurrent only arm and
consistently lower than CRT+adjuvant
More followup needed to see DM?
54-59% quit concurrent weekly
chemotherapy. 18% randomized to
adjuvant arm did not get it.
I thought the ideal experimental arm would have
been induction CT followed by concurrent cisplatin
and RT…. However, some physicians were reluctant
to treat tumors that had been “down-staged” with
the then relatively new concept concurrent therapy
(especially those tumors that had a complete clinical
response). Also, induction CT precluded the head-to-
head comparison of response rates and possible
side effects. After considerable discussion, we
decided that the experimental arm would consist of
concurrent cisplatin [and RT] followed by the
combination of [cisplatin-5FU]… for a total of three
additional courses.
-- Muhyi Al-Sarraf, J Radiat Oncol 2012
Accrued 803 patients, stage III-IVB
Tested 3 questions: conventional vs accelerated RT,
induction vs adjuvant PF, induction 5FU vs Xeloda
Endpoint: 5 year PFS
• Changing the fractionation from conventional to
accelerated did not achieve any benefit but
incurred higher toxicities (acute mucositis and
dehydration)

• Comparisons of induction PF versus adjuvant PF

did not indicate a significant improvement

• Comparisons of induction PX versus induction

PF revealed fewer toxicities (neutropenia and
electrolyte disturbance)
Lee AW, Cancer. 2014 Dec 19. doi: 10.1002/cncr.29208.
Randomized phase II/III
216 patients
Arm 1: concurrent weekly cisplatin x 8 with
IMRT 33 fractions
vs
Arm 2: induction gem/carbo/paclitaxel q21
days x 2, then same as arm 1
Endpoint: 5 year OS
ASTRO 2014: no difference, stopped early
Epstein-Barr Virus is a common virus
95 percent of people in the U.S. are
exposed to EBV by 30–40 years of age
The World Health Organization does not
have preventative measures because it is
so easily spread and is worldwide
Very rarely does Epstein-Barr virus lead to
cancer
High levels of Epstein Barr Virus in the blood predict
the outcome of the treatment
Pretreatment

1 week after RT completion

Lin, NEJM 2004;350:2461

 Basic Eligibility: Stage II-IVB NPC; detectable EBV-DNA pre-treatment Control:
Consolidation 5-
FU/cisplatin X 3
Register
and R
Stratify “Detectable” (Ph II) Consolidation
Assess
All Pts Re- Gemcitabine/
N-stage EBV-DNA Receive Assess Paclitaxel X4
N0-1 vs. N2-3
BIQSFP Standard EBV-
T-stage RT/cisplatin DNA
T1-2 vs. T3-4
Control:
Consolidation 5-
PS
“Undetectable” R
0 vs. 1
(Ph III)
FU/cisplatin X 3

Overall Sample Size: 924 patients, 27pts/mo

Observation

Basic Statistical Design:

•Phase IIR sub-study (detectable EBV after chemo-RT): 1-year PFS 55% vs. 40% superiority design. 120 analyzable pts, 4.2 yr
•Phase III sub-study (undetectable EBV after chemo-RT): 2-year OS 91% both arms noninferiority. 600 analyzable pts, 7.7yr

Quality of Life: FACT-NP, HHIE-S (audiometry), FACT-Taxane, EQ-5D

Unique advantages of IMRT in NPC: CTVs
curving around optics and temporal lobe
CTV2 (blue):
• Nasopharynx
• ½ for T1-2 vs
entire sphenoid
sinus for T3-4
• 1/3 max sinus
• Carotid canal,
foramen ovale
and spinosum
• Pterygoid
plates
• Parapharyngeal
space
• Ant ½ clivus
• Around nodes
In the right context, little clustered nodes
should count … especially for NPC
For NPC
T1 FSE post gad
• Cover bilateral level
cover VB IB-5 and RP nodes in
CTV2 (60 Gy) or CTV3
(54 Gy)
• May drop bilateral level
1B for N0 status
• Like OPC, may drop
contralateral 1B if
32 yo M with T3 N3b
nasopharynx cancer contralateral levels 1-2
are not involved
 Changes during Treatment Course
Note coverage of upper
32 yo M mediastinum to aortic arch
T3N3bM0 type IIB NPC (cover level of innominate vein

Prompted replanning at ~36 Gy

Locoregionally controlled, metastasized to the abdomen
Prospective study of stages I-IV M0 NPC
Chinese versions of EORTC QLQ-C30 and the
EORTC QLQ-H&N35
N=129: 43 refused replanning; 86 were
replanned before 25th fraction
Replanning improved global QOL, functional
QOL (role, social function), and symptoms e.g.
dyspnea, appetite loss, constipation/diarrhea,
speech problems, trouble with social contact,
teeth, opening the mouth, dry mouth, and
sticky saliva
Conclusions: Nasopharyngeal Carcinoma
• Concurrent chemoradiation + 3 adjuvant cycles is the
accepted standard for ≥T2 and N+ stages.
• IMRT is uniquely able to provide excellent
locoregional control and avoid toxicities for NPC.
• The necessity of adjuvant chemotherapy is in dispute
given its high toxicity and recent data suggesting
potential lack of additional benefit.
• Induction chemotherapy may be as effective as
adjuvant chemotherapy but has not shown a benefit
over concurrent CRT alone.
• Standardized EBV DNA as a biomarker to determine
need for adjuvant chemotherapy is in clinical trials.
Laryngeal Cancers
 Surgical Options T1 - Glottic
• Vocal Cord Stripping – remove mucosa during
direct laryngoscopy
• Laser Excision – appropriate for lesions
involving middle third of cord
• Cordectomy – endoscopic or open
– Contraindicated in large lesions involving entire
cord or commissure
– Voice compromise
• Total Laryngectomy may be required in 10% of
patients
 Surgical Options T2 - Glottic
• Vertical Partial Laryngectomy
• Contraindicated if lesion involves:
– Epiglottis
– Pre-epiglottic space
– Subglottic extension
• Remove entire affected cord and <1/3 of
contralateral cord
• Total Laryngectomy may be required in 55% of
patients
Radiation Technique: Lateral
opposed fields
• If there is anterior ½ cord
involved and the patient
has a thin neck, use 5 mm
bolus
• Make sure there is always
anterior flash on skin
• I recommended using CT
based planning with real
bolus placed on the field
• Do not over-wedge or you
risk anterior failures; I try
to use 15 degree wedges
60
 Radiation Therapy for Larynx Cancer
• T1 Tumors
– Local control 85-95%
– Ultimate local control with surgical salvage about
95%
• T2 Tumors
– Local control 65-85%
– Ultimate local control with surgical salvage about
90%
• Surgical salvage most often with total
laryngectomy
• Randomized trial of CO2 laser vs RT to 66 Gy
• 60 patients with T1a glottic SCCA in Helsinki
• At 6 and 24 months, compared voice quality, roughness,
breathiness, asthenia, strain, videolaryngostroboscopic
findings, self-rated voice quality and impact on daily life
• Overall voice quality was similar but RT patients showed
improvement in breathiness over time, better glottal
closure, and less inconvenience in their daily lives
• Conclusion: “Radiation therapy may be the treatment of
choice when the requirements for voice quality are
demanding.”
Possible Long Term Complications of RT
• Laryngeal edema 1-4%
• Webbing
• Stenosis
• Soft tissue or cartilage necrosis
• Long term dysphagia
• Very long term risk of second malignancy
 T3 “Organ Preservation” Options
• Partial laryngectomy
– Supracricoid How can we:
1. Avoid a stoma?
– Supraglottic
2. Maintain swallowing?
– Vertical hemilaryngectomy

• Partial laryngectomy followed by post-op radiation therapy

for intermediate risk features or post-op chemoradiation
for high risk features

• Chemotherapy  radiation

• Concurrent chemoradiation
T3 supraglottic SCCA, s/p T1 FOM WLE and
B neck dissection with left N2b with ECE
• GTV  7 mm to CTV  5 mm to
PTV to account for motion
• Daily soft tissue based CBCT to
align laryngeal tissues
• For oral cavity, cover levels 1A-
1B-2-3, ipsi level 4 for N+, ipsi
level 5 for N2b; bolus for ECE
• Cover bilateral 2-4 for larynx
cancers, ipsi level 5 for N2b, and
level 6 if he had subglottic or
hypopharyngeal extension
• RPs if he had post pharyngeal
wall or hypopharynx involvement
 Organ Preservation
• Not a new debate

• Kernan JD. Malignancies of the larynx: shall

we employ surgery or radiation therapy. Med
Rec 1946 Jun; 159:351
 What Spawned This Debate?
Patient reported quality of life/the morbidity of
total laryngectomy

• The Toronto experience

Harwood AR, Rawlins E. The quality of life of patients
following treatment for laryngeal cancer. In J Radiat
Oncol Biol Phys 1983 Mar:9(3):335-8.
– 79% of T3 and T4 patients were working 9-15 months
after RT compared to 44% of surgery patients
– Survival was the same comparing radical radiation
with surgery in reserve with primary surgery upfront
 VA LARYNGEAL CA. STUDY
Stage III-IV
excl T1N1 Surgery Radiation Therapy

R PR Surgery
A
CR or PR
N (3rd Cycle Radiation
D of Chemo) Therapy
O
M CR
I Induction
Chemotherapy
Z (2 Cycles) < PR Surgery Radiation
E

Induction Chemotherapy: Cisplatin and 5-FU

 VAH Laryngeal Carcinoma Study
Patterns of First Failure – higher in CRT arm

S + RT CT + RT P
(N = 166) (N = 166) value

Persistent Disease 6 (4%) 15 (9%) .042

Recurrent Disease
Primary only 0 (0%) 21 (13%) .001
Nodes (+ prim) 15 (9%) 27 (16%) .001
Distant Mets 30 (18%) 20 (12%) .004
VAH Laryngeal Carcinoma Study
Cause of Death – similar in the end
Cause S + RT CT + RT
(N = 166) (N = 166)

Local/Regional 20 (12%) 29 (17%)

Distant Mets 22 (13%) 20 (12%)
Second Primary 4 ( 2%) 7 ( 4%)
Complications 6 ( 4%) 4 ( 2%)
Other causes 22 (14%) 17 (10%)
Unknown 5 ( 3%) 10 ( 6%)

Total 79 (48%) 87 (52%)

 VAH Laryngeal Carcinoma Study
at Four Years
S + RT CT + RT
(N = 166) (N = 166)
Larynx preserved 20* (12%) 103 (62%)

Total laryngectomy 146 (88%) 63 (38%)

Patients alive 87 (52%) 79 (48%)

without larynx 79 27
with larynx 8 (5%) 52 (31%)

* Supraglottic Laryngectomy
VA larynx, long term QOL: significant
differences in mental health and pain

Terrell Arch Otolaryngol 1998

VAH Laryngeal Carcinoma Study
Salvage Laryngectomy - Worse for T4

Stage III 29%

Stage IV 44% p = 0.048

< T4 29%

T4 56% p = 0.001
 RTOG 91-11 selection criteria
• Patient selection
– T3
– Limited T4

• Patient exclusions
– Large volume T4a
• Extending through thyroid cartilage
• Greater than 1 cm extension into base of tongue
 RTOG 91-11
Phase III Trial to Preserve the Larynx
N = 547 stage III/IV
R Arm 1 : Neoadjuvant CT + RT
S Location:
CR, PR Cis + 5-FU RT
A
T Glottic x 1 Cycle
Supraglottic N
R Cis + 5-FU X 2 Cycles
T Stage: D
A
T2 O NR Surgery RT
T T3 M
I Early T4
I Arm 2 : RT + cisplatin
F N Stage: Z
Y N0, N1 Arm 3 : RT Alone
E
N2, N3
Neck dissections for all pts with node > 3cm or
multiple nodes, 8 weeks after RT
 RTOG 91-11 at 3 years
Arm LPR LRC OS G3/4 (G5)

Neoadj CT 75% 61% 76% 66% (5)

Conc CT 88% 78% 74% 77% (9)

RT alone 70% 56% 75% 47% (5)

 RTOG 91-11 10 year update:
CRT  highest rates of
laryngeal preservation and LRC

Forastiere JCO 2013

 RTOG 91-11 10 year update:
ICRT produced higher rates
of LFS than RT alone

? Late “non-cancer related Forastiere JCO 2013

death” in CRT arm?
 Putting the induction issue in
perspective
• The inductionRT arm vs RT:
– ICRT was better for composite endpoint
of laryngectomy free survival
– No statistical difference for LP, LRC, or OS
• The inductionRT arm vs CRT:
– ICRT was worse for larynx preservation
and local control
– No statistical difference in other endpoints

Forastiere JCO 2013 70

 Unanswered “real-life” dilemmas
• Should induction-RT be an option along with
concurrent chemoradiation?
• Should “induction” mean TPF or PF?
• Should induction be followed by chemoradiation
instead of RT, in keeping with original TPF vs PF
protocol?
• Which T3 cancers should have surgery and would
they do better with partial larygectomy?
• Should “minimal” T4 cancers be considered for organ
preservation?
 GORTEC Phase III Trial: Docetaxel/Cisplatin/5-FU
vs Cisplatin/5-FU ICT for Organ Preservation in
Hypopharynx and Larynx Cancer
ICT
Docetaxel (75 mg/m2, day 1)
R Cisplatin (75 mg/m2 ,day 1)
Surgery
Treatment-naïve resectable A 5-FU (750 mg/m2, days 1-5 C-I)
Post-op RT
larynx or hypopharynx N every 3 weeks, 3 cycles
D (54-66 Gy)
cancer (N=112)
• Requiring total (pharyngo) O
M
laryngectomy Cisplatin (100 mg/m2, day 1)
I RT (70 Gy)
Z 5-FU (1000 mg/m2, days 1-5)
N=210
E every 3 weeks, 3 cycles
(N=108)

• No response=tumor regression <50% and/or persistent larynx fixation

• Response=tumor regression >50% and larynx recovering normally

Pointreau, JNCI 2009

 GORTEC: Docetaxel/Cisplatin/5-FU vs Cisplatin/
5-FU ICT for Organ Preservation in Hypopharynx
and Larynx Cancer: Results
100 100
DFS OS
80 80
Percentage

Percentage
60 60
P (Log-rank test)=0.096
40 40
P (Log-rank test)=0.105
20 Induction TPF (N=108) 20 Induction TPF (N=108)
Induction PF (N=112) Induction PF (N=112)
0 0
0 6 12 18 24 30 36 42 0 6 12 18 24 30 36 42
Months Months
100 Larynx Preservation*
80
Percentage
• DFS and OS trends favor TPF but 60
are not statistically significant
40 P (Log-rank test)=0.036

20 Induction TPF (N=108)

*European definition. Induction PF (N=112)
0
0 6 12 18 24 30 36 42
Months
Pointreau, JNCI 2009
 T4 larynx cancers
• T4: outer cortex of thyroid cartilage
– Full thickness destruction of the thyroid cartilage
 total laryngectomy
– These patients will do poorly with failure of CRT
requiring salvage laryngectomy
• T4: extralaryngeal extension
– Consider pre-existing function (patient’s age)
– Consider volume of tumor e.g. >12cc is concerning
Long-Term Outcomes for T4 Larynx
Cancer

Rosenthal et al. Cancer 2015 Jan 13.

 Accelerated fractionation in the absence of concurrent
chemotherapy: long term update of RTOG 9003
• If CRT is not an option, and surgery not possible or not desired,
consider hyperfractionation or accelerated fractionation for
oropharynx, larynx, hypopharynx cancers

Beitler et al IJROBP 2014

Conclusions: Larynx Preservation Trials
Organ preservation does not compromise survival IF
patients are appropriately selected and treated
T4 tumors with extensive/complete cartilage invasion
should have primary laryngectomy
For bulky T4 tumors, surgical salvage is less successful
after concurrent chemoradiation; also, chemo and RT
prior to TL decrease quality of life and increase
feeding tube dependence
The highest rates of organ preservation are seen with
CRT but there is non-cancer related late death and
late toxicities increase over time
This is a very challenging area requiring careful
multidisciplinary evaluation and patient counseling
 Postoperative Radiation: Clinical
Indications
• Tumor at or close to surgical margin
• Perineural Invasion
• Cartilage invasion
• Invasion of bone or soft tissues of the neck
• Emergent Tracheostomy
• Lymph-vascular Invasion
• Multiple (> 2) lymph node metastasis
• Extra capsular extension
 Historical PORT results
• Locoregional control 69-72%
• 5-year survival 30-40%
Radiation Dose
 MD Anderson randomized dose-
finding study
N=240
R
Stratification Low risk -> no radiation
A
• Oral Cavity N Dose A 57 Gy/32 Fx
D
Int Risk*
• Larynx O
Dose B 63 Gy/35 Fx
M
• Hypopharynx I High Risk
Z Dose C 68.4 Gy/38 Fx
• Larynx • Based on T- & N-stage, margin, PNI
E
• Raised midway from 52.2-54 Gy/29-30 Fx
 MDA dose finding results
• <54 Gy had significantly higher failure rate
• ECE needed at least 63 Gy
• 2-3 negative factors increased LR recurrence risk:
– oral cavity
– close/pos margins
– perineural
– >2 involved nodes
– node >3 cm
– treatment delay >6 wks
– Zubrod performance status>2
4+ negative factors  locoregional
recurrence risk similar to ECE

Peters, IJROBP, 1993, 26:3-11

Radiation Timing
 MD Anderson study on accelerated RT
oral cavity,
oropharynx,
larynx,
hypopharynx

Last 2 wks
CCB

Pathologic T stage was T3–4 in 129 (61%)

and N2–3 in 123 (58%) patients
Ang KK, IJROBP 2001, 51:571
LRC & OS by
package time
(date of
surgery to
PORT
completion) –
for high risk
pts
LRC and OS based on interval
from surgery to PORT
median = 31d
Chemotherapy
Randomized trials of RT vs chemoRT: EORTC
22931 & RTOG 9501

NEJM 2004; 350:1945-1952

NEJM 2004: 350:1937-1944 80
EORTC vs RTOG – LRC 11-13%
improvement
EORTC RTOG
EORTC vs RTOG – OS 10-11%
improvement
EORTC RTOG

NOT STATISTICALLY
SIGNIFICANT
EORTC & RTOG - Combined data

30%
reduction
in risk of
death
 RTOG 9501: 10 year followup
• No overall benefit for LRC or OS from postop
chemoradiation at 10 years
– LRC still better for ECE or pos margins
• Multiple nodes without ECE or pos margin: shows
no LRC benefit from postop CRT
– Analysis of patients with up to 6 involved nodes
• Conclusion: Multiple nodes is not an indicator in
itself for postoperative CRT
– Faint suggestion of unexplained non-cancer related deaths in
patients who received chemo in absence of ECE/+marg
 RTOG 1216: Phase II-III Randomized Trial of
Surgery Followed by Chemoradiation
for High Risk SCCHN
N=475
Register:
p16 and EGFR
R 60-66 Gy/6 wks
A CDDP 40mg/m2 wkly
Stratify by:
Tumor Site N
Zubrod D 60-66 Gy/6 wks
EGFR level O Docetax 15mg/m2 wkly
M
High Risk:
Positive margins I 60-66 Gy/6 wks
Extranodal extension Z wkly Cetuximab
E wkly Docetaxel
Intermediate Risk: Using
Targeted Therapy
 RTOG 0920 for intermediate (NOT HIGH
RISK) cancers
OC, larynx,
OPX p16+/- R
RT: 60 Gy in 30 fractions
A
Intermediate
risk factors: N
cT2-3, N0-2 D
(minimal T4a)
Stage III-IVA O RT: 60 Gy in 30 fractions
PNI M Cetuximab 400 mg/m2
LVSI I loading, 250 mg/m2 x 10
Close <5mm cycles
>5mm deep Z
E
Open and accruing, goal is 700+ pts
CTVs for T3N0 oral tongue with close
inferior margin at FOM
• Refused chemotherapy
• 66 Gy (red) at area of inferior
close margin
• 60 Gy (blue) to remainder of
postop bed and flap
• Bilateral necks radiated
electively given midline
tumor location including level
1A and bilateral 1B
• No PNI, so did NOT cover V3
to base of skull
 For oral cavity cases, assess status of:
1) lingual nerve, 2) hypoglossal nerve and
3) inferior alveolar nerve
 Inferior alveolar nerve (V3) foramen
infiltration into mandible
T1-weighted MRI
V3 invasion easily
travels to skull base –
for major PNI, cover
pathway along
masticator space to
foramen ovale

• Alveolar ridge SCCA

• Invading inferior
alveolar nerve
• Traveling on V3 in
the masticator
space
• Invading through
foramen ovale to
cavernous sinus
Very pragmatic problem: Review
imaging carefully after surgery
• T4a (extrinsic tongue
muscle) N2b (right
neck) tongue SCCA
• Postop chemo-RT
• Early regrowth
detected at the
margin of the flap 
66 Gy
• Bilateral neck
irradiated 60 Gy
levels 1-3 and 54 Gy
level 4
 Very pragmatic problem: Do not assume
surgery removes all nodes (or tumor)
Radonc CT
s/p s\p total
Water T2 supraomohyoid parotidectomy
IDEAL neck dissection

Check postsurgical bed! If questions, order diagnostic scan.

 Conclusions: Postoperative Radiation
• Postoperative not preoperative radiation is standard.
• Accelerated fractionation may benefit patients with a
delayed RT/chemo-RT start.
• Total treatment package time is highly prognostic for high
risk patients.
• Patients with ≥2 LN, ECE, +margins are at the highest risk
for recurrence.
• 4+ intermediate factors have prognosis similar to ECE.
• Postop chemo-RT is beneficial for patients with involved
margins or ECE or both.
• Current trials incorporate targeted therapies; immune-
based therapy is a future possibility.
 Learning Objectives
• IMRT is ideal for HN cancer treatment and its adoption is
near-universal, but delineation requires greater
understanding of anatomical and nodal spread patterns.
• OPC is undergoing a series of major revolutions due to the
etiology of HPV; strategies at present can be radiation-,
surgery-, and chemotherapy-based.
• Induction chemotherapy does not have a clear role at present
in the standard management of OPC or NPC; it may be part of
future development of larynx preservation strategies.
• Postoperative RT is given for intermediate risk factors and
postop CRT is advised for high risk patients; high risk patients
are being investigated for further intensification.