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Radiation Therapy for Oral Cavity and
Oropharyngeal Cancers:
Indications and Current Trends
Farzan Siddiqui MD, PhD
Vice-Chair, Radiation Oncology
Director, Head and Neck Radiation Oncology
Disclosure
 No conflicts of interest
Outline
1.
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5.
Incidence of OC and OPC
Oral cavity cancer
Oropharyngeal cancer
HPV epidemiology and background
Counseling of patients with HPVassociated OPC
Incidence and Epidemiology of Oral Cavity
and Oropharyngeal cancers
 Rising incidence of oral tongue cancers
 Rising incidence of HPV-related oropharyngeal
cancers
 Both trends being seen in young adults
 These are patients who have minimal co-morbidities
and are expected to have a normal life expectancy
 Will have to live with all the side effects and
consequences of aggressive cancer treatmentsRadiation, Surgery, Chemotherapy
Total
HPV+
HPV-
Oral tongue
Trends in age-adjusted (2000 US standard)
squamous cell carcinoma of the oral cavity and
pharynx incidence rates by race/ethnicity, subsite,
and gender for whites and blacks SEER 9 1975–1
979 to 2004–2008 and for whites (non-Hispanic),
blacks, Hispanics (white), and Asian/PIs SEER 13
1992–1997 to 2004–2008 according to year of
diagnosis (excludes lip, salivary glands, and
nasopharynx). Shaded bands portray 95% CI.
Journal of Oncology, Volume 2012 (2012)
Oral Cavity and Pharynx Cancer Incidence Trends by
Subsite in the United States: Changing Gender Patterns
Linda Morris Brown, David P. Check, and Susan S. Devesa
25-44 yrs
Journal of Oncology, Volume 2012 (2012)
Oral Cavity and Pharynx Cancer Incidence Trends by
Subsite in the United States: Changing Gender Patterns
Linda Morris Brown, David P. Check, and Susan S. Devesa
Trends in age-specific
squamous cell Ca of
the oral cavity and
pharynx male/female
incidence rate ratios
among whites by
subsite.
Journal of Oncology,
Volume 2012 (2012)
Oral Cavity and Pharynx Cancer
Incidence Trends by Subsite in the
United States: Changing Gender
Patterns
Linda Morris Brown, David P.
Check, and Susan S. Devesa
The net drifts and 95% CIs from age-period-cohort models are shown for oropharyngeal (OP)
cancers (gold squares), oral cavity (OC) cancers (blue squares), and lung cancers (gray
circles).
Anil K. Chaturvedi et al. JCO 2013;31:4550-4559
Incidence in population
≤ 45 yrs
Oral Cavity Cancers
Oral Cavity

Sites- 2.1 Lip (C00)
1. External upper lip (vermilion border) (C00.0)
2. External lower lip (vermilion border) (C00.1)
3. Commissures (C00.6)
2.2 Oral Cavity (C02-C06)
1. Buccal mucosa
i. Mucosa of upper and lower lips (C00.3, 4)
ii. Cheek mucosa (C06.0)
iii. Retromolar areas (C06.2)
iv. Bucco-alveolar sulci, upper and lower (vagina of mouth) (C06.1)
2. Upper alveolus and gingiva (upper gum) (C03.0)
3. Lower alveolus and gingiva (lower gum) (C03.1)
4. Hard palate (C05.0)
5. Tongue
i. Dorsal surface and lateral borders anterior to vallate papillae (anterior twothirds) (C02.0, 1)
ii. Inferior (ventral) surface (C02.2)
6. Floor of mouth (C04)
Principles of Treatment
 SURGERY, SURGERY, SURGERY & SURGERY
 Adjuvant treatment based on risk factors
pT3 or pT4
N2 or N3
Nodal disease in levels IV and V
Perineural invasion
Vascular embolism
Extracapsular nodal
spread
Positive margins
• RT
• RT
• Concurrent
Cisplatin
Chemotherapy
Evidence for adjuvant RT

Adjuvant radiotherapy improves overall survival for patients with lymph node-positive head and neck
squamous cell carcinoma. Lavaf A, Cancer. 2008 Feb 1;112(3):535-43.
– Population based SEER analysis. 8795 patients, HNSCC, treated with surgery, pN+. (Use of
chemo not tracked)
– Median F/U 4.7 years
– Outcome: Adjuvant RT used in 84% (preop 7%, postop 89%).
– 5-year OS surgery alone 33% vs. surgery + RT 43% (SS); 5-year CSS 42% vs. 51% (SS)
– Conclusion: Adjuvant RT improved 5-year CSS and OS by 10%

Postoperative radiation as adjuvant treatment for carcinoma of the oral cavity, larynx, and pharynx:
preliminary report of a prospective randomized trial. Kokal WA, J Surg Oncol. 1988 Jun;38(2):71-6.
– City of Hope-- surgery +/- postop RT. Randomized. Stopped early due to lack of benefit at interim
analysis. 51 patients, stage III-IV SCC of oral cavity, pharynx, or larynx. Arm 1) surgery alone vs.
Arm 2) surgery + postop RT
– Median F/U 2.5 years
– Outcome: Recurrence rate surgery alone 56% vs. postop RT 37% (NS); trend due to higher
recurrence rate in contralateral nonoperated neck (5% vs. 15%). No difference in DFS or OS
– Conclusion: Adjuvant postop RT doesn't improve DFS or OS; trend toward better control
Randomized trials for adjuvant RT and CT
 RTOG 95-01: Cooper JS NEJM 2004.
–
–
–
–
–
–
RCT N=416; OC/OPX/Larynx/HPX s/p resection with ≥LN+, +margins, or ECE.
Randomized: 60 Gy +/- 6 Gy boost alone vs RT with concurrent cisplatin (100 mg/m2 q3weeks x 3).
27% of patients with OC primary.
Median follow-up 45 months. 2 year LRC 72% (RT) vs 82% (chemo+RT) (SS), DFS significantly
increased with a HR of 0.78, but OS not sig. different.
Increased grade 3-4 toxicity in chemo+RT arm (77% vs. 34%).
Conclusion: Improved LRC, DFS in patients with risk factors.
 EORTC 22931: Bernier NEJM 2004.
–
–
–
–
RCT N=334. OC/OPX/Larynx/HPX s/p resection w/ T3/4 any N (except T3N0 of larynx w/ -margins);
T1-2N2-3; T1-2N0-1 w/ ECE, +ve margins (<5 mm), PNI or vascular embolism; or OC/OPX w/ +LN
levels IV/V.
26% OC primary.
Randomized to RT (54 Gy +/- 12 Gy boost) alone vs RT w/ concurrent cisplatin (100 mg/m2 q3wk
x3). Median follow-up of 60 months.
5-year PFS 47% (chemo+RT) vs 36% (RT), OS 53% vs 40%, LRF 18% vs 31%. Increased grade
3-4 toxicity w/chemo-RT (41 vs. 21%).
 Combined analysis. Bernier Head Neck 2005. Major risk factorsECE, microscopically involved surgical margins. Minor- stage III-IV
disease, PNI, LVI and/or clinically enlarged level IV-V lymph nodes
secondary to tumors arising in the oral cavity or oropharynx.
 ECE or involved surgical margins were the only risk factors for which
the impact of post-op concurrent chemo-RT was significant in both
trials.
 Patients with ≥2 +LN without ECE as their only risk factor did not seem
to benefit from the addition of CT.
 (These major and minor criteria now adopted by the NCCN)
RTOG 0920: Phase III study of Post op IMRT with or without Cetuximab
for locally advanced H&N ca
Dose escalation for “Intermediate” risk factor patients:
 Perineural invasion
 Lymphovascular invasion
 Single lymph node > 3 cm or ≥ 2 lymph nodes (all < 6 cm) [no extracapsular
extension]
 Close margin(s) of resection, defined as cancer extending to within 5 mm of a
surgical margin, and/or an initially focally positive margin that is subsequently
superseded by intraoperative negative margins.
 Pathologically confirmed T3 or T4a primary tumor
 T2 oral cavity cancer with > 5 mm depth of invasion.
Eligibility
Oral cavity,
oropharynx, larynx
Treatment
Arms
Arm 1:
RT alone
60Gy in 30 fractions
Arm 2:
RT + Concurrent
Cetuximab
Primary endpoint: Overall survival
Current accrual: ~460/ 700
RTOG 1216: Randomized phase II/III trial of Surgery
and postop RT with concurrent Cisplatin VS
Docetaxel VS Docetaxel and Cetuximab
 Dose escalation for High-risk patients
 Positive inked margins
 Extracapsular nodal extension
IMRT 60Gy with
weekly concurrent
Cisplatin
Oral cavity, larynx,
hypopharynx,
HPV neg
oropharynx
IMRT 60Gy with
weekly concurrent
Docetaxel
IMRT 60Gy with
weekly concurrent
Cetuximab and
Docetaxel
Primary endpoint: Overall survival
Current accrual: ~120/ 675
Ca Oral Tongue –
Simultaneous Intergrated Boost (SIB) IMRT60Gy and 54Gy in 30 fractions
Oropharyngeal cancer
Oropharynx Sites
– Anterior wall (glosso-epiglottic area)
i. Base of tongue (posterior to the vallate papillae or
posterior third) (C01)
ii. Vallecula (C10.0)
– Lateral wall (C10.2)
i. Tonsil (C09.9)
ii. Tonsillar fossa (C09.0) and tonsillar (faucial) pillars
(C09.1)
iii. Glossotonsillar sulci (tonsillar pillars ) (C09.1)
– Posterior wall (C10.3)
– Superior wall
i. Inferior surface of soft palate (C05.1)
ii. Uvula (C05.2)
82.4%
57.1%
Human Papillomavirus and Survival of Patients with Oropharyngeal Cancer. K. Kian Ang, et al
N Engl J Med 2010; 363:24-35
93%
70.8%
- HPV +, ≤ 10 p.y.
- HPV+, >10 p.y., N0-2a
- HPV+, >10 p.y., N2b-3
- HPV-, ≤ 10 p.y., T2-3
46.2%
- HPV-, ≤ 10 p.y., T4
- HPV-, >10 p.y.
Human Papillomavirus and Survival of Patients with Oropharyngeal Cancer. K. Kian Ang, et al
N Engl J Med 2010; 363:24-35
Distant control (DC) profile by STREE analyses.
Brian O'Sullivan et al. JCO 2013;31:543-550
Oropharyngeal ca- 2 distinct types!
HPV-positive
HPV-negative
- Race
White> black
Black> white
- Age
4th-6th decade
7th decade
- Gender
M:F= 8:1
M:F= 3:1
- Smoking/ alcohol
Minimal
Significant
- Early sexual debut
+++
?
- Multiple sexual partners
+++
?
Small T/ Large N
Large T/ Small N
- Distant mets
10-30%
10-30%
- 2nd primary risk
~5%
~10%
- Response to Rx
~80%
~50%
- OS2y
95%
62%
Epi/ risk factors
Clinical Features
- T/N
Outcomes in St. III &IV
Adapted from- Curr Opin Oncol. 2014 May;26(3):252-8.
Oropharyngeal squamous cell carcinoma treatment: current standards and future directions.
Marur S, Burtness B.
Possible reasons for improved outcomes
in HPV + OPC
 May have fewer or different genetic
alterations
 May have higher radiosensitivity due to
intact apoptotic response to RT
 Absence of field cancerization
 Stimulation of immune response directed
against viral specific tumor antigens
 Younger age, good performance status, few
co-morbidities
Current and ongoing trials for
oropharyngeal cancers
Opx Ca
HPV +
RTOG
1016
ECOG
1308
ECOG
3311#
HPV -
NRG
HN002
RTOG
1221@
#- transoral surgery for treatment de-escalation- reduced dose of RT
@- transoral surgery for treatment intensification
E 1308: A phase II trial of induction chemotherapy (IC) followed by
cetuximab with low dose versus standard dose IMRT in patients with HPV
associated resectable squamous cell carcinoma of the oropharynx
Eligibility
HPV positive Opx ca
Resectable
Induction
Chemotherapy
Cisplatin
Taxol
Cetuximab
Concurrent
RT+CT
Clinical CR
Low dose IMRT
54Gy in 27 fr
Clinical PR/ SD
Standard dose IMRT
69.3Gy in 33 fr
ASCO abstract 2013
 80 analyzable
 Median follow up is 11.8 months.
 Centrally reviewed and investigator reported primary site
CCR rate to IC was 63.8% and 71.3%, respectively.
 Radiation: 73.8% (59/80 pts) received low dose IMRT/C to
primary [54Gy (56), 52Gy (1), 40Gy (2)].
 Best overall clinical response was 86% (CR +PR+SD) with
14% UE.
RTOG 1016: Phase III trial of IMRT+ Cisplatin VS IMRT+
Cetiximab in HPV-associated oropharyngeal ca
Eligibility
Concurrent RT
+ Chemo
Accelerated IMRT
70Gy / 6 weeks
with Cisplatin
q3weeks
p16 positive Opx ca
Accelerated IMRT
70Gy / 6 weeks
with Cetuximab q
wkly
Primary endpoint- Overall survival
Accrual- 987/ 834
ECOG 3311- Phase II Randomized Trial of Transoral Surgical Resection followed by
Low-dose or Standard-dose IMRT in Resectable p16+ Locally Advanced Opx Ca
92/377
NRG-HN002: Randomized Phase II Trial for Patients with
p16 Positive, Non-Smoking Associated, Locoregionally
Advanced Oropharyngeal Cancer
Eligibility
p16 positive
oropharyngeal
ca
Arms
60Gy / 6 weeks
with weekly
Cisplatin
60Gy in 5
weeks
(NO CHEMO)
Primary endpoint2yr progression free
survival
Reqd. n=296
RTOG-1221: Randomized Phase II Trial of Transoral Endoscopic H&N Surgery
Followed by Risk-Based IMRT + Weekly Cisplatin VS IMRT + Weekly Cisplatin for
HPV Negative Oropharynx Cancer
Eligibility
Stage III-IV
T1-2, N1-2
p16 negative
oropharyngeal ca
Schema
Risk-based post-op
adjuvant therapy - IMRT
60Gy +/- Wkly cisplatin*
>4 LNs, +ve margins, ECE
Trial Closed
0/144
IMRT 70Gy with weekly
cisplatin
Table 4 Selected studies in progress with targeted therapies in head and neck squamous cell cancer
Oropharyngeal squamous cell carcinoma treatment: current standards and future directions.
Marur, Shanthi; Burtness, Barbara
Current Opinion in Oncology. 26(3):252-258, May 2014.
© 2014 Lippincott Williams & Wilkins, Inc. Published by Lippincott Williams & Wilkins, Inc.
2
Current treatment paradigm for patients not enrolled on
clinical trials at HFHS
Newly diagnosed Opx Ca
Tumor board discussion
pT1-2N0
Observation
TORS
Radiation
T1-2, select T3, rare T4
Any T, Any N, M0
pT3-4 OR N+
Adjuvant RT
60Gy/30 fr/ 6 weeks
No difference yet based on HPV status
Positive margin OR
ECE+
Adjuvant RT
66Gy/ 33 fr/ 6.5 weeks
+
Concurrent
Chemotherapy
RT (70Gy/ 35
fractions/ 7 weeks)+
Concurrent
chemotherapy
Ca Tonsil –
Simultaneous Intergrated Boost (SIB) IMRT70Gy-63Gy-56Gy in 35 fractions
Clinical Challenges in Counseling Patients
with HPV- associated Oropharyngeal Cancer
Education/
Knowledge
Vaccines??
Population
issues
HPV ASSOCIATED
OROPHARYNGEAL
CANCER
Partner/ Caregiver
Patient
Social, political, economic, cultural, spiritual implications
Challenges
 Increase awareness of HPV related
infections and relationship to HNC
 Educate about common patient
concerns/distress
 Provide framework for more effective
patient-centered counseling
HPV Epidemiology
 HPV is most common sexually transmitted
infection (STI)
 >100 types
 >80% sexually active adults infected during
lifetime—most clear in 1-2 years
 Related to cancers of the cervix, vagina, vulva,
anus, penis, and head & neck
 ~7% of total US adults have oral HPV, but only
1% have type that can cause cancer (16 & 18)
 Prevalence 3-4x higher in those with HIV
HPVOPC Epidemiology
 Increase incidence HPV+ OPSCC
– ~15% 1980s
– 65-70% 2000s
 HPV-16 accounts for ~90-95% HPV OPSCC
 Men 3-5x more likely than women
 Younger age of onset than HPV-
Risk Factors For HPVOPC
 Early sexual debut/ young age at first
intercourse
 Increased number lifetime sexual partners
 Unprotected sex
 Current tobacco (and alcohol) use
Role of Vaccines
 No studies for OPX cancers
 Gardasil
– quadrivalent vaccine
– HPV 6, 11, 16, 18
– Males and females 9-26
 Cervarix
– HPV 16, 18
 Gardasil 9
– Females ages 9 through 26 and males ages 9 through 15.
– Prevention of cervical, vulvar, vaginal and anal cancers caused by HPV types 16,
18, 31, 33, 45, 52 and 58.
– Prevention of genital warts caused by HPV types 6 or 11.
Patient Counseling & Education
 Clarify/correct beliefs about HPV and HPV
OPC
 Minimize emotional distress
 Optimize treatment compliance
 Improve patient satisfaction
Transmission of HPV
 HPV is a very common STI
– Most adults will get it
– Most won’t know they have it
 Transmission—vaginal, anal, oral sex, kissing,
genital-to-genital, and genital-hand-oral contact.
(?perinatal transmission)
 Risk for contracting and spreading increases with
number of sexual partners
 Hygiene habits—towels/razors not contributor
 HPV infection/transmission does not = cancer
Prevention of HPV & HPVOPC
 Lifetime monogamy/abstinence best for
prevention
– No sexual changes indicated for current partner
– Fewer lifetime sex partners recommended
 Condoms can help, but HPV can still be
present on non-genital mucosa
 Early life HPV vaccination
 Smoking and excessive alcohol use can
increase risk of developing HPV+ cancer
Partner Notification of HPV
 No set guidelines (like HIV) and no research to
demonstrate risks/benefits of partner
notification
 Advise patients there should be no blame or
shame
– Partner likely already has/had exposure
– HPV+ does not imply infidelity
 Partners may have slightly increased risk of
HPV associated cancers, but risk remains low
overall
HPV Duration &
HPVOPC Recurrence
 Treatments for cancer caused by HPV exist,
but there is no treatment for virus itself
 Exposure to HPV likely occurs 10-20 years
prior to developing cancer
 Those with HPVOPC respond better to
treatment and have better overall survival than
HPV- cancers
 Smoking (and alcohol) increases risk of
HPVOPC progression and death
Courtesy- Michael Ryan. Psy. D.
Oncologist. 2013;18(2):180-9.
A patient-centered approach to counseling patients with head and neck
cancer undergoing human papillomavirus testing: a clinician's guide.
Chu A, Genden E, Posner M, Sikora A.
Oral Oncol. 2013 Sep;49(9):863-71. Discussing the diagnosis of HPV-OSCC:
common questions and answers. Fakhry C, D'Souza G.
Oral Oncol. 2013 Sep;49(9):863-71. Discussing the diagnosis of HPV-OSCC:
common questions and answers. Fakhry C, D'Souza G.
Support & Education Referrals
 SPONHC—Support for people with oral
head & neck cancer
– http://www.spohnc.org/
 Head & Neck Cancer Guide
– http://www.headandneckcancerguide.org/
 Cancer Support Community
– http://www.cancersupportcommunity.org/Default.aspx
 HPV Support Network
– http://www.thehpvsupportnetwork.org/
References
1.
2.
3.
4.
5.
6.
7.
8.
9.
10.
11.
12.
13.
Chu A, Genden E, Posner M, Sikora A. A patient-centered approach to counseling patient with head and neck cancer undergoing human
papillomavirus testing: A clinician’s guide. The Oncologist 2013; 18:180:180-189
Chaturvedi A, Engels E, Pfeiffe R, et al. Human papillomavirus and rising oropharyngeal cancer incidence in the united states. Journal of
Clinical Oncology: 2011; 29:23: 4294-4301
Fakhry C, D’Souza
G. Discussing the diagnosis of HPV-OSCC: Common questions and answers. Oral Oncology: 2013
Finnigan J, Sikora A. Counseling the patient with potentially HPV-related newly diagnosed head and neck cancer. Curr Oncol Rep 2014;
16:375,
D’Souza G, Gross N, Pai S et al. Oral human papillomavirus infection in HPV-positive patients with oropharyngeal cancer and their partners.
Journal of Clinical Oncology: 2014; 55:1341
Chaturvedi A. Epidemiology and clinical aspects of HPV in head and neck cancers. Head and Neck Pathology 2012; 6:S16-S24.
Center for Disease Control and Prevention. Human papillomavirus and oropharyngeal cancer. Retrieved from
http://www.cdc.gov/std/HPV/STDFact-HPVandoralcancer.htm , May 2014
National Cancer Institute at the National Institutes of Health. HPV a risk factor of oropharyngeal cancer. Retrieved from
http://www.cancer.gov/cancertopics/hpv-oropharyngeal-cancer0507, May 2014
Kreimer A, Clifford G, Boyle P et al. Human papillomavirus types in head and neck squamous cell carcinomas worldwide: A systematic
review. Cancer Epidemiol Biomarkers Prev 2005; 14:467-475.
Daley E, Perrin K, McDermott R et al. The psychosocial burden of HPV: A mixed-method study of knowledge, attitudes and behaviors
among HPV+ women. Journal of Health Psychology 2010; 15:279-290
Klug S, Hukelmann M, Blettner M. Knowledge about infection with human papillomavirus: A systematic review. Prev Med 2008; 46:87-98
Milbury K, Rosenthal D, El-Nagger A, Badr H. An exploratory study of the informational and psychosocial needs of patients with human
papillomavirus-associated oropharyngeal cancer. Oral Oncology. 2013; 49(11):1067-71
Thank you!