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.Incidence of OC and OPC 2.Oral cavity cancer 3.Oropharyngeal cancer 4.HPV epidemiology and background 5.Counseling of patients with HPV- associated 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 treatments- Radiation, Surgery, Chemotherapy

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 –1 979 to 2004–2008 and for whites (non-Hispanic), blacks, Hispanics (white), and Asian/PIs SEER –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 Total HPV+ HPV- Oral tongue

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:

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 two- thirds) (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 RT pT3 or pT4 N2 or N3 Nodal disease in levels IV and V Perineural invasion Vascular embolism RT Concurrent Cisplatin Chemotherapy Extracapsular nodal spread Positive margins

Evidence for adjuvant RT  Adjuvant radiotherapy improves overall survival for patients with lymph node-positive head and neck squamous cell carcinoma. Lavaf A, Cancer Feb 1;112(3): –Population based SEER analysis 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 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 –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/m 2 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 –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 Major risk factors- ECE, 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.

Primary endpoint: Overall survival Current accrual: ~460/ 700 Treatment Arms Eligibility Oral cavity, oropharynx, larynx Arm 1: RT alone 60Gy in 30 fractions Arm 2: RT + Concurrent Cetuximab

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

Oral cavity, larynx, hypopharynx, HPV neg oropharynx IMRT 60Gy with weekly concurrent Cisplatin 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) IMRT- 60Gy 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

Human Papillomavirus and Survival of Patients with Oropharyngeal Cancer. K. Kian Ang, et al N Engl J Med 2010; 363: % 70.8% 46.2% -HPV +, ≤ 10 p.y. -HPV+, >10 p.y., N0-2a -HPV+, >10 p.y., N2b-3 -HPV-, ≤ 10 p.y., T2-3 -HPV-, ≤ 10 p.y., T4 -HPV-, >10 p.y.

Distant control (DC) profile by STREE analyses. Brian O'Sullivan et al. JCO 2013;31:

Oropharyngeal ca- 2 distinct types! HPV-positiveHPV-negative Epi/ risk factors - RaceWhite> blackBlack> white - Age4 th -6 th decade7 th decade - GenderM:F= 8:1M:F= 3:1 - Smoking/ alcoholMinimalSignificant - Early sexual debut+++? - Multiple sexual partners+++? Clinical Features - T/NSmall T/ Large NLarge T/ Small N Outcomes in St. III &IV - Distant mets10-30% - 2 nd primary risk~5%~10% - Response to Rx~80%~50% - OS2y95%62% Adapted from- Curr Opin Oncol May;26(3): 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 CaHPV + RTOG 1016 ECOG 1308 ECOG 3311 # NRG HN002 HPV - RTOG #- transoral surgery for treatment de-escalation- reduced dose of 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 Concurrent RT+CT Induction Chemotherapy Eligibility HPV positive Opx ca Resectable Cisplatin Taxol Cetuximab 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 Concurrent RT + Chemo Eligibility p16 positive Opx ca Accelerated IMRT 70Gy / 6 weeks with Cisplatin q3weeks Accelerated IMRT 70Gy / 6 weeks with Cetuximab q wkly Primary endpoint- Overall survival Accrual- 987/ 834

ECOG 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 Arms Eligibilit y p16 positive oropharyngeal ca 60Gy / 6 weeks with weekly Cisplatin 60Gy in 5 weeks (NO CHEMO) Primary endpoint- 2yr 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 SchemaEligibility Stage III-IV T1-2, N1-2 p16 negative oropharyngeal ca Risk-based post-op adjuvant therapy - IMRT 60Gy +/- Wkly cisplatin* >4 LNs, +ve margins, ECE IMRT 70Gy with weekly cisplatin Trial Closed 0/144

© 2014 Lippincott Williams & Wilkins, Inc. Published by Lippincott Williams & Wilkins, Inc. 2 Oropharyngeal squamous cell carcinoma treatment: current standards and future directions. Marur, Shanthi; Burtness, Barbara Current Opinion in Oncology. 26(3): , May Table 4 Selected studies in progress with targeted therapies in head and neck squamous cell cancer

Current treatment paradigm for patients not enrolled on clinical trials at HFHS Newly diagnosed Opx Ca Tumor board discussion TORS T1-2, select T3, rare T4 pT1-2N0 Observation pT3-4 OR N+ Adjuvant RT 60Gy/30 fr/ 6 weeks Positive margin OR ECE+ Adjuvant RT 66Gy/ 33 fr/ 6.5 weeks + Concurrent Chemotherapy Radiation Any T, Any N, M0 RT (70Gy/ 35 fractions/ 7 weeks)+ Concurrent chemotherapy No difference yet based on HPV status

Ca Tonsil – Simultaneous Intergrated Boost (SIB) IMRT- 70Gy-63Gy-56Gy in 35 fractions

Clinical Challenges in Counseling Patients with HPV- associated Oropharyngeal Cancer

HPV ASSOCIATED OROPHARYNGEAL CANCER HPV ASSOCIATED OROPHARYNGEAL CANCER Population issues Population issues Patient Partner/ Caregiver Education/ Knowledge Vaccines?? 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 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): 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 Sep;49(9): Discussing the diagnosis of HPV-OSCC: common questions and answers. Fakhry C, D'Souza G.

Oral Oncol Sep;49(9): 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 –  Head & Neck Cancer Guide –  Cancer Support Community –  HPV Support Network –

References 1.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: 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: Fakhry C, D’Souza 4.G. Discussing the diagnosis of HPV-OSCC: Common questions and answers. Oral Oncology: Finnigan J, Sikora A. Counseling the patient with potentially HPV-related newly diagnosed head and neck cancer. Curr Oncol Rep 2014; 16:375, 6.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: Chaturvedi A. Epidemiology and clinical aspects of HPV in head and neck cancers. Head and Neck Pathology 2012; 6:S16-S24. 8.Center for Disease Control and Prevention. Human papillomavirus and oropharyngeal cancer. Retrieved from May National Cancer Institute at the National Institutes of Health. HPV a risk factor of oropharyngeal cancer. Retrieved from May 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: 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: Klug S, Hukelmann M, Blettner M. Knowledge about infection with human papillomavirus: A systematic review. Prev Med 2008; 46: 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):

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