HPV-Related Head and Neck Cancer

Guilherme Rabinowits M.D.Center for Head and Neck OncologyInstructor in MedicineHarvard Medical SchoolBoston, MA

Disclosures

• Scientific Advisory Board for Onyx Pharmaceuticals Inc.• Clinical Trial Support to Institution from Exelixis and

Millenium

2

Introduction

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• HNC - 6th most common cancer worldwide• Historically tobacco and ETOH-related cancer• Strong evidence linking HPV infection to HNC• Increasing incidence of oropharynx cancers, while

decrease incidence of other HNCs• Proportion of HPV+ disease is increasing: epidemic

North European and North American patients• Preferentially identified in oropharynx cancer - tonsil and

base of tongue • HPV 16 is the predominant subtype (>90%)

Ang NEJM 2010Abogunrin BMC Cancer 2014

Patient and Tumor Characteristics

• Younger patient population• Lower smoking rates• Men > women• Multiple sexual partners• Oral sex practice• Oropharynx most common location• Small primary tumors and advanced nodal disease• Cystic nodes• Poorly differentiated, basaloid tumors

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D’Souza NEJM 2007 Gillison JNCI 2008Chatuverdi JCO 2011

Molecular and Biological Events in HNC

HPV-Related Cancers

• Caused by high-risk HPV– HPV 16– Driven by viral oncogenes

• Restricted to oropharynx• Distinct molecular markers• “Good” prognosis• Young, good general health

Environment-Related Cancers

• Caused by environmental mutagens

– Smoking, alcohol

• Throughout oral mucosa• Distinct molecular markers• “Poor” prognosis, comorbidity• Second primary cancers

HNC Can Now Be Divided Into 2 Large and Distinct Subtypes

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Genomic Landscape

6 Hayes et al ASCO 2013

Proportion of Oropharynx Cancer, USA 1973-2005

18%

32%

Chaturvedi and Gillison

New data from 2005 – 2011 revealed continuing alarming increases in age-specific incidence rates by birth cohort among all men born after 1940, age 40-70 years

OPC is one of the only 5 cancer types that increased in incidence from 1975 – 2009 (CDC)

Jemal JNCI 2013

Tumor HPV Prevalence

8 D’Souza Prev. Med 2011

Latency Period

9 Gillison JCO 2015

Screening

• Screening at this time for HPV+ OPC is infeasible

– Inability to detect precursor lesions and subclinical or early-stage cancers

– Absence of an established intervention to reduce cancer incidence and mortality

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HPV Diagnostic Testing

• p16 immunohistochemistry (very sensitive)• In situ hybridization for high risk HPV (very

specific)• PCR (both sensitive and specific)

HPV Oncoproteins

12 Mohanti doi:10.4172/scientificreports.452

HPV Status as a Prognostic Factor

Modality Time HPV+ HPV- p

Radiation (DAHANCA)1 5 yrs 62% 26% 0.0003

ChemoRT (TROG)2 2 yrs 91% 74% 0.004

ChemoRT (RTOG 0129)3 3 yrs 82% 57% 0.001

Sequential (ECOG)4 2 yrs 95% 62% 0.005

Sequential (TAX324)5 5 yrs 82% 35% 0.0001

1Lassen, JCO, 2009; 2Rischin, JCO, 2010; 3Ang NEJM, 2010; 4Fakhry, JNCI, 2008; 5Posner Ann Onc, 2011

• Acute: mucositis, dermatitis, dysphagia, odynophagia

• Chronic: xerostomia, dysgeusia

• Can therapy for all HPV+ OPC be deintensified to decrease risk of acute and long-term toxicities?

• Are there other prognostic factors within OPC other than HPV status?

Treatment Toxicity

RTOG 0129 Phase III Trial: Concomitant CRT With Standard vs. Accelerated Fractionation RT

Stage III/IV (T2, N2-3, M0 or T3-4, any N, M0) SCCHN

•Oral cavity, oropharynx, hypopharynx, and larynx•No previous treatment

N=743

Cisplatin(IV on d1, d22, d43)

Standard fractionation RT(5 d/wk for 7 wks)

CRT

RANDOMIZE

Cisplatin(IV on d1 and d22)

Accelerated fractionation RT(5 d/wk for 3.5 wks; then bid,

5 d/wk for 2.5 wks)

Ang NEJM 2010

3-year OS, PFS or pattern of relapse were similar between groups

RTOG 0129: HPV Analysis

433 (60%) of 721 had OP primary 323 (75%) of 433 had HPV testing 206 (64%) of 323 were HPV+

P16-positive P16-negative

HPV-positive 192 (93%) 7 (3%)

HPV-negative 22 (19%) 94 (80%)

Kappa = 0.80: 95%CI 0.73-0.87

Ang NEJM 2010

RTOG 0129: OS and PFS by HPV Status

3-Yr Outcomes HPV Positive (%) HPV Negative (%) P ValueOS 82.4 57.1 <0.001PFS 73.7 43.4 <0.001Locoregional failure 13.6 35.1 <0.001Distant metastases 8.7 14.6 0.23

PFSOS100

75

50

25

0

100

75

50

25

0

HPV negativeHPV positive

HPV negativeHPV positive

HR=0.38 (95% CI: 0.26-0.55); P<0.001 HR=0.40 (95% CI: 0.29-0.557; P<0.001

Ang NEJM 2010

RTOG 0129 RPA: HPV, Smoking Status, Staging

Ang NEJM 2010

Risk Groups

19 Ang NEJM 2010

• Retrospective analysis– OPC treated with RT or CRT 2001-2009 – Risk of distant metastasis HPV+ OPC

• Similar risk of distant metastasis despite differences in loco-regional control

O’Sullivan JCO 2013

Median f/u 3.9 years

PMH RPA

HPV Positive Low Risk Modified*N2c removed from final grouping -Difference for RT vs CRT*Also remove N2b heavy smokers O’Sullivan JCO 2013

PMH Results

• HPV-– Low risk: T1-T2, N0-N2c (DC 93%; LRC

76%)– High risk: T3-T4, N3 (DC 72%; LRC 62%)

• HPV+– Low risk: T1-T3, N0-N2c (DC 93%; LRC 95%)– High risk: T4, N3 (DC 78%; LRC 82%)

HPV+ group recommended for deintensification:T1-T3, N0-N2aT1-T3, N2b <10 Pack-Years O’Sullivan JCO 2013

What about Clinical Trials and Future Directions?

Treatment Deintensification Strategies

E1308: Phase II HPV-specific Trial Chemotherapy to Select Patients for Lower Dose Radiation

INDUCTION

(3 cycles)

Weekly Paclitaxel

+

Weekly Cetuximab

+

Q3 wks Cisplatin

ELIGIBILITY

Stage III, IVA

Resectable

HPV or P16+

OropharynxCONCURRENT

IMRT 69.3Gy/33fxs

Cetuximab 250mg/m2 qwk

CR

<CR

CONCURRENT

IMRT 54Gy/27 fxs

Cetuximab 250mg/m2 qwk

Cetuximab loading dose = 400mg/m2 on Day1 of Cycle1 with Induction

N=80

E1308: Results

Cohort (n) 2-year PFS (90% CI) 2-year OS (90% CI)All low dose pts (62) 0.8 (0.7, 0.88) 0.93 (0.85, 0.97)

T4a (7) 0.54 (0.19, 0.79) 0.86 (0.45, 0.97)

Non-T4a (55) 0.84 (0.73, 0.91) 0.94 (0.86, 0.98)

N2c (19) 0.77 (0.56, 0.89) 0.95 (0.76, 0.99)

Non-N2c (43) 0.82 (0.69, 0.9) 0.93 (0.82, 0.97)

Smoker > 10pk-yrs (22) 0.57 (0.35, 0.73) 0.86 (0.67, 0.94)

Smoker < 10 pk-yrs (40) 0.92 (0.81, 0.97) 0.97 (0.87, 0.995)

Smoker < 10pk-yrs, <T4, <N2c (27) 0.96 (0.82, 0.99) 0.96 (0.82, 0.99)All high dose pts (15; 3 didn’t get RT) 0.65 (0.41, 0.82) 0.87 (0.63, 0.96)

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Endpoint: 2-year PFS and OS

23% dose reduction in RT allowed for a significant reduction in toxicity while maintaining high PFS and OS

Cmelak ASCO 2014, adapted

RTOG 1016: A Randomized Phase III Trial of RT with Cisplatin or Cetuximab in P16+ OPC

RANDOMIZE

IMRT 70Gy

Cetuximab400/250

mg/m2 weekly

Cisplatin100 mg/m2/q21d

Stratify: HPV, smoking, stage

Cetuximab loading dose = 400 mg/m2 on Day 1 of Cycle1 with induction

ELIGIBILITY

Stage

III, IVA/B

Resectable

P16+

Oropharynx

Cancer

IMRT 70Gy

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RTOG 1333: A Randomized Phase II Trial of Lower Dose RT with or without Cisplatin in HPV+ OPC

RANDOMIZE

IMRT 60Gy

Cisplatin40 mg/m2/qwk

ELIGIBILITY

Stage

T1-2 N1-2b

T3N0-2b

< 10 pack/yr

HPV+

OPCIMRT 60Gy

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INTERMEDIATE:Close margins

< 1 mm ECS2–4 metastatic LN

PNILVI

HIGH RISK:Positive Margins> 1 mm ECS or

≥ 5 metastatic LN

Radiation TherapyIMRT 60 Gy/30 Fx

Evaluate for 2-yr PFSLocal-Regional

Recurrence, Functional Outcomes/QOL

Transoral Resection (any approach)

with neck dissection

Radiation TherapyIMRT 50Gy/25 Fx

ECOG 3311 – Phase II Randomized Trial of TORS followed by Low- or Standard-dose IMRT in Resectable p16+ Locally

Advanced OPC

Assess Eligibility:HPV (p16+)

OPC

Stage III-IV: cT1-2, N1-2b

(no T1N1)

Baseline Functional/

QOL Assessment

Observation

RANDOMIZE

Radiation TherapyIMRT 66 Gy/33 Fx +CDDP 40 mg/m2 wkly

LOW RISK:T1-T2N0-N1

negative margins

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Conclusions

• Majority of OPC are now HPV 16 related• Better prognosis regardless of standard therapy applied• Specific HPV+ sub-groups do better independent of staging• Future standard treatment for these patients is undefined• Deintensification remains investigational and should not be

done outside of a clinical trial• As treatment deintensification proves successful, we hope the

quality of life for cured patients significantly improves

Thank You !!