HPV INDUCED OROPHARYNGEAL CARCINOMA radiation-oncologist point of view Prof. dr. Sandra Nuyts Dep. Radiation-Oncology UH Leuven Belgium
DISCLOSURE OF INTEREST Nothing to declare
HEAD AND NECK CANCER -HPV Change in incidence: Chaturvedi AK J Clin Oncol 2011
HEAD AND NECK CANCER -HPV D Souza Prev Med 2011
TWO DISTINCT HEAD AND NECK CANCERS Gillison M J Natl Cancer Inst 2008
OVERALL SURVIVAL BY HPV STATUS IN PROSPECTIVE PHASE III RT TRIALS Regimen HR(95% CI) Author Induction + CRT (ECOG) 0,36 (0,15-0,85) Fakhry CRT (TROG 2.2) 0,29 (NR) Rischin CRT (RTOG 0129) 0,44 (0,2-0,69) Ang Induction + CRT (TAX324) 0,20 (NR) Settle Radiation (DAHANCA5) 0,44 (0,28-0,68) Lassen
INFLUENCE OF HPV AFTER CONVENTIONAL RADIOTHERAPY IN HNSCC (5FX/WEEK) DAHANCA 5 (N=156) HPV/p16-positivity is a favourableand strong independent prognosticfactor in head and neck cancer radiotherapy Lassen P J Clin Oncol 2009
CHEMORADIOTHERAPY: RTOG 0129 93% 3y DFS <50% 3y DFS Ang KK New Eng J Med 2010
Trotti et al Lancet Oncol 2007
WHAT S NEXT? Separate trials for HPV+ and HPV- disease Can we de-intensify treatment in low risk HPV+/ nonsmokers while mainting overall survival What are the means to customize radiotherapy? dose Fractionation schedules Customize radiotherapy volumes Follow up Concomitant therapies
RTOG 0129 93% 3y OS 71% 3y OS 46% 3y OS Ang NEJM 2010 O Sullivan JCO 2013
1.DOSE REDUCTION dose Fractionation schedules Customize radiotherapy Concomitant volumes therapies Follow up HN002: randomized Phase 2 trial for patients with p16+, non-smoking associated, locoregionally advanced OPC
95% 3y OS NCT01520997 Phase II trial Univ North Carolina and Florida 44 patients Low risk HPV+ OPC T0-T3, N0-N2C Less 10 packyears De-intensified CRT IMRT 60Gy + 6 weekly cisplatin 30mg/m2 Prim Endpoint: pcr 86% (98% at primary, 84% at neck) Chera et al IJROBP 2015 Cancer 2018
2. SELECTION BASED ON INDUCTIONCHEMO Rationale: -HPV associated OPC responds better to chemotherapy -Omission/reduction of radiotherapy But: 9 weeks of chemo for 1 week reduction of RT -Improve distant control But: distant M+ rate similar in HPV+ and HPV- disease (Ang, O Sullivan, Huang)
SELECTION BASED ON INDUCTIONCHEMO ECOG 1308: randomized Phase II trial 70% CR at primary 58% CR at nodal site Cmelak A ASCO 2014, abstract LBA6006
ECOG 1308 Cmelak A ASCO 2014, abstract LBA6006 Marur JCO 2017
SELECTION BASED ON INDUCTIONCHEMO Quarterback
SELECTION BASED ON INDUCTIONCHEMO UCLA St III-IV HPV+ OPC 2 cycles IC (paclitaxel carboplatin) followed by CRT paclitaxel + 54 or 60 Gy RT Chen et al Lancet Oncol 2017
3. SELECTION BASED ON TRANSORAL SURGERY Rationale: Omission/reduction of RT Single modality therapy: significant reduction in toxicity (but only 11% of ECOG3311) Pathological risk based assessment 4 to 10Gy reduction (70Gy to 66/60Gy) Omission of chemotherapy Positive margins and ECE are indications for postop RCT Used less often after transoral surgery
POSTOP DOSE REDUCTION dose Fractionation schedules Customize radiotherapy Concomitant volumes therapies Follow up 11% 58% 31%
POSTOP DOSE REDUCTION dose Fractionation schedules Customize radiotherapy Concomitant volumes therapies Follow up PATHOS -Phase II trial 242 pts - P16+ OPSCC -T1T3N0N2b -transoral surgery to primary + neck dissection Low risk: no adjuvant therapy Intermediate risk: T3 tumours (or T1T2 tumours with additional risk factors) N2a or N2b perineural and/or vascular invasion or close margins (15mm) High risk positive (<1mm) margins and/or evidence of cervical lymph node extracapsular spread PORT 60Gy 6 wks PORT 50Gy 5 wks POCRT 60Gy 6 wks + cisplat PORT 60Gy 6 wks
POSTOP DOSE REDUCTION dose Fractionation schedules Customize radiotherapy Concomitant volumes therapies Follow up ADEPT -P16+ OPSCC -Transoral resection T1- T4a primary negative margin -Neck dissection: ECE in nodal metastasis IMRT 60Gy/2Gy IMRT 60Gy/2Gy + cisplatinum 40mg/m2 weekly
4.CONCOMITANT THERAPIES SUBSTITUTE CETUXIMAB FOR CISPLATIN? Fractionation dose schedules Customize radiotherapy volumes Follow up Concomitant therapies Bonner JA Lancet Oncol 2010
SUBSTITUTE CETUXIMAB FOR CISPLATIN? Fractionation dose schedules Customize radiotherapy volumes Follow up Concomitant therapies P16 is a strong prognostic factor in locally advanced oropharyngeal cancer: overall survival Rosenthal D ASCO 2014 Abstract 6001
SUBSTITUTE CETUXIMAB FOR CISPLATIN? Fractionation dose schedules Customize radiotherapy volumes Follow up Concomitant therapies Rosenthal D ASCO 2014 Abstract 6001
Concomitant therapies SUBSTITUTE CETUXIMAB FOR CISPLATIN? Biological rationale to use cetuximab in HPV+ disease? Controversial Inverse correlation EGFR gene copy number, EGFR protein expression and HPV status or p16 expression Immune stimulatory effect of C225 could potentiate the cytoxic T-Cell base antitumor immune response already present in HPV+ OPSCC EXTREME trial: cetuximab beneficial independent of p16 status, SPECTRUM trial: panitumumab only effect in p16- disease Clinical rationale to use cetuximab in HPV+ disease? Controversial Tremplin study JCO 2013, Hitt ASCO 2013: toxicity difference cetuximab/cddp??
Concomitant therapies SUBSTITUTE CETUXIMAB FOR CISPLATIN? RTOG 1016 TROG 12.01 RT 70Gy 7 wks+ weekly cisplatin -P16+ OPSCC -st III (excl T1-2N1) or IV (excl T4, N3 and distant M+) -if smoking history > 10 pack years: nodal disease must be N0- N2a RT 70Gy 7 wks + weekly cetuximab De-ESCALaTE
5. REDUCE IRRADIATED VOLUMES dose volumes Fractionation schedules Customize radiotherapy Concomitant Follow up therapies Unilateral-only IMRT First Author, Year N N0-1, % T1-2, % Contralateral Neck failure, % Jackson, 1999 178 87 65 3 Kagei, 2000 32 84 56 0 O Sullivan, 2001 228 83 84 3 Rusthoven, 2009 20 20 90 0 Chronowski, 2012 102 56 100 2
5. PROTON THERAPY PROTON therapy MD Anderson Cancer Centre Randomized phase II III study 360 pats HPV+ OPC concurrent CRT IMRT vs IMPT 70 Gy/2Gy +cisplatin100 mg/m2 The primary endpoint: late grade 3 5 toxicity Widesott L Int J Radiat Oncol Biol Phys 2008
EXPECTED BENEFITS? Langendijk Recent Results in Cancer Res 2017
6. HYPOXIA MODIFICATION? Hypoxia modification Excellent radiotherapy response (Rishin JCO 2010; Ang NJEM 2010) No benefit from hypoxia targeted therapy (Lassen 2010 R&O; Rishin JCO 2010) Hypoxia seems not to affect prognosis (Toustrup, R&O 2012) AdaptedfromToustrupK et al., R&O 2012
7. ALTERED FRACTIONATION? Fractionation schedules
8. IMMUNOTHERAPY? Economopoulou P et al Ann Oncol 2016
ROLE OF FOLLOW UP AFTER RT 1, lymph node regression 2, metastasis dose volumes Fractionation schedules Customize radiotherapy Concomitant therapies Follow up both show distinct pattern in HPV+ versus HPV- disease
FOLLOW UP AFTER RT 1, lymph node regression During RT, enlargement of cystic lymph nodes has been described, with need for replanning dose volumes Fractionation schedules Customize radiotherapy Concomitant therapies Follow up Sanguineti G Head&Neck 2012
FOLLOW UP AFTER RT 1, lymph node regression After RT, lymph nodes involute more quickly, but undergo a prolonged process to eventual CR dose volumes Fractionation schedules Customize radiotherapy Concomitant therapies Follow up Huang H IJROBP 2013
FOLLOW UP AFTER RT 1, lymph node regression dose volumes Fractionation schedules Customize radiotherapy Concomitant therapies Follow up Huang H IJROBP 2013
FOLLOW UP AFTER RT 2, metastasis DM rate is similar for HPV+ and HPV- disease But DM tend to occur later Tend to be more disseminating, unusual sites Prolonged survival is described after salvage for DM dose volumes Fractionation schedules Customize radiotherapy Concomitant therapies Follow up Huang S Oral Oncol 2013
CONCLUSIONS +? - Altered fractionation Cetuximab Hypoxia modification Cisplatin Dose de-escalation Protontherapy DNA repair inhibitors Immunotherapy
CONCLUSIONS Oropharyngeal carcinoma is on the rise with HPV as important causative factor Many interesting trials are ongoing Results to be awaited, sufficient follow up Risk stratification! Several phase II studies show excellent outcomes Current recommendations: treat patients according to their stage of disease at presentation, irrespective of HPV status Encourage enrollment in clinical trials