Comparing Alternative treatment Regimens for intermediate and high risk oropharyngeal cancer CompARE. Prof. Hisham Mehanna.

Transcription

1 Comparing Alternative treatment Regimens for intermediate and high risk oropharyngeal cancer CompARE Prof. Hisham Mehanna

2 Chief investigator: Hisham Mehanna Arm 1: Mehmet Sen Arm2: John Chester/Martin Forster Arm 3: Paul Sanghera Arm 4: Vin Paleri RT QA: Andrew Hartley Chris Nutting Hoda Booz Andrew Chan Tom Roques CTU: Sarah Bowden Jaspreet Babrah RTQA group: Liz Miles Huiqi Yang Rada Zotova Path: Max Robinson Surgery QA: Jim McCaul SAEs: Bernie Foran John Chester Statistics: Cindy Billingham Piers Gaunt Deescalate liaison: Janet Dunn Health economics: Andrew Sutton Qualitative study: Jenny Donovan Marcus Jepson

3 CRT and HPV RCT: Cisplatin with standard fractionation vs accelerated fractionation 323 patients 78% Stage IV, 22% Stage III 81% T3 and T4, no T1

4 Risk factors in the new age 3 risk categories: Low risk: HPV+ / no or low smokers (50% patients) OS 3 yr 93% Intermediate: HPV+ + smokers+n2b-n3 and HPV- + low-no smoker + T2-3 OS 3yr 70.8% High: HPV- /high smokers or low smoker+t4 OS 3yr 46.3% Ang, NEJM, 2010

5 Options for improving Locoregional control Add induction chemotherapy Add more RT intensification of RT? Add surgery

6 Add more chemotherapy

7 Ghi et al ASCO, 2014 TPF followed by: CRT CET/RT 421 LAHNSCC pts, stage III/IV 3yr PFS 3yr OS HR CRT 36.7% 45.7% Induction+C RT 46.8% 57.6% 0.72 (p=0.025)

8 Increase RT dose

9 Increase RT dose OPC- Slevin et al 62.5 Gy in 25 daily fractions over 5 weeks + Cetuximab Only 1 patients missed last fraction of RT 85% completed all 6 doses of cetuximab 4 year follow-up 3 yr OS =75.5% 3 yr DSS= 85.2% Thomson IJROBP 2014 S

10 Increase RT dose OPC- Slevin et al Toxicity 4% needed PEG after 1 year LATE TOXICITY Grade 3 pain 8% Anorexia 8% Weight loss 4% Dental problems 8%

11 Increase RT dose OPC- Archimedes phase I dose-escalation pilot RT regimen: 64Gy in 25F 15 patients Intermediate and high risk OPC Outcomes : toxicity awaiting results

12 Add surgery

13 Open Surgery +/- RT Surgery +/-RT CRT HPV+ 2yr OS 92% HPV- 2 yr OS 75% HPV+ 2yr OS 93% HPV- 2yr OS 62%

14 OS DFS

15 Add immunotherapy

16 PD-L1 inhibitor PD-L1 expression in: HPV+ 75% HPV 25%

17 MAMS Activity (interim) stages: assess OS or another outcome that is related eg PFS, failure free survival Efficacy stage (final stage): OS At activity (interim) stages, use High power (95%) to ensure that any treatment with true effect is not discarded Low significance levels which become more stringent: may allow some treatments to progress inappropriately to next stage, but not a big problem, coz assessment criteria in the next stage is more stringent

18 Power 95% 90% 85% 80% p-value Arm 1 Control Arm 2 Stop Arm 3 Arm 4 Stop Arm 5 Activity stages Efficacy stage

19 CompARE Popula on Intermediate or high risk OPC, >18yrs, ECOG PS 0-1, Fit for surgery and chemotherapy. CompARE RANDOMISE to ARMS 1-4 or ARMS 1-3 only Stra fy Intermediate vs High risk & Centre. Adjust for Site (Tonsil vs Base of Tongue) and size (T1-3 vs T4) of tumour and nodes (N0-2A vs N2B-3) Arm 1 (Control) Concomitant Cispla n + IMRT Arm 2:Induc on TPF + Arm 1 Arm 3:Cispla n + Dose-escalated IMRT Arm 4: Transoral Surgery + selec ve ND +Arm1 Interim stages (1yr DFS) Efficacy stage (2yr OS) Primary Outcome Overall survival (2 years) Secondary Outcomes Disease free survival, Acute and Late severe toxicity using CTCAE, QoL using EORTC QLQ-C30 & HN35, & MDADI (for Swallowing), Cost-effec veness using EQ-5D, Surgical complica ons, Molecular markers NB All RT is IMRT

20 Stratification variables Differential Randomisation 3 arms vs 4 arms Centres can randomise only to the non-surgical arms if they do not do surgical resection Centres can randomise patients who are not eligible for surgery just to the non-surgical arms Stratification Intermediate vs high risk Centre Adjust for : Site (BoT vs tonsil) Tumour (T) stage Nodal (N) status

21 End-points Primary: Overall survival 10% survival benefit to justify additional toxicity Secondary: Toxicity CTCAEv4 QoL EORTC C30/ HN35 Swallowing - MDADI Surgical complications Cost-effectiveness- EQ-5D Other: molecular

22 ?

23 Arms ARM 1: control concomitant CRT +/- neck dissection on PET CT at 12 weeks IMRT 70Gy in 35F Cisplatin: 3 weekly 100mg/m 2 or weekly 40mg/m 2 ARM2: Induction TPF + ARM 1 Taxotere 75mg/m 2 + Cisplatin 80mg/m fluorouracil 800mg/m 2 (3 cycles)

24 Arms ARM3: Chemo + dose-escalated RT 64Gy in 25F accelerated hypo-fractionated regimen, as per ArChIMEDEs-Op phase I study.

25 Arms ARM4: Surgery + Arm1 Surgery T1-2: transoral laser or robotic T3-4: transoral, but if not possible open Selective neck dissection minimum levels 2-4+ any involved levels Level 5 to be spared if not clinically involved Level 1 can be spared if not clinically involved

26 Eligibility OPC SCC Intermediate or high risk disease (not HPV+/-) MDT recommending CRT Fit for Chemotherapy For those considered to be eligible for surgical arm: must be eligible for resection

27 Pilot phase 1 year Nested qualitative study Study feasibility, consenting, toxicity

28 Sample size calculation Stages 4,4,3,2 Overall power 80% Overall p =0.05 HR= control events needed Recruitment = 5.5 years Follow-up following end of recruitment=1.6 years Sample size = 627 patients

29 Sensitivity analyses Cumulative Recruitment ,80,140,140,150,75 130,130,130,130, ,114,114,114,114,57 25,100,130,130,130,130 40,80,130,130,130,130 40,80,150,150,150,150 40,80,130,130,150,75 8 years Month Trial Duration (years)

30 More sensitivity analyses Cumulative Recruitment ,80,140,140,150,75 25,60,130,130,130 25,60,130,130,130,130 25,80,130,130,130 25,80,130,130,130,130 8 years 130,130,130,130, Month Trial Duration (years) Set-up

31 QA Same QA as De-Escalate volumetric IMRT Planning same as Deescalate, NIMRAD and Pathos May need outlining of a post-resection case Same HPV testing as De-Escalate p16 and HPV Surgical QA

32 For more info: Hisham Mehanna Jaspreet Babrah senior trial coordinator

33 Chief investigator: Hisham Mehanna Arm 1: Mehmet Sen Arm2: John Chester/Martin Forster Arm 3: Paul Sanghera Arm 4: Vin Paleri RT QA: Andrew Hartley Chris Nutting Hoda Booz Andrew Chan Tom Roques CTU: Sarah Bowden Jaspreet Babrah RTQA group: Liz Miles Huiqi Yang Rada Zotova Path: Max Robinson Surgery QA: Jim McCaul SAEs: John Chester Bernie Foran Statistics: Cindy Billingham Piers Gaunt Deescalate liaison: Janet Dunn Health economics: Andrew Sutton Qualitative study: Jenny Donovan Marcus Jepson

34 Clinical trials and effectiveness Experimental and translational medicine Quality of life

35

36 Feasibility OPC cases Pet Neck: Low = 33.7% Int = 46.9% High = 20.4% Therefore eligible population: high and int risk = 1190p.a. Only 75% receive CRT = % resectable= 669 p.a