A subsidiary analysis of the UK NCRI RAPID study S F Barrington E H Phillips N Counsell B Hancock R Pettengell P Johnson J Wimperis D Culligan B Popova L CliftonHadley A McMillan A Brownell A Kruger A Lister P Hoskin ID: 1045177
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1. Treatment escalation in patients with early stage Hodgkin lymphoma and a positive PET scan after initial chemotherapy is not always required A subsidiary analysis of the UK NCRI RAPID studyS. F. Barrington, E. H. Phillips, N. Counsell, B. Hancock, R. Pettengell, P. Johnson, J. Wimperis, D. Culligan, B. Popova, L. Clifton-Hadley, A. McMillan, A. Brownell, A. Kruger, A. Lister, P. Hoskin, M. O'Doherty, T. Illidge, J. Radford
2. Risk Stratification in Early Stage HLGoal is to maximise cure and minimise toxicityNeeds accurate risk stratification to individualise treatmentUsually reliant on pre-treatment clinical risk factorsInterim 18FDG-PET assessment identified as one of the strongest prognostic indicators EORTC GHSGAge ≥50 yearsExtra-nodal diseaseESR >50 (A)ESR >30 (B)ESR >50 (A)ESR >30 (B)Large mediastinal massLarge mediastinal mass4 or more involved sites3 or more involved sites
3. Positron Emission TomographyRadioactive glucose tracer (18fludeoxyglucose or FDG) to show areas of high metabolic activityInterim PET in Early Stage Hodgkin Lymphoma Zinzani et al EJNMMI 2012CT scanPET scanPET-CT scan
4. PET-Adapted Treatment in Hodgkin LymphomaJohnson et al N Engl J Med 2016Radford et al N Engl J Med 2015
5. H10 study (LYSA/EORTC/FIL) Risk adapted treatment by interim PET resultsPatients with a +ve PET after 2 ABVD benefit from intensification to eBEACOPPButGreater toxicity in eBEACOPP armAndre et al J Clin Oncol 2017
6. H10 study (LYSA/EORTC/FIL) Risk adapted treatment by interim PET resultsPatients with a +ve PET after 2 ABVD benefit from intensification to eBEACOPPButGreater toxicity in eBEACOPP armPET ‘positivity’ defined by IHP criteriaNow replaced by Deauville scoreScore 3 regarded as PET negative with standard treatment Barrington et al J Clin Oncol 2017
7. Aim of this subsidiary analysis of RAPID Assess prognostic value of: PET score after 3 ABVD Pre treatment clinical risk factors EORTC GHSGRadford et al N Engl J Med 2015Do all PET positive patients have equivalent outcomes?Can we identify a higher risk group within PET+?
8. Patients: Stages IA/IIA HL with no mediastinal bulkTreatment: ABVD chemotherapy x 3 4th cycle ABVD then IFRTRandomisation30 Gy IFRTNo further therapyPET +ve: N=145 (25%)PET -ve: N=426 (75%)RAPID - Trial Design
9. MethodsPET scans centrally reviewed at St Thomas’ Hospital- NCRI PET networkProspectively assigned PET score 1-5 PET positive equivalent to Deauville score 3, 4, 5 Cox regression used for association between PET score, baseline risk stratification, treatment arm and HL-specific EFSEFS defined as progression or HL-related death
10. Patient CharacteristicsPET -ve: IFRT arm (N=209)PET -ve: no further therapy (N=211)PET +ve(N=145)Age34 (16 – 74)34 (16 – 75)36 (18 – 75)Stage IA69 (33.0%)70 (33.2%)48 (33.1%)Stage IIA140 (67.0%)141 (66.8%)97 (66.9%)EORTC favourable118/184 (64.1%)122/185 (65.9%)70/126 (55.6%)GHSG favourable114/175 (65.1%)136/184 (73.9%)77/123 (62.6%)
11. Primary endpoint: PFS in PET negative randomised patients (ITT)PET negative: PET score 1 or 25y PFS 91.2% (95% CI: 88.3 - 94.1)IFRT: 93.2% (95% CI: 89.7-96.7)NFT: 89.2% (95% CI: 84.7-93.7) Radford et al N Engl J Med 2015Outcomes According to Treatment Arm
12. Primary endpoint: PFS in PET negative randomised patients (ITT)PET negative: PET score 1 or 25y PFS 91.2% (95% CI: 88.3 - 94.1)IFRT: 93.2% (95% CI: 89.7-96.7)NFT: 89.2% (95% CI: 84.7-93.7) PET positive: PET score 3, 4 or 55y PFS 87.2% (95% CI: 81.7-92.7) Outcomes According to Treatment ArmRadford et al N Engl J Med 2015
13. EFS by PET Scorep < 0.01
14. Outcomes by PET ScorePET ScoreNAlive with progressionn (%)HL deathsn (%)5-year EFS(95% CI)129919 (6.4%)0 (0.0%)93.9%(91.2 – 96.6)21219 (7.4%)1 (0.8%)91.8%(86.1 – 97.5)3903 (3.3%)1 (1.1%)95.3%(90.8 – 99.8)4322 (6.3%)0 (0.0%)93.5%(84.9 – 100)5235 (21.7%)3 (13.0%)61.9% (41.1 – 82.7)
15. PET ScoreNAlive with progressionn (%)HL deathsn (%)5-year EFS(95% CI) 5-year PFS(95% CI)129919 (6.4%)0 (0.0%)93.9%(91.2 – 96.6)91.2%(87.9 – 94.5)21219 (7.4%)1 (0.8%)91.8%(86.1 – 97.5)91.1%(85.2 – 97.0)3903 (3.3%)1 (1.1%)95.3%(90.8 – 99.8)95.3%(90.8 – 99.8)4322 (6.3%)0 (0.0%)93.5%(84.9 – 100)87.5%(76.1 – 98.9)5235 (21.7%)3 (13.0%)61.9% (41.1 – 82.7)56.5%(36.3 – 76.7)Outcomes by PET ScorePET ScoreNAlive with progressionn (%)HL deathsn (%)5-year EFS(95% CI)129919 (6.4%)0 (0.0%)93.9%(91.2 – 96.6)21219 (7.4%)1 (0.8%)91.8%(86.1 – 97.5)3903 (3.3%)1 (1.1%)95.3%(90.8 – 99.8)4322 (6.3%)0 (0.0%)93.5%(84.9 – 100)5235 (21.7%)3 (13.0%)61.9% (41.1 – 82.7)
16. Outcome by EORTC risk groupFavourable (n=310, events=26)5y EFS = 91.7% (95% CI: 88.6-94.8)Unfavourable (n=185, events=13)5y EFS = 92.5% (95% CI: 88.4-96.6)EFS According to Risk Stratificationp = 0.68
17. EFS According to Risk Stratificationp = 0.68p = 0.58
18. Multivariable analysisComparisonUnadjustedAdjusted for EORTC groupPET score 1 versus 5HR=0.14 (95% CI: 0.06-0.32, p<0.001)HR=0.15 (95% CI: 0.06-0.37, p<0.001)PET score 2 versus 5HR=0.20 (95% CI: 0.08-0.52, p<0.01)HR=0.22 (95% CI: 0.08-0.59, p<0.01)PET score 3 versus 5HR=0.11 (95% CI: 0.03-0.35, p<0.001)HR=0.13 (95% CI: 0.04-0.46, p<0.01)PET score 4 versus 5HR=0.15 (95% CI: 0.03-0.71, p=0.02)HR=0.19 (95% CI: 0.04-0.94, p=0.04)Adjusted for PET scoreEORTC favourable vs unfavourableHR=1.15 (95% CI: 0.59-2.23, p=0.68)HR=1.29 (95% CI: 0.66-2.53, p=0.46)Similar results with GHSG risk stratificationand when corrected for study group (NFT, IFRT or PET+)
19. Conclusions 1Early PET score has greater prognostic impact than clinical risk stratification in early stage HLIn patients with stage IA/IIA HL (and no mediastinal bulk) receiving PET guided treatment only PET score 5 predicted poor outcome‘Positive’ PET score does not carry uniform prognostic weight as reported in other lymphoma subtypes 1-31. Ceriani et al Int J Radiat Oncol Biol Phys 20172. Hertzberg et al Haematologica 20173. Mikhaeel et al ICML 2015
20. Patients with a PET score of 3 have excellent outcomes with ABVD and radiotherapy aloneSome patients with early stage HL and PET score 4 may be adequately treated with ABVD and radiotherapy and not require treatment escalationFuture trials should consider treatment escalation based on PET score 5 for early stage HLConclusions 2
21. *in some circumstances pts in CMR may receive ISRT if intention declared prior to randomisationContact: ctc.RADAR@ucl.ac.uk
22. AcknowledgementsPatients and their familiesAll RAPID investigatorsCore Lab at St Thomas’ and participating PET CentresCRUK and UCL Cancer Trials CentreFunders