Is chemotherapy alone sufficient for the treatment of Hodgkin s lymphoma? The 1 st World Congress on Controversies in Hematology (COHEM) Rome, Italy September 5, 2010 David J. Straus, M.D. Memorial Sloan-Kettering Cancer Center New York, NY USA
Hodgkin Lymphoma Historical Perspective In HL, treatment with RT, RT+CT and CT has resulted in high cure rates for 30 years It is unclear that results have improved over 30 years The late toxicity associated with these treatments are significant Unlike many other cancers, a major challenge is to achieve excellent treatment results with less toxicity
Hodgkin Lymphoma Survival MSKCC 1975-2000 1.0 0.9 0.8 Proportion Surviving 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0.0 Patients: 746 (519 Alive) Median Overall Survival: 32.0 years Median Follow-up for Survivors: 21.6 years Range: 6.3-33.0 years 0 5 10 15 20 25 30 35 Years Since Treatment Start Median age at initiation of treatment: 29 years (14-66 years)
Hodgkin Lymphoma Cause-Specific Survival MSKCC 1975-2000 Incidence of HL and non HL related death Probability 0.0 0.1 0.2 0.3 0.4 DOD Died nonhl causes Died of Unknown 0 5 10 15 20 25 30 Years
Hodgkin Lymphoma Cause-Specific Survival MSKCC 1975-2000 Incidence of HL and non HL related death Probability 0.0 0.1 0.2 0.3 0.4 DOD Died of SPM Died of Cardiac Died of Other Died of Unknown 0 5 10 15 20 25 30 Years
MSKCC Hodgkin Lymphoma Survival Study Data from 233/519 survivors Commonly reported specific late morbidities: Second malignancies (24%) Coronary artery disease (13%) Varicella zoster reactivation (20%) Osteoporosis (15%) Chronic dental disease (27%).
Hodgkin Lymphoma Chemotherapy: Early Stages
MSKCC 90-44 Freedom From Progression 1.0 0.8 Proportion Progression-Free 0.6 0.4 ABVD+RT (76 pts, 11 failures) ABVD (76 pts, 12 failures) P-value=0.70 0.2 0.0 0 20 40 60 80 100 Time to Progression in (months) Straus et al. Blood 104: 3483-89, 2004
NCIC-CTG HD-6 (ECOG JHD6) Exclude Low Risk IA 1 with: LP or NS Bulk < 3 cm ESR < 50 high neck or epitrochlear Design CS I-IIA HD Exclude High Risk Bulk > 10 cm Bulk > 1/3 CTD B symptoms Abd. disease Stratify Age > 40 ESR > 50 Use MC / LD histology > 4 sites Randomize Meyer et al. J Clin Oncol 23: 4634-4642, 2005
NCIC-CTG HD-6 (ECOG JHD6) Design Randomize Standard Arm Favourable RT (M+PA/spleen) Unfavourable CMT (ABVD x 2 + RT) Experimental Arm Both Strata ABVD x 2 If CR: x 2 more = 4 If PR: x 4 more = 6 Assess Outcomes Primary: 12 yr OS Meyer et al. J Clin Oncol 23: 4634-4642, 2005
NCIC-CTG HD-6 (ECOG JHD6) Interim Results 5-yr FFP: 93% STNI +/- 2 ABVD, 87% 4-6 ABVD (P=.006) 5-yr EFS: 88% STNI +/- 2 ABVD, 86% 4-6 ABVD (P=.06) 5-yr OS: 94% STNI +/- 2 ABVD, 96% 4-6 ABVD (P=.4) Meyer et al. J Clin Oncol 23: 4634-4642, 2005
EORTC-GELA H9-F ASCO 2005 abs. 6505 783 pts. enrolled, early stop with >20% events, med. F/U 33 mo. EBVPx6 4-yr EFS 70% EBVPx6+20Gy IFRT 4-yr EFS 84% EBVPx6+36Gy IFRT 4-yr EFS 87% p<.001 OS 98% for all 3 arms EBVPx6+IFRT inferior to MOPP/ABV hybridx6+ifrt in H7-U trial Noordjik EM et al. J Clin Oncol 24: 3128-35, 2006
BCCA: Management of Advanced Stage Hodgkin Lymphoma Definition of Advanced stage: - Stage III/IV and/or Bulky disease (>10cm) and/or B symptoms - Stage I/II and Bulky disease (>10cm) - Stage II and B symptoms Before July 2005: ABVD x 6-8 cycles Bulky tumors: ABVD x 6 + RT After July 2005: ABVD x 6 cycles No residual mass Observe Residual mass > 2cm then PET/CT PET- neg - Observe PET- pos Consolidative RT
Progression-free survival PET-neg Bulky vs Non-bulky Cumulative Survival 1.0.9.8.7.6.5.4.3 Non- bulky p=.42 Bulky NPV Non-bulky.95 NPV Bulky.92.2.1 0.0 0 1 2 3 4 5 6 Progression Free Survival (y) Savage et al. Blood 2007 110: Abstract 213
Hodgkin Lymphoma Chemotherapy: Late Stages
Kaplan-Meier Estimates of Event-free Survival among Patients in Complete Remission after Chemotherapy Who Were Randomly Assigned to Receive Either No Radiotherapy or Involved-Field Radiotherapy Aleman, B. et al. N Engl J Med 2003;348:2396-2406
Kaplan-Meier Estimates of Overall Survival According to the Patients' Response to Initial Chemotherapy and to Whether They Underwent Randomization Aleman, B. et al. N Engl J Med 2003;348:2396-2406
Hodgkin Lymphoma: Untreated US Intergroup Studies (CALGB, SWOG, ECOG) CALGB 50604 (Stages I/II non-bulky disease) AVBD x 2 cycles PET scan PET- 2 more ABVD cycles PET+ 2 cycles escalated BEACOPP + IF RT CALGB 50801 (Stages I/II bulky disease) ABVD x 2 cycles PET scan PET - 4 more ABVD cycles PET+ 4 cycles escalated BEACOPP + IF RT S0816 (Stages III/IV) ABVD x 2 cycles PET- 4 more ABVD cycles PET+ 6 cycles escalated BEACOPP
Hodgkin Lymphoma Chemotherapy alone an option for most patients Stages I/II Non-bulky: possible slight increase in relapses with adequate CT only off-set by late complications of CMT Bulky: CMT standard, but PET may define subgroup that does not need RT Stages III/IV With adequate CT additional IFRT does not improve PFS or OS for patient who achieve CR after CT IFRT may improve PFS for patients who achieve PR after CT Risk-adapted approach with interim PET may define a PET+ subgroup that would benefit from intensified Rx including RT for stages I/II
Phase III Trials of PET-Directed Therapy in Early Stage HL Trial Sponsor Active Eligibility Study Design RAPID UK 2003 Non-bulky I-II ABVD x 3: If PET ve obs vs. 30 Gy RT If PET +ve ABVD x1 + 30 Gy RT H10 EORTC/ GELA 2006 Favorable I-II ABVD x 3 + INRT vs. PET directed therapy ABVD x 2: If PET +ve, escbeacopp x 2 + INRT If PET ve ABVD x 2 Unfavor. I-II ABVD x 4 + INRT vs. PET directed therapy ABVD x 2: If PET +ve, escbeacopp x 2 + INRT If PET ve ABVD x 4 HD16 GHSG 2009 Favorable I-II ABVD x 2 +30 Gy IFRT vs. PET directed therapy ABVD x 2: If PET +ve 30 Gy IFRT If PET ve ABVD x 2 HD17 GHSG Pending Unfavor. I-II escbeacopp x2 + ABVD x2 + 20 Gy IFRT vs. PET directed therapy (EscBeaCOPP x 2. If PET +ve ABVD x 2 + 20 Gy INRT, if PET ve ABVD x 2).
Phase III Trials of PET-Directed Therapy in Early Stage HL Trial Sponsor Active Eligibility Study Design RAPID UK 2003 Non-bulky I-II ABVD x 3: If PET ve obs vs. 30 Gy RT If PET +ve ABVD x1 + 30 Gy RT H10 EORTC/ GELA (Amended Aug. 2010) 2006 Favorable I-II ABVD x 3 + INRT vs. PET directed therapy ABVD x 2: If PET +ve, escbeacopp x 2 + INRT If PET ve ABVD x 1 + INRT Unfavor. I-II ABVD x 4 + INRT vs. PET directed therapy ABVD x 2: If PET +ve, escbeacopp x 2 + INRT If PET ve ABVD x 2 + INRT HD16 GHSG 2009 Favorable I-II ABVD x 2 +30 Gy IFRT vs. PET directed therapy ABVD x 2: If PET +ve 30 Gy IFRT If PET ve ABVD x 2 HD17 GHSG Pending Unfavor. I-II escbeacopp x2 + ABVD x2 + 20 Gy IFRT vs. PET directed therapy (EscBeaCOPP x 2. If PET +ve ABVD x 2 + 20 Gy INRT, if PET ve ABVD x 2).