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 0.7 Proportion Surviving 0.6 0.5 0.4 0.3 Patients: 746 (519 Alive) Median Overall Survival: 32.0 years 0.2 Median Follow-up for Survivors: 21.6 years 0.1 Range: 6.3 - 33.0 years 0.0 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 0.4 DOD Died nonHL causes Died of Unknown 0.3 Probability 0.2 0.1 0.0 0 5 10 15 20 25 30 Years
Hodgkin Lymphoma Cause-Specific Survival MSKCC 1975-2000 Incidence of HL and non HL related death 0.4 DOD Died of SPM Died of Cardiac Died of Other 0.3 Died of Unknown Probability 0.2 0.1 0.0 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 ABVD+RT (76 pts, 11 failures) ABVD (76 pts, 12 failures) 0.4 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) Design Exclude Low Risk Exclude High Risk CS I-IIA HD IA 1 with: • Bulk > 10 cm • Bulk > 1/3 CTD • LP or NS • B symptoms • Bulk < 3 cm • Abd. disease • ESR < 50 • high neck or epitrochlear Stratify Use • Age > 40 • ESR > 50 • 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 Experimental Arm • Favourable • Both Strata RT (M+PA/spleen) ABVD x 2 • Unfavourable If CR: x 2 more = 4 CMT (ABVD x 2 + RT) 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: After July 2005: ABVD x 6-8 cycles ABVD x 6 cycles Bulky tumors: No residual mass – Observe ABVD x 6 + RT Residual mass > 2cm then PET/CT PET- neg - Observe PET- pos Consolidative RT
Progression-free survival PET-neg Bulky vs Non-bulky 1.0 Non- bulky NPV Non-bulky .95 .9 Bulky NPV Bulky .92 .8 Cumulative Survival p=.42 .7 .6 .5 .4 .3 .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/ 2006 Favorable I-II ABVD x 3 + INRT vs. PET directed therapy ABVD x 2: GELA If PET +ve, escBEACOPP x 2 + INRT If PET –ve ABVD x 2 ABVD x 4 + INRT vs. PET directed therapy Unfavor. I-II 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/ 2006 Favorable I-II ABVD x 3 + INRT vs. PET directed therapy ABVD x 2: GELA If PET +ve, escBEACOPP x 2 + INRT (Amended If PET –ve ABVD x 1 + INRT Aug. 2010) ABVD x 4 + INRT vs. PET directed therapy Unfavor. I-II 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).
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