Is chemotherapy alone sufficient for the treatment of Hodgkins - - PowerPoint PPT Presentation

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Is chemotherapy alone sufficient for the treatment of Hodgkins - - PowerPoint PPT Presentation

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Is chemotherapy alone sufficient for the treatment of Hodgkins 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

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SLIDE 1

Is chemotherapy alone sufficient for the treatment of Hodgkin’s lymphoma?

The 1st 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

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SLIDE 2

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

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SLIDE 3

Hodgkin Lymphoma Survival MSKCC 1975-2000

Patients: 746 (519 Alive) Median Overall Survival: 32.0 years Median Follow-up for Survivors: 21.6 years Range: 6.3 - 33.0 years

Proportion Surviving

0.0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0

Years Since Treatment Start

5 10 15 20 25 30 35

Median age at initiation of treatment: 29 years (14-66 years)

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SLIDE 4

Hodgkin Lymphoma Cause-Specific Survival MSKCC 1975-2000

5 10 15 20 25 30 0.0 0.1 0.2 0.3 0.4

Incidence of HL and non HL related death

Years Probability DOD Died nonHL causes Died of Unknown

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SLIDE 5

Hodgkin Lymphoma Cause-Specific Survival MSKCC 1975-2000

5 10 15 20 25 30 0.0 0.1 0.2 0.3 0.4

Incidence of HL and non HL related death

Years Probability DOD Died of SPM Died of Cardiac Died of Other Died of Unknown

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SLIDE 6

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%).

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SLIDE 7

Hodgkin Lymphoma

Chemotherapy: Early Stages

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SLIDE 8

MSKCC 90-44 Freedom From Progression

Time to Progression in (months) Proportion Progression-Free 20 40 60 80 100 0.0 0.2 0.4 0.6 0.8 1.0 ABVD+RT (76 pts, 11 failures) ABVD (76 pts, 12 failures) P-value=0.70

Straus et al. Blood 104: 3483-89, 2004

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SLIDE 9

NCIC-CTG HD-6 (ECOG JHD6) Design

CS I-IIA HD Stratify Randomize

Exclude Low Risk IA1 with:

  • LP or NS
  • Bulk < 3 cm
  • ESR < 50
  • high neck or

epitrochlear Exclude High Risk

  • Bulk > 10 cm
  • Bulk > 1/3 CTD
  • B symptoms
  • Abd. disease

Use

  • Age > 40
  • ESR > 50
  • MC / LD histology
  • > 4 sites

Meyer et al. J Clin Oncol 23: 4634-4642, 2005

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SLIDE 10

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

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SLIDE 11

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

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SLIDE 12

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
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SLIDE 13

BCCA: Management of Advanced Stage Hodgkin Lymphoma

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

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
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SLIDE 14

Progression-free survival PET-neg Bulky vs Non-bulky

Progression Free Survival (y) 6 5 4 3 2 1 Cumulative Survival 1.0 .9 .8 .7 .6 .5 .4 .3 .2 .1 0.0

Bulky Non- bulky p=.42

NPV Non-bulky .95 NPV Bulky .92

Savage et al. Blood 2007 110: Abstract 213

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SLIDE 15

Hodgkin Lymphoma

Chemotherapy: Late Stages

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SLIDE 16

Kaplan-Meier Estimates of Event-free Survival among Patients in Complete Remission after Chemotherapy Who Were Randomly Assigned to Receive Either No Radiotherapy

  • r Involved-Field Radiotherapy

Aleman, B. et al. N Engl J Med 2003;348:2396-2406

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SLIDE 17

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

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SLIDE 18

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
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SLIDE 19

Hodgkin Lymphoma

Chemotherapy alone an option for most patients

  • Stages I/II

– Non-bulky: possible slight increase in relapses with adequate CT only

  • ff-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

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SLIDE 20

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

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SLIDE 21

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).

Phase III Trials of PET-Directed Therapy in Early Stage HL