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Management of Advanced Management of Advanced Stage Hodgkin LymphomaStage Hodgkin Lymphoma
Michael Crump, MD, FRCPCPrincess Margaret Hospital
University of TorontoToronto, Canada
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Outline of this presentationOutline of this presentation
• Definition and incidence• Historical results and the need for
change• Recent trials of new approaches• Nodular lymphocyte predominant HL• Late effects in advanced stage HL• Conclusions
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Aisenberg, Blood, 1999; Reprinted from Ries; NIH Publ 97-2789, 1997
Decline in mortality rate from HL in North America
MOPPABVD
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HL Outcomes – Continued ImprovementBrenner, et al. Blood, 2008
US SEER database: >16,000 pts 1980-2004
Relative survival: 5 y 73% 85%10 y 62% 80%
1980-84 2000-04
all 25-34y >60y
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Advanced HL: definitionsAdvanced HL: definitions
• NA intergroup: stage III, IV; relapse after prior extended field radiotherapy
• British: B symptoms (any stage); II with bulky mediastinal mass; stage III, IV
• German Hodgkin Study Group:– Stage IIB + E extension or LMM; III, IV– Early, unfavourable: stage I,II with E lesions,
LMM, ↑ ESR, > 3 sites
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Prognostic factors in advanced HLPrognostic factors in advanced HL• Hasenclever-Diehl index NEJM 1998• >5000 patients (13% stage I-IIB)
– Complete data for model: ~1600
• 7 clinical variables:– Age > 45 y– Male sex– Hb <105g/L– Stage IV– Albumen < 40 g/L– WBC > 15– Lymphocytes <0.6 or <8%
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Biologic prognostic factors?Biologic prognostic factors?• Epstein-Barr Virus (EBV)
~25-35% +ve by IHC (LMP-1), ISH (EBER-1)More common: males, older age (>45), mixed
cellularity histologyOlder adults → less favourable outcome
• BCL-2• Cytokine levels• Cytokine gene polymorphisms• Tumour microenvironment etc…
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Previous Therapeutic Observations in Previous Therapeutic Observations in Advanced DiseaseAdvanced Disease
• ABVD is superior to MOPP, and equal to but less toxic than alternating MOPP-ABVD – Canellos G, et al, NEJM, 1992, 2002
• ABVD is equivalent to alternating and hybrid multidrug regimens, with less toxicity– Johnson PW, et al, JCO 2005
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Recent Recent Therapeutic Observations in Therapeutic Observations in Advanced Stage DiseaseAdvanced Stage Disease
ABVD is equivalent to MOPP/ABV but has less serious/fatal toxicity– Duggan D et al; JCO 2006
Esc BEACOPP is superior to COPP-ABVD – Diehl V, et al: NEJM, 2003
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Advanced Hodgkin LymphomaABVD vs MOPP/ABV Hybrid
Intergroup CALGB, ECOG, SWOG, NCIC
n 433 419
CR% 76 80 0.16Progression % 10 11
5 y FFS% 63 66 0.425 y OS% 82 81 0.82
ABVD MOPP/ABV p
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• Definition and incidence• Historical results and the need for
change• Recent trials of new approaches• Nodular lymphocyte predominant HL• Late effects in advanced stage HL• Conclusions
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New concepts evaluated in phase New concepts evaluated in phase II trials to improve results in HLII trials to improve results in HL
• Consolidation with high-dose therapy and ASCT (high risk pts)
• Optimization of combined modality therapy: Stanford V
• Intensification with non-cross-resistant agents, increased dose intensity + G-CSF– escalated BEACOPP, other regimens
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Not usefulNot useful• Intensification of COPP-ABV with IMEP
(ifos, MTX, etoposide, prednisone) vs C-AGHSG HD6 trial Ann Oncol 2004
• Intensification with ASCT in high risk HL after CR/PR to ABVD/other x 4 cycles
Federico M, JCO 2003
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Recent Randomized Trials of Novel Regimens in Advanced Hodgkin Lymphoma
Esc BEACOPP 466 96 2 87 91 (5)BEACOPP 469 88 8 76 88COPP-ABVD 260 85 10 69 83
ABVD 99 70 12 65 84 (5)BEACOPP 98 81 2 78 92COPP-EBV-CAD 98 69 10 71 91
ABVD 261 67 5 85 90 (5) Stanford V 259 57 6 73 92
N pts CR(%) Progr’n (%) 5 y FFTF OS (yr)
CR: complete response rate; FFTF: freedom from treatment failure; OS: overall survival
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BEACOPP Escalated mg/m2 day• Bleomycin 10 IV 8• Etoposide 200 IV 1-3• Doxorubicin 35 IV 1• Cyclophos 1200 IV 1• Vincristine 1.4 IV 8• Procarbazine 100 PO 1-7• Prednisone40 PO 1-14Cycle length 21 days G-CSF day 8-15
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BEACOPP is superior to BEACOPP is superior to COPP-ABVDCOPP-ABVD
• Recent HD9 update: follow-up > 9 yrs • 10 y FTFF and OS favour
escBEACOPP over BEACOPP, COPP-ABVD
Engert A, et al, J Clin Oncol 2009
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GISL HD 2000GISL HD 2000BEACOPP v ABVD v CECBEACOPP v ABVD v CEC
Federico M, J Clin Oncol 2009
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Should escBEACOPP now be the Should escBEACOPP now be the standard?standard?
…maybe not yet• Toxicity vs (COPP-)ABVD:
– Greater male, female infertility (vs ABVD: fertility is unaffected)
– More significant Hb, plt toxicity; fever/infection– Higher secondary AML risk? (second cancers:
no difference)– Elderly (age >60): more toxic, not more effective
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Other trials of this strategyOther trials of this strategy• GHSG HD12:
8 escBEACOPP vs 4 esc + 4 BEACOPPAdvanced disease, age <65No difference in 5 y OS, FFTF
• EORTC-NCIC-GELA HD8:4 esc + 4 BEACOPP vs 8 ABVD--accrual recently completed
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ABVD remains the standard for ABVD remains the standard for advanced HLadvanced HL
Doxorubicin 25 mg/m2 d1, 15Bleomycin 10 mg/m2 d1, 15Vinblastine 6 mg/m2 d1, 15Dacarbazine 375 mg/m2 d1, 15
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ABVD remains the standard for ABVD remains the standard for advanced HLadvanced HLPractical points:• Are pulmonary function tests required?
– Bleomycin lung toxicity: up to 30% of patients; high case fatality rate (esp elderly)
– No PFT at baseline, unless older or underlying lung disease (smokers)
– In follow-up: if symptoms (cough, dyspnea, fever) or if > 6 cycles ABVD planned
– Omission of bleo does not seem to compromise treatment
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ABVD remains the standard for ABVD remains the standard for advanced HLadvanced HLPractical points:• Is G-CSF (neupogen) required?
– Not generally: several cohort studies of Rx regardless of treatment-day ANC→ no increase febrile neutropenia
– ? Association with bleomycin toxicity– Should be used for pts at high risk of febrile
neutropenia: elderly, bone marrow involvement, HIV+
– PMH recipe: daily x4-5, starting D5, A cycle• (not needed with each treatment)
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Hodgkin Lymphoma Hodgkin Lymphoma Older PatientsOlder Patients
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Advanced stage Hodgkin lymphoma
Age > 60
Progression Free Survival (y)
109876543210
Cum
Sur
viva
l
1.0
.8
.6
.4
.2
0.0 MOPP 38
ODBEP 51
ABVD 72HYBRID 38
Data courtesy of J Connors, BCCA
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Advanced stage Hodgkin lymphoma
Age > 60
Disease Specific Survival (y)
109876543210
Cum
Sur
viva
l
1.0
.8
.6
.4
.2
0.0
MOPP 38
ODBEP 51
ABVD 72Hybrid 38
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Hodgkin Lymphoma Hodgkin Lymphoma Older PatientsOlder Patients
Chemotherapy recommendations– No special regimen superior
• ABVD remains the gold standard• If drugs must be omitted due to underlying organ dysfunction
– Consider 7 – 8 drug combinations, then drop offender(s)
– Anticipate increased toxicity• Hematologic• Neurologic• Pulmonary• Cardiac
– Enhance supportive care• G-CSF
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FDG PET?FDG PET?
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Gallamini A, J Clin Oncol 2007
Outcome of HL according to interim FDG PET and IPS
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RCT of Observation vs RT for Patients with Bulky HL and Negative Post Chemo PET Scan
Bulk: > 5 cm long axis*Chemo: VEBEP 6 cyclesRT: 32 Gy
Negative PET: no uptakePositive PET: “uptake in …abnormal area”
260 patients 2000-2006 n = 160 randomizedstage I, II 2/3B symptoms ½
Radiation: mantle, inv Y, para-aortic
Picardi M, et al. Leuk Lymph, 2007
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Relapse:Chemo alone: 11/80 (14%)Chemo + RT: 2/80 (2.5%)
Picardi,et al. Leuk Lymph, 2007
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PET Scans and Early Progressionin Advanced Hodgkin Lymphoma
German HL Study Group Trial HD15
Patients: stage IIEB or IIB + LMM; III + IV
esc BEACOPP x 8
esc BEACOPP x 6
BEACOPP-14 x 8
residual> 2.5 cm PET
R
PET +, > 2.5 cm on CT 30 Gy IFRT
Total n: 1788 For analysis: 817Blood 2008
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PET Scans and Early Progressionin Advanced Hodgkin Lymphoma
311 patients: <CR after chemo PET scan66 positive (21%) - 63 received XRT
CR
PET-ve
PET+ve
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Patients with FDG avid lesions following chemotherapy should have a biopsy, if PET scan is to be used to modify treatment:
Variable false positive rates: 21 +ve scans→10 benign Zinzani, Hematologica 2007
27 +ve scans→ 4 benignSchaefer, Radiology 2007
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• Definition and incidence• Historical results and the need for
change• Recent trials of new approaches• Nodular lymphocyte predominant HL• Late effects in advanced stage HL• Conclusions
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Pathology:Nodular lymphocyte predominant HL
Marker Classical HL Nodular LP HLCD30 + -CD15 + -CD45 - +CD20 -/+ +PAX5 + +
sIg - +/-EBV LMP1 +/- -
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NLPHL: German experienceNLPHL: German experienceNogova, et al. J Clin Oncol 2008
LP HL(%) classical HL(%)
n=394 n= 7904 pCR 8782 .003PD 0.3 3.9 .0001relapse 8.1 8.0
late rel 7.4 4.7 .02death 4.6 9.6 .0004second Ca 2.5 3.7 .27
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Nodular LP Hodgkin Nodular LP Hodgkin LymphomaLymphoma • Favourable prognosis with
current therapies according to disease extent
• No increase in relapse vs cHL
• No increase in secondary malignancies
→ treatment as per advanced cHL
GHSG J Clin Oncol 2008
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• Definition and incidence• Historical results and the need for
change• Recent trials of new approaches• Nodular lymphocyte predominant HL• Late effects in advanced stage HL• Conclusions
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Long-Term Cause-Specific Mortality of Long-Term Cause-Specific Mortality of Patients Treated for Hodgkin’s Disease Patients Treated for Hodgkin’s Disease
J Clin Oncol 2003
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GELA H89 Trial: Chemotherapy +/- GELA H89 Trial: Chemotherapy +/- radiation for advanced stage HL;radiation for advanced stage HL;
Causes of DeathCauses of Death• N = 533, median f/u 10 yrs• 129 deaths:
Hodgkin lymphoma PD/rel 60 (46%)– treatment 15– salvage treatment 7Second cancer 24 (19%)Cardiovascular 1Unknown/not spec. 22
Ferme C, Blood 2006
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Lung Cancer – Dramatic Effects of Age,Treatment, Smoking History
no no 1.0 6.0yes no 20.2 7.2
no yes 16.8 4.3yes yes 49.1 7.2
>1 ppdsmoker others
RT>5 Gy AA chemo RR RR
Treatment
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Change in Systemic Chemotherapy?
Example of secondary AML (JNCI, 2006)
• >35,000 1 yr HL survivors• 14 cancer registries (Nordic, N America)• pts treated 1970-2001
1. Excess absolute risk higher in 1st 10 yrs of follow-up
2. Decline in AML incidence for pts treated after 1985, esp among those getting chemotherapy
--more widespread use of non-alkylator based therapy (ABVD)
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General population
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ConclusionsConclusions• ABVD 6-8 cycles remains standard for
advanced HL outside of a clinical trial• Use of interim PET to modify therapy is a
question, not the answer• Radiation should not be routinely
administered, nor forgotten: role in LMM, E lesions…
• Decisions re: adopting more toxic regimens involves trade-offs for patients