Management of Advanced Management of Advanced Stage Hodgkin LymphomaStage Hodgkin Lymphoma
Michael Crump, MD, FRCPCPrincess Margaret Hospital
University of TorontoToronto, Canada
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
Aisenberg, Blood, 1999; Reprinted from Ries; NIH Publ 97-2789, 1997
Decline in mortality rate from HL in North America
MOPPABVD
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
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
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%
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…
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
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
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
• 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
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
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
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
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
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
GISL HD 2000GISL HD 2000BEACOPP v ABVD v CECBEACOPP v ABVD v CEC
Federico M, J Clin Oncol 2009
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
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
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
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
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)
Hodgkin Lymphoma Hodgkin Lymphoma Older PatientsOlder Patients
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
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
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
FDG PET?FDG PET?
Gallamini A, J Clin Oncol 2007
Outcome of HL according to interim FDG PET and IPS
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
Relapse:Chemo alone: 11/80 (14%)Chemo + RT: 2/80 (2.5%)
Picardi,et al. Leuk Lymph, 2007
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
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
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
• 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
Pathology:Nodular lymphocyte predominant HL
Marker Classical HL Nodular LP HLCD30 + -CD15 + -CD45 - +CD20 -/+ +PAX5 + +
sIg - +/-EBV LMP1 +/- -
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
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
• 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
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
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
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
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)
General population
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
