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Management of Advanced Stage Hodgkin Lymphoma Michael Crump, MD, FRCPC Princess Margaret Hospital University of Toronto Toronto, Canada.

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Presentation on theme: "Management of Advanced Stage Hodgkin Lymphoma Michael Crump, MD, FRCPC Princess Margaret Hospital University of Toronto Toronto, Canada."— Presentation transcript:

1 Management of Advanced Stage Hodgkin Lymphoma Michael Crump, MD, FRCPC Princess Margaret Hospital University of Toronto Toronto, Canada

2 Outline 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

3 Aisenberg, Blood, 1999; Reprinted from Ries; NIH Publ , 1997 Decline in mortality rate from HL in North America MOPP ABVD

4 HL Outcomes – Continued Improvement Brenner, et al. Blood, 2008 US SEER database:>16,000 pts Relative survival: 5 y73%85% 10 y62%80% all25-34y>60y

5 Advanced 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

6 Prognostic factors in advanced HL Hasenclever-Diehl index NEJM 1998 >5000 patients (13% stage I-IIB) –Complete data for model: ~ clinical variables : –Age > 45 y –Male sex –Hb <105g/L –Stage IV –Albumen < 40 g/L –WBC > 15 –Lymphocytes <0.6 or <8%

7 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 histology Older adults → less favourable outcome BCL-2 Cytokine levels Cytokine gene polymorphisms Tumour microenvironment etc…

8 Previous Therapeutic Observations in Advanced 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

9 Recent Therapeutic Observations in Advanced 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

10 Advanced Hodgkin Lymphoma ABVD vs MOPP/ABV Hybrid Intergroup CALGB, ECOG, SWOG, NCIC n CR% Progression % y FFS% y OS% ABVDMOPP/ABVp

11 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

12 New concepts evaluated in phase II 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

13 Not useful Intensification of COPP-ABV with IMEP (ifos, MTX, etoposide, prednisone) vs C-A GHSG 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

14 Recent Randomized Trials of Novel Regimens in Advanced Hodgkin Lymphoma Esc BEACOPP (5) BEACOPP COPP-ABVD ABVD (5) BEACOPP COPP-EBV-CAD ABVD (5) Stanford V N ptsCR(%)Progr’n (%)5 y FFTFOS (yr) CR: complete response rate; FFTF: freedom from treatment failure; OS: overall survival

15 BEACOPP Escalated mg/m 2 day Bleomycin10IV8 Etoposide200IV1-3 Doxorubicin35IV1 Cyclophos1200IV1 Vincristine1.4IV8 Procarbazine100PO1-7 Prednisone40PO1-14 Cycle length 21 daysG-CSF day 8-15

16 BEACOPP is superior to COPP-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

17 GISL HD 2000 BEACOPP v ABVD v CEC Federico M, J Clin Oncol 2009

18 Should escBEACOPP now be the 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

19 Other trials of this strategy GHSG HD12: 8 escBEACOPP vs 4 esc + 4 BEACOPP Advanced disease, age <65 No difference in 5 y OS, FFTF EORTC-NCIC-GELA HD8: 4 esc + 4 BEACOPP vs 8 ABVD --accrual recently completed

20 ABVD remains the standard for advanced HL Doxorubicin25 mg/m 2 d1, 15 Bleomycin10 mg/m 2 d1, 15 Vinblastine6 mg/m 2 d1, 15 Dacarbazine375 mg/m 2 d1, 15

21 ABVD remains the standard for advanced HL ABVD remains the standard for advanced HL Practical 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

22 ABVD remains the standard for advanced HL ABVD remains the standard for advanced HL Practical 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)

23 Hodgkin Lymphoma Older Patients

24 MOPP 38 ODBEP 51 ABVD 72 HYBRID 38 Data courtesy of J Connors, BCCA

25 MOPP 38 ODBEP 51 ABVD 72 Hybrid 38

26 Hodgkin Lymphoma Older 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

27 FDG PET?

28 Gallamini A, J Clin Oncol 2007 Outcome of HL according to interim FDG PET and IPS

29 RCT of Observation vs RT for Patients with Bulky HL and Negative Post Chemo PET Scan Bulk:> 5 cm long axis* Chemo:VEBEP6 cycles RT: 32 Gy Negative PET:no uptake Positive PET:“uptake in …abnormal area” 260 patients n = 160 randomized stage I, II  2/3 B symptoms  ½ Radiation:mantle, inv Y, para-aortic Picardi M, et al. Leuk Lymph, 2007

30 Relapse: Chemo alone:11/80 (14%)  Chemo + RT: 2/80 (2.5%) Picardi,et al. Leuk Lymph, 2007

31 PET Scans and Early Progression in Advanced Hodgkin Lymphoma German HL Study Group Trial HD15 Patients: stage II EB or II B + 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: 1788For analysis: 817 Blood 2008

32 PET Scans and Early Progression in Advanced Hodgkin Lymphoma 311 patients:

33 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 ve scans→ 4 benign Schaefer, Radiology 2007

34 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

35 Pathology:Nodular lymphocyte predominant HL MarkerClassical HLNodular LP HL CD30+- CD15+- CD45-+ CD20-/++ PAX5++ sIg-+/- EBV LMP1+/--

36 NLPHL: German experience NLPHL: German experience Nogova, et al. J Clin Oncol 2008 LP HL (%) classical HL (%) n=394 n= 7904 p CR PD relapse late rel death second Ca

37 Nodular LP Hodgkin Lymphoma 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

38 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

39 Long-Term Cause-Specific Mortality of Patients Treated for Hodgkin’s Disease Long-Term Cause-Specific Mortality of Patients Treated for Hodgkin’s Disease J Clin Oncol 2003

40 GELA H89 Trial: Chemotherapy +/- radiation for advanced stage HL; Causes of Death N = 533, median f/u 10 yrs 129 deaths: Hodgkin lymphoma PD/rel60(46%) – treatment 15 – salvage treatment 7 Second cancer 24(19%) Cardiovascular 1 Unknown/not spec. 22 Ferme C, Blood 2006

41 Lung Cancer – Dramatic Effects of Age, Treatment, Smoking History nono yesno noyes yesyes >1 ppd smokerothers RT>5 GyAA chemo RRRR Treatment

42 Change in Systemic Chemotherapy? Example of secondary AML (JNCI, 2006) >35,000 1 yr HL survivors 14 cancer registries (Nordic, N America) pts treated Excess absolute risk higher in 1 st 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)

43 General population

44 Conclusions 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


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