Transatlantic Differences in the Treatment of Hodgkin Lymphoma Joseph M Connors Centre for Lymphoid Cancer British Columbi...
Conceptual Basis for Cancer Staging <ul><li>Purposes </li></ul><ul><li>Estimation of tumor burden </li></ul><ul><li>Commun...
Conceptual Basis for Cancer Staging <ul><li>Purposes </li></ul><ul><li>Estimation of tumor burden </li></ul><ul><ul><li>Pa...
Hodgkin Lymphoma  Staging <ul><li>Required staging tests </li></ul><ul><li>Hematopathology review </li></ul><ul><li>Histor...
Hodgkin Lymphoma  Staging <ul><li>Ann Arbor Staging System </li></ul><ul><li>Stage  Criteria </li></ul><ul><li>I  Single l...
Hodgkin Lymphoma Clinical Trial Treatment Groups North America  Stage Limited stage   CS IA, IIA, non-bulky  CS IIB Advanc...
Hodgkin Lymphoma Clinical Trial Treatment Groups Europe Europe Stage (GSHG, GELA, EORTC) Early favorable stage  CS I,IIA,B...
Hodgkin Lymphoma Clinical Trial Treatment Groups Europe vs North America  Europe   Stage   USA / Canada   Clinical trial  ...
Hodgkin Lymphoma, Stage II Where does the “Unfavorable” patient fit?  16 cm Limited stage Unfavorable  stage II Advanced s...
<ul><li>Case identification BC Cancer Agency </li></ul><ul><li>Hodgkin lymphoma, all histologies  </li></ul><ul><li>Age 16...
<ul><ul><li>Gender </li></ul></ul><ul><ul><ul><li>Male 54 %  Female 46 % </li></ul></ul></ul><ul><ul><li>Age  range 16-64 ...
<ul><li>Treatment </li></ul><ul><ul><li>ChemoTx </li></ul></ul><ul><ul><ul><li>ABVD-type  6-8 cycles </li></ul></ul></ul><...
5-y TTP 83 % median follow-up  8 y
II A bulky II B bulky II B non-bulky P = 0.30 By group II A bulky, II B non-bulky, II B bulky
II B bulky P = 0.62 By stage group 5-y OS 94 % II A bulky II B non- bulky
I A, II A, non-bulky 2BB P < 0.0001 HR 4.2 I A, II A non-bulky  n = 459  ABVD x 2  +  IFRT (= true limited stage) 2BB  n =...
Stage III or IV 2BB P = 0.0059 HR = 1.5 By stage group, 2BB vs III or IV 2BB  n = 416  ABVD x 6 +/- IFRT III or IV  n = 67...
Stage III or IV 2BB P < 0.0001 II A, II A, non-bulky By stage group 5-y TTP  Lim 95 % 2BB 83 % III, IV 77 % 6 %, HR 1.5 12...
Hodgkin Lymphoma Clinical Trial Treatment Groups Europe vs North America  Europe   Stage   USA / Canada   Clinical trial  ...
<ul><li>Conclusions </li></ul><ul><li>Considering… </li></ul>Hodgkin Lymphoma Stage II B or Stage II Bulky Disease <ul><li...
Hodgkin Lymphoma Clinical Trial Treatment Groups Europe vs North America  Europe Stage   USA / Canada (GSHG, GELA, EORTC) ...
Hodgkin Lymphoma  Treatment by Stage <ul><li>Limited stage </li></ul><ul><ul><ul><ul><li>Ann Arbor stage I or II </li></ul...
Advanced Stage Hodgkin Lymphoma <ul><li>Peter, 23 y o male violinist, asymptomatic </li></ul><ul><li>Supraclavicular lymph...
Advanced Stage Hodgkin Lymphoma <ul><li>Mary, 53 y o schoolteacher </li></ul><ul><ul><li>weight loss ~ 18 kg, drenching ni...
ABVD v MOPP v MOPP/ABVD Failure-free survival Overall survival Canellos et al,  NEJM, 2002
Advanced Hodgkin Lymphoma ABVD vs MOPP/ABV Hybrid  Intergroup CALGB, ECOG, SWOG, NCIC <ul><li>  ABVD  MOPP/ABV   p </li></...
Intergroup CALGB, ECOG, SWOG, NCIC: ABVD vs MOPP/ABV
Intergroup CALGB, ECOG, SWOG, NCIC: ABVD vs MOPP/ABV
International Prognostic Factors Project on Advanced Hodgkin Lymphoma <ul><li>Factor Criteria in SI units </li></ul><ul><l...
Advanced Stage Hodgkin Lymphoma <ul><li>Peter, 23 y o  male  violinist, asymptomatic </li></ul><ul><li>Left supraclavicula...
Advanced Stage Hodgkin Lymphoma <ul><li>Mary,  53 y o  farmer </li></ul><ul><ul><li>weight loss ~ 18 kg, drenching night s...
International Prognostic Factors Project on Advanced Hodgkin Lymphoma Treatment era = 1980s, ABVD
42 % 12 % 26 % 94 % 675 Consecutive Adult Patients with Advanced Stage Hodgkin Lymphoma Treated at BCCA through 2009 Compa...
International Prognostic Factors Project on Advanced Hodgkin Lymphoma Treatment era = 1980s, ABVD 50 %
675 Consecutive Adult Patients with Advanced Stage Hodgkin Lymphoma Treated at BCCA through 2009 Compared to Original IPFP...
B  Bleomycin E  Etoposide A  Adriamycin C  Cyclophos O  Vincristine P  Procarbazine P  Prednisone Std mg/m 2 10 100 25 650...
HD9 Trial Design( 1992-97 ) (1281 patients recruited) CS IIB-IIIA with risk factors CS IV Arm A 4x  COPP+ABVD    RT Arm B...
Engert,  JCO  2009; 27:4548 Kaplan-Meier analysis of the probability of (A) freedom from treatment failure COPP/ABVD arm c...
Kaplan-Meier analysis of the probability of (B) overall survival in each treatment arm Engert,  JCO  2009; 27:4548
1990s 1980s 1970s 1960s n = 2170 Progression = 80 % Progression = 20 % Time to Progression (years)
German Hodgkin Study Group, Schmitz,  Lancet  2002;359:2065 n  161  117  HSCT Chemo
German Hodgkin Study Group, Schmitz,  Lancet  2002;359:2065 HSCT Chemo
Early relapse < 12 months n = 38 German Hodgkin Study Group, Schmitz,  Lancet  2002;359:2065 HSCT Chemo
Late relapse > 12 months n = 55 German Hodgkin Study Group, Schmitz,  Lancet  2002;359:2065 HSCT Chemo
 
Cure esc BEACOPP Potential Strategies to Cure Advanced Stage Hodgkin Lymphoma ABVD High dose chemotherapy + autologous ste...
Potential Strategies to Cure Advanced Stage Hodgkin Lymphoma Study Regimen 5-y PFS (%) P 5-y OS (%) P Reference GHSG HD9 e...
Kaplan-Meier analysis of the probability of the progression-free survival and overall survival according to intention to t...
ABVD for Advanced Stage Hodgkin Lymphoma ~ 90 % 5-y OS % Year of publication First author 73 1992 Canellos 78 1998 Hasencl...
Advanced Hodgkin Lymphoma Major Late toxicity <ul><li>Toxicity Frequency (%) </li></ul><ul><li>  ABVD  esc BEA + RT   </li...
Advanced Stage Hodgkin Lymphoma <ul><li>Peter, 23 y o violinist, asymptomatic </li></ul><ul><li>Left supraclavicular lymph...
Advanced Stage Hodgkin Lymphoma <ul><li>Mary, 53 y o farmer </li></ul><ul><ul><li>weight loss ~ 18 kg, drenching night swe...
Thanks and acknowledgements  Berthe Aleman Gianni Bonadonna George Canellos Vincent DeVita Volker Diehl David Duggan Andre...
<ul><li>Extra slides </li></ul>
Eich, JCO 2010;28:4199-4206 German Hodgkin Study Group HD 11 Trial ABVD x 4 or BEACOPP x 4  + IFRT  20 Gy vs 30 Gy 5-y TTP...
Eich, JCO 2010;28:4199-4206 ABVD x 4 Or BEACOPP x 4  + IFRT 5-y OS 94 % 2BB 5-y OS 93 %
<ul><li>Outcome (median follow-up  8 y) </li></ul><ul><ul><ul><ul><li>  5 y 10 y </li></ul></ul></ul></ul><ul><ul><ul><ul>...
Hodgkin Lymphoma Stage II B or Stage II Bulky Disease Stage group n PFS% TTP% OS% 5-y 10-y 5-y 10-y 5-y 10-y II A bulky 13...
Eich, JCO 2010;28:4199-4206 ABVD x 4 Or BEACOPP x 4  + IFRT
EFRT INRT IFRT
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LLA 2011 - J.M. Connors - Neurological problems in patients with haematological neoplasms

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  • Kaplan-Meier analysis of the probability of the failure-free survival, progression-free survival, relapse-free survival, and overall survival according to intention to treat. ABVD, doxorubicin, bleomycin, vinblastine, and dacarbazine; BEA, bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine and prednisone; CEC, cyclophosphamide, vincristine, procarbazine, prednisone, epidoxirubicin, bleomycin, vinblastine, lomustine, doxorubicin, and vindesine.
  • LLA 2011 - J.M. Connors - Neurological problems in patients with haematological neoplasms

    1. 1. Transatlantic Differences in the Treatment of Hodgkin Lymphoma Joseph M Connors Centre for Lymphoid Cancer British Columbia Cancer Agency University of British Columbia Center for Lymphoid Cancer Lymphoma Leukemia Myeloma
    2. 2. Conceptual Basis for Cancer Staging <ul><li>Purposes </li></ul><ul><li>Estimation of tumor burden </li></ul><ul><li>Communication of treatment results </li></ul><ul><ul><li>Accurate comparison of outcomes across trials and populations </li></ul></ul><ul><li>Planning of extent of local treatment </li></ul><ul><ul><li>Surgery </li></ul></ul><ul><ul><li>Radiation </li></ul></ul><ul><li>Planning of duration of systemic treatment </li></ul><ul><ul><li>Cycles of chemotherapy </li></ul></ul><ul><li>Assignment of prognosis </li></ul>
    3. 3. Conceptual Basis for Cancer Staging <ul><li>Purposes </li></ul><ul><li>Estimation of tumor burden </li></ul><ul><ul><li>Particularly important for cancers curable with non-targeted systemic Tx </li></ul></ul><ul><ul><ul><li>Choriocarcinoma </li></ul></ul></ul><ul><ul><ul><li>Acute leukemia </li></ul></ul></ul><ul><ul><ul><li>Testicular carcinoma </li></ul></ul></ul><ul><ul><ul><li>Lymphoma </li></ul></ul></ul><ul><ul><ul><ul><li>Hodgkin lymphoma </li></ul></ul></ul></ul><ul><ul><ul><ul><li>Diffuse large B cell lymphoma </li></ul></ul></ul></ul><ul><ul><ul><ul><li>Burkitt lymphoma </li></ul></ul></ul></ul><ul><ul><ul><ul><li>Lymphoblastic lymphoma </li></ul></ul></ul></ul><ul><ul><ul><ul><li>Peripheral T cell lymphoma </li></ul></ul></ul></ul>
    4. 4. Hodgkin Lymphoma Staging <ul><li>Required staging tests </li></ul><ul><li>Hematopathology review </li></ul><ul><li>History </li></ul><ul><li>Physical examination </li></ul><ul><li>Chest radiograph </li></ul><ul><li>CBC, creatinine, bilirubin, alkaline phosphatase, alb </li></ul><ul><li>CT scan of neck, thorax, abdomen and pelvis </li></ul><ul><li>Bone marrow aspiration and biopsy </li></ul><ul><ul><ul><li>Only if B Sx or blood cell cytopenia </li></ul></ul></ul><ul><li>PET/CT (clinical trials) </li></ul> Purpose detection of B Sx Extent, bulk Extent, bulk Extent, bulk Extent, bulk Extent Extent, bulk
    5. 5. Hodgkin Lymphoma Staging <ul><li>Ann Arbor Staging System </li></ul><ul><li>Stage Criteria </li></ul><ul><li>I Single lymph node region (I) or one extralymphatic site (I E) </li></ul><ul><li>II Two or more lymph node regions, same side of the diaphragm (II) </li></ul><ul><li>or local extralymphatic extension plus one or more lymph node </li></ul><ul><li>regions same side of the diaphragm (II E) </li></ul><ul><li>III Lymph node regions on both sides of the diaphragm (III) which </li></ul><ul><li>may be accompanied by local extralymphatic extension (III E) </li></ul><ul><li>IV Diffuse involvement of one or more extralymphatic organs or sites </li></ul><ul><li>B symptoms: weight loss > 10%; unexplained fever; drenching sweats </li></ul>Cotswolds modification* Bulky = Mediastinal mass ratio > 1/3 or largest tumor diameter > 10 cm *Lister, J Clin Oncol , 1989;7:1630
    6. 6. Hodgkin Lymphoma Clinical Trial Treatment Groups North America Stage Limited stage CS IA, IIA, non-bulky CS IIB Advanced stage CS IIA, bulky CS III – IV
    7. 7. Hodgkin Lymphoma Clinical Trial Treatment Groups Europe Europe Stage (GSHG, GELA, EORTC) Early favorable stage CS I,IIA,B no risk factors Early unfavorable stage CS I,IIA,B with risk factors Advanced stage CS III – IV, Selected CS IIB B Sx & ESR > 30 ESR > 50 mm Bulky disease > 3 Nodal sites Men over 40 y of age Derivation To estimate likelihood of finding intra-abdominal involvement at laparotomy Based on lymphangiography without CT scanning
    8. 8. Hodgkin Lymphoma Clinical Trial Treatment Groups Europe vs North America Europe Stage USA / Canada Clinical trial goal (GSHG, GELA, EORTC) Early favorable stage CS I,IIA,B no risk factors Limited stage Early unfavorable stage CS I,IIA,B with risk factors Advanced stage CS III – IV, Selected CS IIB Advanced stage B Sx ESR > 50 mm Bulky disease > 3 Nodal sites Men over 40 y of age Reduce toxicity ??????? Increase disease control
    9. 9. Hodgkin Lymphoma, Stage II Where does the “Unfavorable” patient fit? 16 cm Limited stage Unfavorable stage II Advanced stage
    10. 10. <ul><li>Case identification BC Cancer Agency </li></ul><ul><li>Hodgkin lymphoma, all histologies </li></ul><ul><li>Age 16 - 65 y </li></ul><ul><li>HIV antibody negative </li></ul><ul><li>Stage </li></ul><ul><ul><li>II A bulky </li></ul></ul><ul><ul><li>II B non-bulky </li></ul></ul><ul><ul><li>II B bulky Hodgkin lymphoma </li></ul></ul><ul><li>Treated in BC since 1981, when ABVD-type chemoTx became standard </li></ul>Hodgkin Lymphoma Stage II B or Stage II Bulky Disease
    11. 11. <ul><ul><li>Gender </li></ul></ul><ul><ul><ul><li>Male 54 % Female 46 % </li></ul></ul></ul><ul><ul><li>Age range 16-64 y (median = 30) </li></ul></ul><ul><ul><li>Histologic subtypes </li></ul></ul><ul><ul><ul><li>nodular sclerosis 86 % </li></ul></ul></ul><ul><ul><ul><li>mixed cellularity 5 % </li></ul></ul></ul><ul><ul><ul><li>not subclassifiable 6 % </li></ul></ul></ul><ul><ul><ul><li>other 3 % </li></ul></ul></ul><ul><ul><li>Stage </li></ul></ul><ul><ul><ul><li>II A bulky 32 % </li></ul></ul></ul><ul><ul><ul><li>II B non-bulky 32 % </li></ul></ul></ul><ul><ul><ul><li>II B bulky 36 % </li></ul></ul></ul><ul><ul><ul><li>localized extranodal extension 35 % </li></ul></ul></ul><ul><ul><ul><li>(E lesion) </li></ul></ul></ul><ul><ul><ul><li>subdiaphragmatic 3 % </li></ul></ul></ul>Hodgkin Lymphoma Stage II B or Stage II Bulky Disease Patient characteristics (n = 416) <ul><ul><li>Largest mass diameter </li></ul></ul><ul><ul><li>non-bulky range 1-9 cm median 6 cm </li></ul></ul><ul><ul><li>bulky range 10-25 cm median 12 cm </li></ul></ul><ul><ul><li>IPFP prognostic score </li></ul></ul><ul><ul><li>(data missing, primarily albumin, 36%) </li></ul></ul><ul><ul><ul><li>0 9 % </li></ul></ul></ul><ul><ul><ul><li>1 33 % </li></ul></ul></ul><ul><ul><ul><li>2 32 % </li></ul></ul></ul><ul><ul><ul><li>3 19 % </li></ul></ul></ul><ul><ul><ul><li>4 6 % </li></ul></ul></ul><ul><ul><ul><li>5 1 % </li></ul></ul></ul>
    12. 12. <ul><li>Treatment </li></ul><ul><ul><li>ChemoTx </li></ul></ul><ul><ul><ul><li>ABVD-type 6-8 cycles </li></ul></ul></ul><ul><ul><li>Radiation for a persistent residual mass </li></ul></ul><ul><ul><ul><li>only if PET positive since 2005 </li></ul></ul></ul><ul><ul><ul><li>50 % of patients received radiation </li></ul></ul></ul><ul><ul><ul><ul><li>extended field 24 % </li></ul></ul></ul></ul><ul><ul><ul><ul><li>involved field 76 % </li></ul></ul></ul></ul><ul><ul><ul><li>patients with bulky disease much more likely to receive radiation </li></ul></ul></ul><ul><ul><ul><ul><li>II A bulky 72 % </li></ul></ul></ul></ul><ul><ul><ul><ul><li>II B non-bulky 11 % </li></ul></ul></ul></ul><ul><ul><ul><ul><li>II B bulky 65 % </li></ul></ul></ul></ul>Hodgkin Lymphoma Stage II B or Stage II Bulky Disease
    13. 13. 5-y TTP 83 % median follow-up 8 y
    14. 14. II A bulky II B bulky II B non-bulky P = 0.30 By group II A bulky, II B non-bulky, II B bulky
    15. 15. II B bulky P = 0.62 By stage group 5-y OS 94 % II A bulky II B non- bulky
    16. 16. I A, II A, non-bulky 2BB P < 0.0001 HR 4.2 I A, II A non-bulky n = 459 ABVD x 2 + IFRT (= true limited stage) 2BB n = 416 ABVD x 6 +/- IFRT By stage group, 2BB vs true limited
    17. 17. Stage III or IV 2BB P = 0.0059 HR = 1.5 By stage group, 2BB vs III or IV 2BB n = 416 ABVD x 6 +/- IFRT III or IV n = 673 ABVD x 6 +/- IFRT
    18. 18. Stage III or IV 2BB P < 0.0001 II A, II A, non-bulky By stage group 5-y TTP Lim 95 % 2BB 83 % III, IV 77 % 6 %, HR 1.5 12%, HR > 4
    19. 19. Hodgkin Lymphoma Clinical Trial Treatment Groups Europe vs North America Europe Stage USA / Canada Clinical trial goal (GSHG, GELA, EORTC) Early favorable stage CS I,IIA,B no risk factors Limited stage Early unfavorable stage CS I,IIA,B with risk factors Advanced stage CS III – IV, Selected CS IIB Advanced stage B Sx ESR > 50 mm Bulky disease > 3 Nodal sites Men over 40 y of age Reduce toxicity Increase disease control Increase disease control
    20. 20. <ul><li>Conclusions </li></ul><ul><li>Considering… </li></ul>Hodgkin Lymphoma Stage II B or Stage II Bulky Disease <ul><li>Estimation of tumor burden Stage II B, II bulky = advanced stage </li></ul><ul><li>Communication of Tx results Stage II B, II bulky = advanced stage </li></ul><ul><li>Planning of extent of local Tx No change, based on post-chemoTx imaging </li></ul><ul><ul><li>Surgery </li></ul></ul><ul><ul><li>Radiation </li></ul></ul>Plan duration of systemic Tx Stage II B, II bulky = advanced stage <ul><li>Assignment of prognosis Stage II B, II bulky = advanced stage </li></ul>
    21. 21. Hodgkin Lymphoma Clinical Trial Treatment Groups Europe vs North America Europe Stage USA / Canada (GSHG, GELA, EORTC) Early favorable stage CS I,IIA,B no risk factors Limited stage Early unfavorable stage CS I,IIA,B with risk factors Advanced stage CS III – IV, Selected CS IIB Advanced stage (intermediate) B Sx ESR > 50 mm Bulky disease > 3 Nodal sites Men over 40 y of age
    22. 22. Hodgkin Lymphoma Treatment by Stage <ul><li>Limited stage </li></ul><ul><ul><ul><ul><li>Ann Arbor stage I or II </li></ul></ul></ul></ul><ul><ul><ul><ul><li>No B symptoms </li></ul></ul></ul></ul><ul><ul><ul><ul><li>No bulky tumor </li></ul></ul></ul></ul><ul><ul><ul><ul><li>Maximum tumor diameter < 10 cm </li></ul></ul></ul></ul><ul><ul><ul><ul><li>{Mediastinal mass ratio < 1/3 (obsolete)} </li></ul></ul></ul></ul><ul><li>Advanced stage </li></ul><ul><ul><ul><ul><li>Ann Arbor stage III or IV or </li></ul></ul></ul></ul><ul><ul><ul><ul><li>Presence of B symptoms or </li></ul></ul></ul></ul><ul><ul><ul><ul><li>Bulky disease at any site </li></ul></ul></ul></ul><ul><ul><ul><ul><ul><li>> 10 cm mass </li></ul></ul></ul></ul></ul>
    23. 23. Advanced Stage Hodgkin Lymphoma <ul><li>Peter, 23 y o male violinist, asymptomatic </li></ul><ul><li>Supraclavicular lymph node biopsy 3 cm nodular sclerosing HL </li></ul><ul><li>Physical exam otherwise negative </li></ul><ul><li>CT </li></ul><ul><ul><li>paratracheal nodes, mediastinal mass ~ 6 cm largest diameter </li></ul></ul><ul><ul><li>multiple high retroperitoneal nodes, largest 3 cm </li></ul></ul><ul><li>Lab </li></ul><ul><ul><li>Hgb 136 g/L, WBC 9.6 x 10 9 /L, lymphs 1.2 x 10 9 /L, albumin 41 g/L </li></ul></ul><ul><ul><li>LDH, liver and renal tests all normal </li></ul></ul><ul><li>Stage III A </li></ul>1
    24. 24. Advanced Stage Hodgkin Lymphoma <ul><li>Mary, 53 y o schoolteacher </li></ul><ul><ul><li>weight loss ~ 18 kg, drenching night sweats </li></ul></ul><ul><ul><li>large retroperitoneal mass -> biopsy mixed cellularity HL </li></ul></ul><ul><li>Physical exam splenomegaly, epigastric mass </li></ul><ul><li>CT </li></ul><ul><ul><li>extensive retroperitoneal nodes, 3 - 6 cm </li></ul></ul><ul><ul><li>splenomegaly with multiple large nodules, 2 - 4 cm </li></ul></ul><ul><ul><li>2 liver masses, 3 cm and 2 cm </li></ul></ul><ul><li>Lab </li></ul><ul><ul><li>Hgb 100 g/L, WBC 8.6 x 10 9 /L, lymphs 0.4 x 10 9 /L, albumin 34 g/L </li></ul></ul><ul><ul><li>LDH, liver and renal tests normal except alkaline phosphatase 2 x ULN </li></ul></ul><ul><ul><li>bone marrow positive, extensive fibrosis, occasional R-S cell </li></ul></ul><ul><li>Stage IV B </li></ul>2
    25. 25. ABVD v MOPP v MOPP/ABVD Failure-free survival Overall survival Canellos et al, NEJM, 2002
    26. 26. Advanced Hodgkin Lymphoma ABVD vs MOPP/ABV Hybrid Intergroup CALGB, ECOG, SWOG, NCIC <ul><li> ABVD MOPP/ABV p </li></ul><ul><li>n 433 419 </li></ul><ul><li>CR % 76 80 0.16 </li></ul><ul><li>Progression % 10 11 </li></ul><ul><li>5 y FFS % 63 66 0.42 </li></ul><ul><li>5 y OS % 82 81 0.82 </li></ul>
    27. 27. Intergroup CALGB, ECOG, SWOG, NCIC: ABVD vs MOPP/ABV
    28. 28. Intergroup CALGB, ECOG, SWOG, NCIC: ABVD vs MOPP/ABV
    29. 29. International Prognostic Factors Project on Advanced Hodgkin Lymphoma <ul><li>Factor Criteria in SI units </li></ul><ul><li>Age > 44 y </li></ul><ul><li>Gender male </li></ul><ul><li>Stage IV </li></ul><ul><li>Albumin < 40 g/L </li></ul><ul><li>WBC > 15 x 10 9 /L </li></ul><ul><li>Hemoglobin < 105 g/L </li></ul><ul><li>Lymphs < 0.6 x 10 9 /L or </li></ul><ul><li>< 8% </li></ul><ul><li>Hasenclever, NEJM 1998;339:1506 </li></ul>
    30. 30. Advanced Stage Hodgkin Lymphoma <ul><li>Peter, 23 y o male violinist, asymptomatic </li></ul><ul><li>Left supraclavicular lymph node biopsy 3 cm nodular sclerosing HL </li></ul><ul><li>Physical exam otherwise negative </li></ul><ul><li>CT </li></ul><ul><ul><li>paratracheal nodes, mediastinal mass ~ 6 cm largest diameter </li></ul></ul><ul><ul><li>multiple high retroperitoneal nodes, largest 3 cm </li></ul></ul><ul><li>Lab </li></ul><ul><ul><li>Hgb 136 g/L, WBC 9.6 x 10 9 /L, lymphs 1.2 x 10 9 /L, albumin 41 g/L </li></ul></ul><ul><ul><li>LDH, liver and renal tests all normal </li></ul></ul><ul><li>Stage III A </li></ul><ul><li>IPFP score = 1 (male) </li></ul>1
    31. 31. Advanced Stage Hodgkin Lymphoma <ul><li>Mary, 53 y o farmer </li></ul><ul><ul><li>weight loss ~ 18 kg, drenching night sweats </li></ul></ul><ul><ul><li>large retroperitoneal mass -> biopsy mixed cellularity HL </li></ul></ul><ul><li>Physical exam splenomegaly, epigastric mass </li></ul><ul><li>CT </li></ul><ul><ul><li>extensive retroperitoneal nodes, 3 - 6 cm </li></ul></ul><ul><ul><li>splenomegaly with multiple large nodules, 2 - 4 cm </li></ul></ul><ul><ul><li>2 liver masses, 3 cm and 2 cm </li></ul></ul><ul><li>Lab </li></ul><ul><ul><li>Hgb 100 g/L , WBC 8.6 x 10 9 /L, lymphs 0.4 x 10 9 /L , albumin 34 g/L </li></ul></ul><ul><ul><li>LDH, liver and renal tests normal except alkaline phosphatase 2 x ULN </li></ul></ul><ul><ul><li>bone marrow positive, extensive fibrosis, occasional R-S cell </li></ul></ul><ul><li>Stage IV B </li></ul><ul><li>IPFP score = 5 (age, stage, albumin, hemoglobin, lymphocytes) </li></ul>2
    32. 32. International Prognostic Factors Project on Advanced Hodgkin Lymphoma Treatment era = 1980s, ABVD
    33. 33. 42 % 12 % 26 % 94 % 675 Consecutive Adult Patients with Advanced Stage Hodgkin Lymphoma Treated at BCCA through 2009 Compared to Original IPFP Publication
    34. 34. International Prognostic Factors Project on Advanced Hodgkin Lymphoma Treatment era = 1980s, ABVD 50 %
    35. 35. 675 Consecutive Adult Patients with Advanced Stage Hodgkin Lymphoma Treated at BCCA through 2009 Compared to Original IPFP Publication 50 %
    36. 36. B Bleomycin E Etoposide A Adriamycin C Cyclophos O Vincristine P Procarbazine P Prednisone Std mg/m 2 10 100 25 650 1,4 100 40 BEACOPP - schedule Escalated mg/m 2 10 200 35 1250 1,4 100 40 G-CSF sc 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 22 restart
    37. 37. HD9 Trial Design( 1992-97 ) (1281 patients recruited) CS IIB-IIIA with risk factors CS IV Arm A 4x COPP+ABVD  RT Arm B 8x BEACOPP standard  RT Arm C 8x BEACOPP escalated  RT+G-CSF RT to initial bulk and residual tumor
    38. 38. Engert, JCO 2009; 27:4548 Kaplan-Meier analysis of the probability of (A) freedom from treatment failure COPP/ABVD arm closed early > 15 y ago
    39. 39. Kaplan-Meier analysis of the probability of (B) overall survival in each treatment arm Engert, JCO 2009; 27:4548
    40. 40. 1990s 1980s 1970s 1960s n = 2170 Progression = 80 % Progression = 20 % Time to Progression (years)
    41. 41. German Hodgkin Study Group, Schmitz, Lancet 2002;359:2065 n 161 117 HSCT Chemo
    42. 42. German Hodgkin Study Group, Schmitz, Lancet 2002;359:2065 HSCT Chemo
    43. 43. Early relapse < 12 months n = 38 German Hodgkin Study Group, Schmitz, Lancet 2002;359:2065 HSCT Chemo
    44. 44. Late relapse > 12 months n = 55 German Hodgkin Study Group, Schmitz, Lancet 2002;359:2065 HSCT Chemo
    45. 46. Cure esc BEACOPP Potential Strategies to Cure Advanced Stage Hodgkin Lymphoma ABVD High dose chemotherapy + autologous stem cell transplant Progression Endpoints = PFS RFS EFS TTP Endpoints = OS FF2F Progression Cure
    46. 47. Potential Strategies to Cure Advanced Stage Hodgkin Lymphoma Study Regimen 5-y PFS (%) P 5-y OS (%) P Reference GHSG HD9 eBEACOPP 87 0.001 91 0.02 Diehl, 2003 COPP/ABVD 69 83 GISL HD2000 eBEACOPP 81 0.038 92 NS Federico, 2009 ABVD 68 84 GSM-HD eBEACOPP 85 0.004 89 0.39 Gianni, 2008 ABVD 73 86
    47. 48. Kaplan-Meier analysis of the probability of the progression-free survival and overall survival according to intention to treat. Federico M et al. JCO 2009;27:805-811 ©2009 by American Society of Clinical Oncology Endpoint = PFS Endpoint = OS
    48. 49. ABVD for Advanced Stage Hodgkin Lymphoma ~ 90 % 5-y OS % Year of publication First author 73 1992 Canellos 78 1998 Hasenclever 82 2003 Duggan 83 2003 Diehl 86 2008 Gianni 84 2009 Federico 90 2009 Hoskin 91 2009 Moccia 88 2010 Gordon
    49. 50. Advanced Hodgkin Lymphoma Major Late toxicity <ul><li>Toxicity Frequency (%) </li></ul><ul><li> ABVD esc BEA + RT </li></ul><ul><li>Cardiac, symptomatic < 5 < 5 </li></ul><ul><li>Pulmonary, symptomatic 0-6 0-6 </li></ul><ul><li>Infertility, male 0 > 80 </li></ul><ul><li>Infertility/menopause, female 0 20-80 </li></ul><ul><li>Leukemia/myelodysplasia < 1 3-5 </li></ul><ul><li>Solid tumors ??? > ?? </li></ul>
    50. 51. Advanced Stage Hodgkin Lymphoma <ul><li>Peter, 23 y o violinist, asymptomatic </li></ul><ul><li>Left supraclavicular lymph node biopsy 3 cm nodular sclerosing HL </li></ul><ul><li>Physical exam otherwise negative </li></ul><ul><li>CT </li></ul><ul><ul><li>paratracheal nodes, mediastinal mass ~ 6 cm largest diameter </li></ul></ul><ul><ul><li>multiple high retroperitoneal nodes, largest 3 cm </li></ul></ul><ul><li>Lab </li></ul><ul><ul><li>Hgb 136 g/L, WBC 9.6 x 10 9 /L, lymphs 1.2 x 10 9 /L, albumin 41 g/L </li></ul></ul><ul><ul><li>LDH, liver and renal tests all normal </li></ul></ul><ul><li>Stage III A </li></ul><ul><li>IPFP score = 1 (male) </li></ul>1 Treatment ABVD Probability of relapse < 15 % auto-HSCT < 15 % cure > 95 %
    51. 52. Advanced Stage Hodgkin Lymphoma <ul><li>Mary, 53 y o farmer </li></ul><ul><ul><li>weight loss ~ 18 kg, drenching night sweats </li></ul></ul><ul><ul><li>large retroperitoneal mass -> biopsy mixed cellularity HL </li></ul></ul><ul><li>Physical exam splenomegaly, epigastric mass </li></ul><ul><li>CT </li></ul><ul><ul><li>extensive retroperitoneal nodes, 3 - 6 cm </li></ul></ul><ul><ul><li>splenomegaly with multiple large nodules, 2 - 4 cm </li></ul></ul><ul><ul><li>2 liver masses, 3 cm and 2 cm </li></ul></ul><ul><li>Lab </li></ul><ul><ul><li>Hgb 100 g/L, WBC 8.6 x 10 9 /L, lymphs 0.4 x 10 9 /L, albumin 34 g/L </li></ul></ul><ul><ul><li>LDH, liver and renal tests normal except alkaline phosphatase 2 x ULN </li></ul></ul><ul><ul><li>bone marrow positive, extensive fibrosis, occasional R-S cell </li></ul></ul><ul><li>Stage IV B </li></ul><ul><li>IPFP score = 5 (age, stage, albumin, hemoglobin, lymphocytes) </li></ul>2 Treatment ABVD Probability of relapse ~ 30 % auto-HSCT ~ 25 % cure > 70 % Treatment escBEACOPP Probability of relapse ~ 25 % auto-HSCT ~ 20 % cure > 75 %
    52. 53. Thanks and acknowledgements Berthe Aleman Gianni Bonadonna George Canellos Vincent DeVita Volker Diehl David Duggan Andreas Engert Massimo Federico Alessandro Gianni Leo Gordon Dirk Hasenclever Sandra Horning Peter Johnson Andrew Lister Alden Moccia Saul Rosenberg Norbert Schmitz Donnall Thomas
    53. 54. <ul><li>Extra slides </li></ul>
    54. 55. Eich, JCO 2010;28:4199-4206 German Hodgkin Study Group HD 11 Trial ABVD x 4 or BEACOPP x 4 + IFRT 20 Gy vs 30 Gy 5-y TTP 85 % 2BB 5-y TTP 83 % B Sx 30 % Bulky 20 % Multivariate only bulk significant (HR ~1.8)
    55. 56. Eich, JCO 2010;28:4199-4206 ABVD x 4 Or BEACOPP x 4 + IFRT 5-y OS 94 % 2BB 5-y OS 93 %
    56. 57. <ul><li>Outcome (median follow-up 8 y) </li></ul><ul><ul><ul><ul><li> 5 y 10 y </li></ul></ul></ul></ul><ul><ul><ul><ul><li>PFS 81 % 76 % </li></ul></ul></ul></ul><ul><ul><ul><ul><li>TTP 83 % 81 % </li></ul></ul></ul></ul><ul><ul><ul><ul><li>OS 94 % 90 % </li></ul></ul></ul></ul>Hodgkin Lymphoma Stage II B or Stage II Bulky Disease
    57. 58. Hodgkin Lymphoma Stage II B or Stage II Bulky Disease Stage group n PFS% TTP% OS% 5-y 10-y 5-y 10-y 5-y 10-y II A bulky 135 85 85 85 85 94 93 II B non-bulky 134 80 70 80 77 95 88 II B bulky 147 78 72 82 79 94 90 All patients 416 81 76 83 81 94 90
    58. 59. Eich, JCO 2010;28:4199-4206 ABVD x 4 Or BEACOPP x 4 + IFRT
    59. 60. EFRT INRT IFRT

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