Hodgkins Disease Chemotherapy

1. Chemotherapy in Hodgkin’s Lymphoma Moderator: Dr S C Sharma Dept of Radiotherapy, PGIMER, Chandigarh

4. Management Outline Stage Stage I & II A Stage IIB, III & IV Radiotherapy alone Chemotherapy alone Combined Modality CCT + Consolidation Radiotherapy

5. Evolution of CCT Single agents MOPP (USA) COPP (UK) MOPP variants ABVD ABVD MOPP Alternating ABVD MOPP Hybrids More intense therapy ?? 1 st Generation 2 nd Generation 3 rd Generation 4 th Generation

10. Overview of Single agents used in Hodgkin’s Disease

12. Efficacy of Single Agents

13. Dose and Administration 3-4 weekly IV 75 mg/m 2 Cisplatin Daily x 5, Variable IV 50-120 mg/m 2 Etoposide Daily x 5, Variable IV 200 mg/m 2 DTIC Variable IV 5 mg/m 2 Bleomycin 3-4 weekly IV 30-60 mg/m 2 Doxorubicin Weekly IV 0.2 mg/kg/wk Vinblastine Daily PO 0.2 mg/kg/d Chlorambucil Daily PO 2 mg/kg/d Cyclophosphamide Daily PO 50-150 mg/kg/d Procarbazine Weekly IV 0.2 mg/kg Vincristine 4-6 weeks IV 0.2-0.4 mg/kg Nitrogen Mustard Frequency Route Dose Agent

14. Mechanisms of Action Class Alkylating Agents Vinca Alkaloids Anthracyclines Non classic Alkylating agents Podphyllotoxins Bleomycin Cisplatin DNA alkylation & DNA cross linking Disruption of Microtubules with Mitotic arrest Topoisomerase II dependant DNA cleavage Single strand DNA breaks & premitotic G2 block ; 0 6 -Methylguanine mediated cellular cytotoxicity. Topoisomerase II inhibitors DNA adducts and crosslinks Direct DNA damage

15. Toxicity Neurotoxicity, Ototoxicity, Nephrotoxicity Cisplatin BMT (leucopenia & neutropenia), Leukemia Etoposide BMT, Flu like syndrome , Hepatic vein thrombosis DTIC Fever, Skin toxicity, Pulmonary toxicity Bleomycin BMT, Alopecia, N&V, Diarrhea, Cardiac, RT recall Doxorubicin BMT (Neutropenia), Mucositis, Hypertension Vinblastine BMT (Neutropenia, Anemia), N&V, Leukemia Chlorambucil BMT (Thrombocytopenia), SIADH, N&V, Bladder toxicity Cyclophosphamide BMT, N&V, Leukemogenic, Infertility, Psychotic reactions, hypertensive crisis with MAO inhibitor Procarbazine Neurotoxicity, constipation & ANS disturbance Vincristine BMT, N&V, Leukemogenic Nitrogen Mustard Dose Limiting Toxicity Agent

17. Advent of Combination Chemotherapy in Hodgkin’s Disease

31. Alternate regimens: Results

36. ABVD alone : Toxicity S 11.3 5.0 Hematological (Gr III or more) NS 2.9 3.3 Pulmonary (Gr II or more) NS 9.3 8.3 Cardiac (Gr II or more) After Treatment S 1.7 0 Hypotension (Gr III or more) S 5.7 1.7 Fatigue (Gr III or more) S 3.2 0.2 Anorexia (Gr III or more) S 74.6 63.6 Hematological (Gr III or more) NS 7.5 6.6 Cardiac (Gr II or more NS 30.6 24.5 Pulmonary (Gr II or more) In Treatment P MOPP ABV (%) ABVD (%) Toxicity

38. Use of CCT in Early Hodgkin’s Disease

45. Number of ABVD cycles FFTF, 94% OS 98% (3y) AV + STLI (S) (36–40 Gy) SWOG 9133 FFTF, 81% OS 96% (3y) STLI (S) (36–40 Gy) 4 ABVD + IFRT (20 Gy) 4 ABVD + IFRT (30 Gy) 2 ABVD + IFRT (20 Gy) Results similar across all 4 arms with FFTF ~ 96% and OS at 2 yrs ~ 99%. 2 ABVD + IFRT (30 Gy) GHSG HD10 FFTF 91% OS 94% (5y) 2 ABVD + EFRT 30 Gy (IFRT 40 Gy) FFTF 75% OS 94% (5y) EFRT 30 Gy (IFRT 40 Gy) GHSG HD7 Outcome Design Trial

47. ABVD alone vs Combined Modality 100% 88% (8yrs) ABVD x 6 + IFRT 89% 76% (8yrs) ABVD x 6 Laskar et al 3 86% (5yrs) ABVD x 6 + EF/IF NS 81% (5yrs) ABVD x 6 MSKCC 2 95% (5 yrs) ABVD x 2 + STLI NS 88% (5 yrs) ABVD x 4-6 NCIC/ECOG HD6 1 OS FFP Design Author

50. Trial results 4 BEACOPP + IFRT (20 Gy) 4 BEACOPP + IFRT (30 Gy) 4 ABVD + IFRT (20 Gy) Results equivalent across all 4 arms at 2yrs with OS of 97% and FFS at 90% 4 ABVD + IFRT (30 Gy) GHSG HD11 EFS 90% (6yrs) 6 MOPP/ABV + IFRT EFS 68% (6yrs) 6 EBVP II + IFRT (36 GY) EORTC H7U EFS 66% (5yrs)* 3 AOPE + IFRT (30 Gy) + 3 AOPE EFS 85% (5yrs) 3 CVPP + IFRT (30 Gy) + 3 CVPP GALTA FFP 72% (5yrs) 3 ABVD + STLI/TLI + 3 ABVD FFP 66% (5yrs) 3 MOPP + STLI/TLI + 3 MOPP Milan FFP 88% (8 yrs)* 3 ABVD + mantle RT + 3 ABVD FFP 76% (8 yrs) 3 MOPP + mantle RT + 3 MOPP EORTC H6U Outcome Regimen Author

52. Chemotherapy in Advanced Hodgkin’s disease

57. More Intense Chemotherapy: Is more better?

59. BEACOPP and variants 22 21 — 40 100 1.4 1250 35 200 10 Dose G-CSF Prednisone Procarbazine Oncovin Cyclophosphamide Adriamycin Etoposide Bleomycin BEACOPP Increased Dose Drug 1-14 1–14 40 Prednisone 1-7 1–7 100 Procarbazine 8 8 1.4 Oncovin (vincristine) 1 1 650 Cyclophosphamide 1 1 25 Adriamycin 1-3 1–3 100 Etoposide 8 8 10 Bleomycin BEACOPP Days Days Dose Drug

61. Stanford Regimen — G-CSF 40 Prednisone (P) 60 x 2 Etoposide (E) 5 Bleomycin (B) 1.4 Vincristine (O) 6 Vinblastine (V) 25 Adriamycin (A) 6 Meclorethamine (M) Stanford Dose Drug    E   12           P      B    M       A       V 11  10 9  8 7  6 5  4 3  2 1 O Week

64. Chemotherapy in special settings

66. Treatment of recurrence Type Post RT Post CCT CCT alone with ABVD RT Salvage CCT High Dose CCT with stem cell support Late Relapse Early Relapse Primary Progressive HL

67. Regimens used 46 75 100 MINE 40 70 56 ASHAP ne 68 19 DHAP 8 63 47 MIME 36 84 44 Mini-BEAM 25 56 56 Dexa-BEAM 22 48 32 CEVD 16 54 58 CEP RFS (%) RR (%) No. Regimen