OVERVIEW

1. MANAGEMENT OF ADVANCED
STAGE HODGKIN LYMPHOMA

3. • ADVANCED STAGE
• Stage 3 n Stage 4

4. Advanced-stage HL: International
Prognostic Score

5. CHEMOTHERAPY
• In advanced stage chemotherapy has the major role

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

7. MOPP
• Devised by Devita and Longo in 1970s
1st CCT regimen to be started with a CURATIVE intent
• Doses:
– Nitrogen Mustard 6 mg/m2 I/V D1 and D8
– Vincristine (Oncovine) 1.4 mg/m2 IV D1 and D8
– Procarbazine 100 mg/m2 D1 to D14
– Prednisone 40 mg/m2 D1 to D 14
• Cycles repeated every 21 days for 6 such cycles

8. • MOPP Regimen -The First Generation
• Complete remission rates of 73% to 81%
• long-term freedom from progression of 36% to 52%,
• long-term OS of 50% to 64% were obtained in
advanced stages

9. • Despite the good initial results with MOPP therapy
• several groups investigated alternative regimens to
improve the efficacy or reduce toxicities
• substitution of an alkylating agent like
cyclophosphamide or chlorambucil for mustargen
• vinca alkaloid like vinblastine or vincristine as well as
alteration of the doses of procarbazine and
prednisone

10. Alternate regimens: ChlVPP (LVPP)
– Chlorambucil 6mg/m2 PO D1-D14 (total dose limited to
10mg/m2 usually)
– Vinblastine 6 mg/m2 IV D1 and D8
– Procarbazine 100 mg/m2 PO D1 to D14
– Prednisone 40 mg PO D1 to D 14
• Contains three oral agents with better ease of administration.
• Acute side effects like myelopsuppresssion, nausea and
vomiting, neuropathy, and alopecia, are much less.
• CR are in the range of 80% and long term results similar to
those expected from MOPP regimen.

11. Other MOPP variants
• MVPP : Designed to
overcome neurotoxicity of
Vincristine by use of
vinblastine
– Nitrogen Mustard
6mg/m2 IV D1 and D8
– Vinblastine 6 mg/m2 IV
D1 and D8
– Procarbazine 100 mg/m2
PO D1 to D14
– Prednisone 40 mg PO D1
to D14
• BCVPP : Designed to
overcome the toxicity of
nitrogen mustard:
– BCNU 100mg/m2 IV D1
– Cyclophosphamide 600
mg/m2 IV D1
– Vinblastine 5 mg/m2 PO
D1
– Procarbazine 50 mg/m2
PO D1 and 100 mg/m2
D2 to D20
– Prednisone 40mg PO D1
to D20

12. • several MOPP-like regimens showed similar efficacy
with less acute gastrointestinal and neurologic
toxicity.
• BUT
• (i) still only about 50% patients could be cured
• (ii) the alkylating-based combination was associated
with an increased risk of sterility and acute leukemia

13. • Bonadonna et al. introduced the ABVD (doxorubicin,
bleomycin, vinblastine, dacarbazine) regimen
• The Second Generation

14. • The authors selected these agents because of:
– Each of the new drugs potentially non cross resistant with
MOPP
– Doxorubicin and Bleomycin has independent efficacy in HD
– Vinblastine is effective in patients failed on Vincristine
– Therapeutic efficacy of DTIC in previously treated HD had
been demonstrated by Frei et al in 1972.
– In addition DTIC has little myelotoxicity so can be
combined with adriamycin or bleomycin with little
synergistic toxicity.

15. • Dosage and Frequency:
– Adriamycin 25 mg/m2 IV D1 and D15
– Bleomycin 10 U/m2 IV D1 and D15
– Vinblastine 6 mg/m2 IV D1 and D15
– Dacarbazine 375 mg/m2 D1 and D15

16. • The Milan group compared three cycles of MOPP or
ABVD
• followed by extended-field irradiation and three
additional cycles of the same chemotherapy

17. • A significant difference in favor of ABVD could be
achieved with freedom from progression rates of
63% MOPP versus 81% of ABVD
• MOPP and ABVD were highly active regimens and
had nonoverlapping toxicities.
• combinations of MOPP and ABVD was tried to
further increase treatment results.

18. • The Milan group randomized patients in stage IV
• MOPP or MOPP/ABVD for up to 12 cycles.
• freedom from progression at 8 years (36% MOPP
versus 65% MOPP/ABVD; P < 0.005).
• Subsequently three large cooperative trial groups
(ECOG, CALGB, and EORTC) have confirmed these
results

19. • The CALGB tested in a three-arm trial 6 to 8 cycles of
MOPP
• 6 to 8 cycles of ABVD
• 12 cycles of MOPP alternating with ABVD.
• At 10 years, the FFS rates were 38% for MOPP, 55%
for ABVD, and 50% for MOPP/ABVD.
• OS was not significantly different, although there was
a trend in favor of ABVD or MOPP/ABVD compared
with MOPP alone.

20. • The EORTC trial
• MOPP/ABVD showed a significantly higher FFS rate
at 6 years (43% MOPP, 60% MOPP/ABVD)
• Thus, ABVD alone and MOPP/ABVD are more
effective than MOPP alone.
• In addition ABVD alone had the advantage of less
acute and long-term toxicities

21. Duration of Therapy
• Bonadonna et al. initially applied up to 12 cycles of
MOPP and later in the alternating program 8 cycles
without reduction in efficacy.
• The CALGB trial demonstrated that 8 cycles of ABVD
was comparable to 12 cycles of alternating
MOPP/ABVD.

22. Hybrid Regimens: The Third
Generation
• The theoretic basis for multidrug regimens is the
predicted advantage of the early introduction of all
active agents to avoid resistant tumor cell clones.
• This idea is based on a model proposed by Goldie
and Coldman who related the drug sensitivity of
tumors to their spontaneous mutation rate.

23. • The NCIC compared the MOPP-ABV hybrid with
alternating MOPP/ABVD
• At 5 years there was no significant difference in the
OS rates between both arms
• however, the hybrid regimen was associated with
higher hematologic and nonhematologic toxicities.

24. • Dose Schedule:
– Nitrogen Mustard 6 mg/m2 IV D1
– Vincristine 1.4 mg/m2 IV D1
– Procarbazine 100 mg/m2 PO D1 to D7
– Prednisone 40 mg PO D1 to D 14
– Adriamycin 35 mg/m2 IV D8
– Vinblastine 6mg /m2 IV D8
– Bleomycin 10 U/m2 IV D8

25. • The Milan group compared their MOPP/ABV hybrid
with alternating MOPP/ABVD.
• Freedom from progression and OS rates at 10 years
revealed no significant difference between the hybrid
and alternating arms

26. • U.S. Intergroup trial in which they compared ABVD
with the MOPP/ABV hybrid in 856 adult patients with
stage IIIA, IIIB, IV
• no statistical difference observed between the ABVD
and the MOPP/ABV arms as far as FFS and OS were
concerned
• greater toxicity was seen during therapy and after
completion of treatment in the MOPP/ABV

27. • the Goldie-Coldman hypothesis could not be proven in
advanced-stage Hodgkin lymphoma
• this could be because the optimal hybrid regimen was
not identified
• ABVD has emerged as the standard against which newer
treatments must be compared
• With ABVD, 60% to 70% of patients will be free of disease
at 5 years.
• ABVD is much less likely to cause severe myelotoxicity,
acute leukemia, or sterility than treatment programs that
contain significant doses of alkylating agents.

28. New Chemotherapy Regimens: The
Fourth Generation
• Pulmonary toxicity of bleomycin, which is especially
pronounced in children and in combination with
mediastinal irradiation, remains a major concern
with ABVD

29. • 20% to 60% response rate in refractory Hodgkin
lymphoma was reported with single-agent etoposide.
• Based on these considerations, several etoposide-
containing drug regimens were developed

30. Stanford Regimen
Drug Dose
Stanford
Meclorethamine (M) 6
Adriamycin (A) 25
Vinblastine (V) 6
Vincristine (O) 1.4
Bleomycin (B) 5
Etoposide (E) 60
Prednisone (P) 40
G-CSF —
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36. • STANFORD V
• BEACOPP Regimen

37. Results Stanford V
• In a pilot study recruiting 126 patients with a FU of 6.9 years.
• The estimated 5-year freedom from progression was 89%
• Overall survival was 96% at a median observation time of 4.5
years

38. • Randomized Phase III Trial of ABVD Versus Stanford V With or
Without Radiation Therapy in Locally Extensive and Advanced-
Stage Hodgkin Lymphoma: An Intergroup Study Coordinated
by the Eastern Cooperative Oncology Group (E2496)
• There was no significant difference in the overall response
rate between the two arms
• with complete remission rates of 73% for ABVD and 69% for
Stanford V.
• At a median follow-up of 6.4 years, there was no difference in
FFS: 74% for ABVD and 71% for Stanford V at 5 years

39. GHSG HD9 study
• compared two different doses (baseline and escalated)
(BEACOPP) chemotherapy regimen in 1,196 patients with
advanced-stage Hodgkin's lymphoma (HL).
• eight cycles of (COPP) alternating with (ABVD)
• eight cycles of BEACOPP baseline
• eight cycles of BEACOPP escalated.

40. • At 10 years, freedom from treatment failure (FFTF) was 64%,
70%, and 82%
• OS rates of 75%, 80%, and 86% for patients treated with
COPP/ABVD (arm A), BEACOPP baseline (arm B), and BEACOPP
escalated (arm C)
• The 10-year follow-up of the HD9 trial demonstrates a
stabilized significant improvement in long-term FFTF and OS
for BEACOPP escalated in advanced-stage HL.

41. The HD15 trial (2003-2008)
• designed to find out whether it is possible to reduce the
number of chemotherapy in patients who are given
additional radiotherapy
• 8 x escalated BEACOPP were compared to
• 6 x escalated BEACOPP and to 8 x BEACOPP 14.
• After completion of chemotherapy, a PET examination was
performed and PET-positive residual tumor tissues larger than
2.5 cm were irradiated.

42. RESULTS
• Treatment with six cycles of BEACOPP(escalated)
followed by PET-guided radiotherapy
• was more effective in terms of freedom from
treatment failure
• less toxic than eight cycles of the same
chemotherapy regimen.

43. ROLE OF RT
• radiotherapy may be used as an adjuvant after
complete remission with standard chemotherapy.
• radiotherapy may be an integrated component of a
combined modality program, possibly with reduced
or brief chemotherapy
• radiotherapy can serve as a non-cross resistant
treatment for patients with partial or uncertain
response after chemotherapy

44. • SWOG study -Sixty-one percent of patients who
achieved complete remission were randomized to
low-dose involved-field radiotherapy or no further
treatment
• no significant differences in remission duration or OS
were detected

45. • The GHSG analyzed the role of low-dose (20 Gy)
involved-field radiotherapy
• versus two cycles of additional consolidation
chemotherapy in 288 patients in complete remission
after initial chemotherapy with COPP/ABVD.
• There were no significant differences in freedom
from progression or OS rates between the two
treatment arms

46. UKLG LY09 Trial
• study analyzed the outcomes of nonrandomized consolidation
radiotherapy (RT)
• given after chemotherapy in the initial treatment of advanced
Hodgkin's lymphoma (HL)
• Postchemotherapy RT for consolidation was given to patients
with bulk disease
• partial response after chemotherapy

47. • PFS and OS was better who received RT
• HD12 trial of the German Hodgkin Study Group
• eight cycles of BEACOPP(escalated) was compared with
• four cycles of BEACOPP(escalated) followed by four cycles of
the baseline dose of BEACOPP (BEACOPP(baseline); 4 + 4),
and RT with no RT in the case of initial bulk or residual disease
• FFTF was inferior without RT particularly in patients who had
residual disease after chemotherapy
• not in patients with bulk in complete response after
chemotherapy

48. TREATMENT GUIDELINES

52. Progressive and Relapsed Disease
• relapse generally occurs within 1 to 5 years following
primary therapy
• new histology should be obtained as the risk for
second tumors NHL or solid tumors are increased
• clinical and radiographic restaging is recommended

53. Prognostic Factors
• the treatment modality used in first-line therapy, age
• relapse sites
• quantity of disease at relapse
• presence or absence of systemic symptoms
• duration of first remission is a major determinant of
a second complete response

54. • Primary progressive Hodgkin lymphoma -patients
who never achieved a complete remission or relapse
within 3 months after the end of treatment.
• Early relapses between 3 and 12 months of complete
remission (approximately 15% of all cases)
• Late relapses after an achieved complete remission
lasting at least 12 months (approximately 15% of all
cases).

55. • SALVAGE RT
• CHEMOTHERAPY
• HDT/ASCT

56. Salvage Radiotherapy
• in patients without B symptoms
• who have not been given radiation previously or
• who relapse locally outside the initial radiation field.

57. • Wirth et al. reported the experience of salvage
radiotherapy in 51 patients
• 45% achieved a complete response following
irradiation.
• Five-year failure-free survival and OS were 26% and
57%, respectively
• who relapsed in supradiaphragmatic nodal sites
without B symptoms has good prognosis

58. • HDT/ASCT VS CONVENTIONAL
CHEMOTHERAPY
• BRITISH NATIONAL LYMPHOMA INVESTIGATION
• Improved EFS and PFS with HDT/ASCT
• No improvement in OS
• TRM was high

59. • Bad prognosis
• Less than 1 yr to relapse
• Presence of extanodal site at relapse
• B symptoms
• Stage at relapse

60. High Dose Chemotherapy
• Given along with stem cell support.
• Usually limited to primary progressive HL and early relapse
after salvage CCT failure
• Regimens used:
– CBV regimen (Cyclophosphamide, BCNU, Etoposide)
– BEAM (BCNU, Etoposide, Ara-C, Melphalan)
• Complications:
– Treatment related mortality : 14% -5%
– Infections: Early and delayed
– MDS / AML risk : 4% -15% within 5yrs.
– Cardiac and Pulmonary complications
– Sterility : Universal

61. • Cyto reduction-
• With 2nd line chemotherapy before HDT/ASCT
• GVD ( gemcitabine, vinorelbine ,liposomal
doxorubicine)
• GCD ( Gemcitabine, carboplatin, dexamethasone )
• Bendamustine, lenalidomide ,everolimus

62. • Brentuximab vedotin a CD-30 directed antibody
conjugate can be used
• It is advocated in who fails after HDT/ASCT or who
are not fit for it

66. RESPONSE CRITERIA
• Restaging after completion of chemotherapy
• To assess the response to therapy

68. ROLE OF PET