MANAGEMENT OF ADVANCED STAGE HODGKIN LYMPHOMA

• ADVANCED STAGE

• Stage 3 n Stage 4

Advanced-stage HL: International Prognostic Score

CHEMOTHERAPY

• In advanced stage chemotherapy has the major role

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

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

• 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

• 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

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.

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

• 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

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

• The Second Generation

• 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.

• 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

• The Milan group compared three cycles of MOPP or ABVD

• followed by extended-field irradiation and three additional cycles of the same chemotherapy

• 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.

• 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

• 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.

• 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

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.

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.

• 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.

• 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

• 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

• 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

• 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.

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

• 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

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 —

Week M A V E O B P

1

2

3

4

5

6

7

8

9

10

11

12

• STANFORD V

• BEACOPP Regimen

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

• 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

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.

• 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.

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.

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.

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

• 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

• 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

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

• 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

TREATMENT GUIDELINES

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

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

• 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).

• SALVAGE RT

• CHEMOTHERAPY

• HDT/ASCT

Salvage Radiotherapy

• in patients without B symptoms

• who have not been given radiation previously or

• who relapse locally outside the initial radiation field.

• 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

• HDT/ASCT VS CONVENTIONAL CHEMOTHERAPY

• BRITISH NATIONAL LYMPHOMA INVESTIGATION

• Improved EFS and PFS with HDT/ASCT

• No improvement in OS

• TRM was high

• Bad prognosis

• Less than 1 yr to relapse

• Presence of extanodal site at relapse

• B symptoms

• Stage at relapse

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

• Cyto reduction-

• With 2nd line chemotherapy before HDT/ASCT

• GVD ( gemcitabine, vinorelbine ,liposomal doxorubicine)

• GCD ( Gemcitabine, carboplatin, dexamethasone )

• Bendamustine, lenalidomide ,everolimus

• 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

RESPONSE CRITERIA

• Restaging after completion of chemotherapy

• To assess the response to therapy

ROLE OF PET