HODGKINS LYMPHOMA ADVANCED STAGE MANAGEMENT
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Transcript of HODGKINS LYMPHOMA ADVANCED STAGE MANAGEMENT
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MANAGEMENT OF ADVANCED STAGE HODGKIN LYMPHOMA
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• ADVANCED STAGE
• Stage 3 n Stage 4
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Advanced-stage HL: International Prognostic Score
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CHEMOTHERAPY
• In advanced stage chemotherapy has the major role
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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
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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
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• 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
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• 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
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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.
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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
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• 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
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• Bonadonna et al. introduced the ABVD (doxorubicin, bleomycin, vinblastine, dacarbazine) regimen
• The Second Generation
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• 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.
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• 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
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• The Milan group compared three cycles of MOPP or ABVD
• followed by extended-field irradiation and three additional cycles of the same chemotherapy
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• 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.
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• 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
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• 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.
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• 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
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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.
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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.
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• 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.
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• 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
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• 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
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• 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
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• 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.
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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
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• 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
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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
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• STANFORD V
• BEACOPP Regimen
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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
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• 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
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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.
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• 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.
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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.
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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.
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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
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• 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
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• 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
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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
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• 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
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TREATMENT GUIDELINES
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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
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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
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• 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).
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• SALVAGE RT
• CHEMOTHERAPY
• HDT/ASCT
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Salvage Radiotherapy
• in patients without B symptoms
• who have not been given radiation previously or
• who relapse locally outside the initial radiation field.
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• 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
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• HDT/ASCT VS CONVENTIONAL CHEMOTHERAPY
• BRITISH NATIONAL LYMPHOMA INVESTIGATION
• Improved EFS and PFS with HDT/ASCT
• No improvement in OS
• TRM was high
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• Bad prognosis
• Less than 1 yr to relapse
• Presence of extanodal site at relapse
• B symptoms
• Stage at relapse
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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
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• Cyto reduction-
• With 2nd line chemotherapy before HDT/ASCT
• GVD ( gemcitabine, vinorelbine ,liposomal doxorubicine)
• GCD ( Gemcitabine, carboplatin, dexamethasone )
• Bendamustine, lenalidomide ,everolimus
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• 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
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RESPONSE CRITERIA
• Restaging after completion of chemotherapy
• To assess the response to therapy
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ROLE OF PET
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