Chemotherapy in

Hodgkin’s
Lymphoma
Moderator: Dr S C Sharma
Dept of Radiotherapy,
PGIMER, Chandigarh
Background
 The search for a magic
bullet called chemotherapy
began with Paul Ehrlich’s
description that some dyes
could be concentrated
within specific cell lines.
 Hodgkin’s Lymphoma,
described by Thomas
Hodgkin in 1832, is one of
the success stories in the
treatment of malignancies
and particularly with
chemotherapy.
Hodgkin’s Disease
 Uncommon: Accounts for ~ 1% of all
malignancies in developed countries.

 In India the disease usually strikes persons

between in the 2nd decade

 The mixed cellularity subtype is most common in

India.
Management Outline
Chemotherapy alone

Stage I & II A Combined Modality

Radiotherapy alone

Stage

CCT + Consolidation
Stage IIB, III & IV
Radiotherapy
Evolution of CCT
1st Generation 2nd Generation 3rd Generation 4th Generation

Single MOPP ABVD MOPP More intense

agents variants Alternating therapy ??

MOPP (USA) ABVD ABVD MOPP

Hybrids
COPP (UK)
Evolution of Rx
1. Clinical Staging equal to Surgical staging
2. Extended field radiotherapy equivalent to IFRT in
terms of overall survival.
3. Use of combined modality therapy reduced the
risk of failure but failed to improve the overall
survival.
4. ABVD showed to be better than MOPP alone and
equivalent to MOPP-ABV hybrid regimens.
Rationale for CCT
 Skipper’s Law:
 Doubling time of proliferating cancer cells is a constant,
forming a straight line on a semilog plot.
 Cell kill by drugs follows first-order kinetics
 A constant fraction of the cell population is killed by the drug every
time.
 From this model, the authors predicted that response to
chemotherapy would be dependent on tumor burden, drug
dose, and kinetics of residual tumor cells.
 Goldie Coldman Hypothesis:
 Based in the presumption that all tumors contain a population
resistant to chemotherapeutic drugs.
 If resistance involved two separate mechanisms then
simultaneous resistance to two drugs less likely.
 Forms the basis for multi drug & hybrid CCT regimens.
History of Chemotherapy in
HD
 During WW II an explosion in
Bairi, Italy exposed service men to S
the myelotoxic effects of mustard
gases.
 In one of the first recorded phase
II trials in medicine, Goodman and
Gilman used a derivative of these
gases called Nitrogen mustard in
the treatment of patients of HD
and Lymphosarcoma at Yale
University (1943).
 In 1947-50 a series of papers by
Dameshek et al and Albert et al
proved that this agent was
effective in HD.
Principles of CCT
 Drugs known to be active as single agents should be selected,
especially those that have produced some complete remissions
 Drugs should be given in doses at or above minimally effective
doses.
 Drugs with different mechanisms of action should be
combined. This should, in theory, allow multiple attacks on the
biochemistry of the cancer cell, with additive, perhaps even
synergistic, effect
 Drugs with different dose-limiting toxicities should be
combined so that each drug can be given at or near full
therapeutic doses.
 Drugs with different patterns of resistance should be
combined.
 A set frequency of administration should be used to eliminate
resistant cell lines as they emerge during replication. Drugs
with overlapping toxicities can cause treatment delay defeating
this purpose too.
Overview of Single
agents used in
Hodgkin’s Disease
Single Agents Used
 Alkylating Agents  Anthracyclines:
 Nitrogen Mustard  Adriamycin
 Chlorambucil  Platinum Analogues:
 Cyclophosphamide  Cisplatin
 Vinca Alkaloids  Podphyllotoxins:
 Vincristine  Etoposide (VP -16)
 Vinblastine  Bleomycin
 Non Classic Alkylating
agents:
 Procarbazine
 Dacarbazine
 BCNU
Efficacy of Single Agents
0 10 20 30 40 50 60 70 80

Nitrogen Mustard
Vincristine
Procarbazine
Prednisone
Cyclophosphamide
Chlorambucil
% RR
Vinblastine
%CR
BCNU
Doxorubicin
Bleomycin
DTIC
Etoposide
Cisplatin
Dose and Administration
Agent Dose Route Frequency
Nitrogen Mustard 0.2-0.4 mg/kg IV 4-6 weeks
Vincristine 0.2 mg/kg IV Weekly
Procarbazine 50-150 mg/kg/d PO Daily
Cyclophosphamide 2 mg/kg/d PO Daily
Chlorambucil 0.2 mg/kg/d PO Daily
Vinblastine 0.2 mg/kg/wk IV Weekly
Doxorubicin 30-60 mg/m2 IV 3-4 weekly
Bleomycin 5 mg/m2 IV Variable
DTIC 200 mg/m2 IV Daily x 5, Variable
Etoposide 50-120 mg/m2 IV Daily x 5, Variable
Cisplatin 75 mg/m2 IV 3-4 weekly
Mechanisms of Action
Alkylating Agents DNA alkylation & DNA cross linking

Disruption of Microtubules with Mitotic

Vinca Alkaloids arrest

Topoisomerase II dependant DNA

Anthracyclines cleavage

Single strand DNA breaks & premitotic

Non classic
Class G2 block ; 06-Methylguanine mediated
Alkylating agents cellular cytotoxicity.

Podphyllotoxins Topoisomerase II inhibitors

Cisplatin DNA adducts and crosslinks

Bleomycin Direct DNA damage

Toxicity
Agent Dose Limiting Toxicity
Nitrogen Mustard BMT, N&V, Leukemogenic
Vincristine Neurotoxicity, constipation & ANS disturbance
Procarbazine BMT, N&V, Leukemogenic, Infertility, Psychotic
reactions, hypertensive crisis with MAO inhibitor
Cyclophosphamide BMT (Thrombocytopenia), SIADH, N&V, Bladder
toxicity
Chlorambucil BMT (Neutropenia, Anemia), N&V, Leukemia
Vinblastine BMT (Neutropenia), Mucositis, Hypertension
Doxorubicin BMT, Alopecia, N&V, Diarrhea, Cardiac, RT recall
Bleomycin Fever, Skin toxicity, Pulmonary toxicity
DTIC BMT, Flu like syndrome , Hepatic vein thrombosis
Etoposide BMT (leucopenia & neutropenia), Leukemia
Cisplatin Neurotoxicity, Ototoxicity, Nephrotoxicity
Problems with Single agents
 Response rates were in the order of 50-60%
 CR were much lower in the tune of 10-30%
 Responses were not durable with unmaintained
remissions lasting ~ 3 months.
 Patients on maintenance chemotherapy had
remissions lasting for ~ 8 months.
 Therefore multiagent CCT began to be developed.
Advent of Combination
Chemotherapy in
Hodgkin’s Disease
MOPP
 Devised by Devita and Longo in TLC Platelet Dose
1970s (lacs) adjustment
 Doses:
 Nitrogen Mustard 6 mg/m2 I/V D1 and > 4000 > 1.3 100% all drugs
D8
 Vincristine (Oncovine) 1.4 mg/m2 IV ≥ 3000 ≥1 100% VCR & PRED
D1 and D8 50% HN2 & PROC
 Procarbazine 100 mg/m2 D1 to D14
≥ 2000 ≥ 0.8 100% PRED
 Prednisone 40 mg/m2 D1 to D 14
50% VCR
 Cycles repeated every 28 days for 6
25% HN2 & PROC
such cycles
 Main features: ≥ 1500 ≥ 0.5 100% PRED
 1st CCT regimen to be started with a 25% VCR
CURATIVE intent
 6 month treatment program < 1500 < 0.5 100% PRED
 Sliding dosage scale devised to
combat bone marrow toxicity.
 All drugs had non overlapping
toxicities and mechanisms of action.
COPP
 Almost simultaneously COPP was developed in
the United Kingdom
 It used:
 Cyclophosphamide 650 mg/m2 D1 and D8
 Vincristine 1.5mg/m2 D1 and D8
 Procarbazine 100 mg/m2 D1 to D 14
 Prednisone 40 mg/m2 D1 to D 14
MOPP : Results
 CR of 81% documented
 Long term disease free survival
rates (10 yrs) in the range of 56%
(47% by actuarial analysis)
 19% of patients attaining CR died
of intercurrent illnesses unrelated
to HD.
 National mortality figures for
Hodgkin lymphoma decreased by
more than 60% in the decade that
followed the introduction of MOPP
chemotherapy.
 Thus, MOPP chemotherapy became
the gold standard of care for Actuarial survival analysis of HD
patients with Stage III / IV patients treated with MOPP
Hodgkin’s Disease. regimen
Toxicity of MOPP
 A highly toxic regimen
 Special precautions indicated while handling nitrogen
mustard – can cause vesication on contact with skin or
mucosa.
 Main dose limiting toxicity is myelopsuppresssion and it
may appear as early as 24 hrs after drug administration.
 Prior to availability of effective anti emetic agents nausea
and vomiting were severe enough to merit indoor
admission in all patients prior to chemotherapy.
 Additional late toxicity also substantial:
 2nd malignancies : Hematological
 Infertility and premature menopause
 Neurotoxicity : Due to vincristine
Overcoming MOPP toxicity
 3 main approaches have been tried:
 Reduction of dose intensity / elimination of drugs from
the regimen
 Using alternate alkylating agents
 Development of newer CCT regimens.
Dose reduction / Drug
elimination
 Initial combinations attempted to eliminate procarbazine or
nitrogen mustard.
 However CR only 45%1 when any of these two drugs are
eliminated.
 A dose response analysis2 revealed that dose of all three
drugs (mustard, vincristine, and procarbazine), and the
rate of drug delivery during the first three cycles are
important in achieving maximal complete response rates,
especially for patients with B-symptoms.
 Another trial3 showed that CR dropped from 80% to 45% in
stage IV lymphoma when prednisone was omitted.
 Thus 3 drug combinations were definitely less effective
when compared to MOPP regimen.
Alternate regimens: ChlVPP
(LVPP)
 Because procarbazine and nitrogen mustard are the two
main toxic drugs people have attempted to replace them
 Several such combinations tried but only one proved
useful: ChlVPP (LVPP) regimen
 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
ABVD
 The four-drug combination of Doxorubicin, Bleomycin,
Vinblastine, and Dacarbazine (ABVD) was developed by
Bonadonna et al at the Istituto Nazionale Tumori in Milan.
 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.
ABVD Schedule
 Dosage and Frequency:
 Adriamycin 25 mg/m2 IV D1 and D14
 Bleomycin 10 U/m2 IV D1 and D14
 Vinblastine 6 mg/m2 IV D1 and D14
 Dacarbazine 375 mg/m2 D1 and D14
 The authors suggested a D1 and D15 schedule for a
minimum of 6 cycles every 28 days.
 Initial 3 patients treated with D1 and D8 schedule had
consistent leucopenia at D 8 and so a D1 and D14 schedule
was adopted.
 Also the original schedule had DTIC administered in the
doses of 150 mg/m2 D1 to D5 which was later changed to
the present schedule.
ABVD results and toxicity
 Comparable response rates of Toxicity MOPP ABVD
75% vs 76% in ABVD vs Leucopenia 56% 45%
MOPP. Thrombocytopenia 16% 15%
 Toxicity was moderately lower Paraesthesias 72% 5%
with ABVD Loss of Hair 48% 75%
 Authors concluded ABVD was Skin Changes - 40%
suitable for patients who had
failure after MOPP and
succeeded in proving it’s non
cross resistance with MOPP.
MOPP & ABVD combinations
 In view of the efficacy of ABVD which was also
cross resistant and the then postulated Goldie
Coldman hypothesis it was thought that giving all
the active non cross resistant drugs given quickly
in the initial part of the treatment would enhance
the chances of a cure.
 Milan again introduced the concept of alternating
MOPP and ABVD in 1980s and several other trials
were conducted to evaluate this.
 Another approach was the introduction of MOPP
ABV hybrids. The aim of the hybrid regimens was
to introduce all the active drugs early in the
treatment to ensure max probability of cure.
Alternate regimens: Results
 MOPP – ABVD are given alternately every 4 or 8 weeks for
12 such cycles.
 Somers et al, Canellos et al and Anderson et al compared
this sequence against MOPP / ABVD alone.

Author Regimens Stage N CR FFS OS

Canellos MOPP x 6 - 8 III A/B 123 67% 51% 66%
et al – ABVD x 6 - 8 IV A/B 115 82% 61% 73%
(CALGB)1
MOPP/ABVD x 12 Relapse 123 83% 65% 75%
Somers MOPP x 8 IIIA 96 57 % 43 % 57 %
et al2 MOPP (2) – ABVD (2) x 8 IVA/B 96 59 % 60 % 65 %
Anderson MOPP x 6-8 III A/B 69 % 48 % 66 %
et al ABVD x 6-8 IV A/B 81 % 64 % 74 %
(NCI)3
MOPP /ABVD x 6-8 Relapse 82 % 64 % 76 %
Alternate regimens: Results
Hybrid Regimens
 In these MOPP and ABV are given simultaneously.
 DTIC is omitted from ABVD due to overlapping toxicity with
procarbazine.
 Hybrid regimen introduced by Kilmo and Connors1
 Best results till date as far as response rates were
concerned.
 Dose Schedule:
 Nitrogen Mustard 6 mg/m2 IV D1
 Vincristine 1.4 mg/m2 IV D1 1st half of MOPP
 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 2nd half of ABV
 Bleomycin 10 U/m2 IV D8
Hybrid Regimens: Results
Author Regimen N Stage CR FFS OS
Connors MOPP-ABV x 8-12 153 Relapse 80 % 71 % 81 %
et al MOPP/ABVD x 8-12 148 IIIB , IVA 76 % 67 % 83 %
Glick et al MOPP-ABV x 6-12 347 Relapse 83 % 64 % 77 %
MOPP x 6  ABVD x 3 344 III & IV 75 % 54 % 69 %

 However in both these studies MOPP ABV was associated with

significantly higher number of higher incidence of
myelopsuppresssion and pulmonary reactions.
 Lesser incidence of leukemia in hybrid regimen (1 vs 9 in
sequential) observed in the trial by Glick et al lend support to the
importance of alkylating agent in the pathogenesis of this S/E
 More importantly results from Glick et al demonstrated that
withholding Adriamycin in the initial part of the therapy may be
detrimental.
Lessons from Alternate/Hybrid
regimens
 Programs that include elements of ABVD are
associated with less toxicity and greater efficacy
than MOPP alone
 Little differenceStage
in efficacy between the programs
set for
that incorporated elements of
evaluation of both ABVD and
MOPP single agent
 Hybrid regimensABVDwhile alone
increasing the response
rates failed to increase the OS.
 At the same time both hybrid and alternate
administration is associated with significant
toxicities.
ABVD alone: Results
 Trials by Canellos et and
Anderson et al had already
demonstrated that ABVD
alone was better than MOPP
alone in terms of CR , FFS
and OS.
 Duggan et al compared ABVD
alone vs MOPP-ABV hybrid in
an intergroup trial
randomizing 875 patients.
 CR: 71% with ABVD (73% for
MOPP-ABV), P = NS
 FFS: 65% with ABVD (67%
for MOPP-ABV), P = NS
 OS: 85% with ABVD (87% for
MOPP-ABV), P = NS
ABVD alone : Toxicity
Toxicity ABVD (%) MOPP ABV (%) P
In Treatment
Pulmonary (Gr II or more) 24.5 30.6 NS
Cardiac (Gr II or more 6.6 7.5 NS
Hematological (Gr III or more) 63.6 74.6 S
Anorexia (Gr III or more) 0.2 3.2 S
Fatigue (Gr III or more) 1.7 5.7 S
Hypotension (Gr III or more) 0 1.7 S
After Treatment
Cardiac (Gr II or more) 8.3 9.3 NS
Pulmonary (Gr II or more) 3.3 2.9 NS
Hematological (Gr III or more) 5.0 11.3 S
ABVD alone : Toxicity
 15 deaths during initial therapy on the MOPP/ABV arm and nine
on the ABVD arm (P = .057)
 In 6 years 25 treatment related deaths seen in hybrid arm
compared to 15 in ABVD arm
 3/4ths of these deaths were in patients older than 55 years
 46% of those older than 40 years who received MOPP/ABV
developed pulmonary toxicity, compared with 30% on the ABVD
arm (P = .068)
 Significantly more patients receiving MOPP/ABV who experienced
pulmonary toxicity necessitated dose adjustment or elimination of
bleomycin.
 46 second malignancies have been recorded, 18 in patients
treated with ABVD and 28 in patients treated with MOPP/ABV (P =
0.13)
 11 cases of MDS or acute myelogenous leukemia (AML) in
patients randomized to the hybrid arm and 2 among patients
randomized to ABVD (P = .011).
Use of CCT in Early
Hodgkin’s Disease
Limited stage disease
 Definition:
 Nonbulky Stage IA
 Nonbulky Stage IIA
 Important features:
 Almost 90-95% cure rates expected.
 Disease is radiosensitive and radiocurable
 Also chemosensitive and chemocurable
 Relapses rare and easily salvaged
 Optimization of treatment needed:
 Reduce long term side effects
 Maintain cure rates
 Deliver Rx in the most cost effective manner.
MOPP vs Radiation: 1970s
Author Regimen Stage RFS OS
Longo et al MOPP x 6 I A/B , II A/B 86% (10 yr) 92% (10 yr)
(NCI) EXRT III1A 60% (10 yr) 75% (10 yr)
Cimino et al MOPP x 6 IA , IB, IIA 71% (8 yr) 56% (8 yr)
(Italy) EXRT 70% (8 yr) 93% (8 yr)

 Results 3 trials showed that MOPP or variants alone were

not superior in early stage disease.
 MOPP CCT was also associated with:
 Greater incidence of S/E
 Poorer results for salvage after failure.
 Greater incidence of 2nd malignancies.
Mortality in Limited Stage
Disease
 In 1989, a pooled analysis of outcome of 9000
patients with HD carried out.
 22% had died at 20 yrs.
 In the 1st decade most deaths : Hodgkin’s Disease
 In the 2nd decade : Other causes.
 Frequency of death due to “other causes” more
than expected in general population.
 Most important other causes:
 Cardiovascular disease
 2nd malignancies
Role of CCT in Limited Stage
 Cure rates with Radiation alone have ranged from
90% in stage IA to 80% in stage IIA.
 The late consequences of RT :
 2nd malignancies: 10-15 % overall risk at 10 years.
 Increased risk of breast cancer in young females: 35%
incidence by 40 yrs age.
 Heart disease
 Approaches to reduce these toxicities:
 Reduction in radiation field size / dose
 Using CMT to reduce the toxic potential of both RT and
CCT.
 Use CCT alone.
Combined Modality
approach
Author Regimen Stage RFS OS
Pavalovsky et CVPP x 6 I & II (A &B) 62% (7 yr) 82% (7 yr)
al CVPP + RT 71% (7 yr) 89% (7 yr)
Zittoun et al MOPP + IFRT I & II (A & B) 90% (6 yr) 93% (6 yr)
MOPP + EFRT III A 86% (6 yr) 90% (6 yr)

 The trial conducted by Zittoun et al revealed that EFRT was

equivalent to IFRT when combined with 3-4 cycles of MOPP.
 Pavalovsky et al also showed that CMT resulted in a slightly
better RFS but overall survival remains same.
Combined Modality...
 ABVD was initially evaluated with RT in early
stage disease.
 Santaro et al established that 4 cycles of ABVD
produced equally good results when combined
with IFRT or STNI.
 4 yr DFS was ~ 95% in both arms
 4 yr OS was 100% in both arms
 Another trial by EORTC (H7) evaluated EBVP x 6
cycles + IFRT vs EFRT alone in patients with
favourable disease:
 6 yr RFS better in CMT arm (92% vs. 81%,; P = .004)
 6 yr OS was similar in both arms 98% vs. 96%,; P =
0.156)
Number of ABVD cycles
Trial Design
GHSG HD7 EFRT 30 Gy (IFRT 40 Gy)
2 ABVD + EFRT 30 Gy (IFRT 40 Gy)
SWOG AV + STLI (S) (36–40 Gy)
9133 STLI (S) (36–40 Gy)
GHSG 2 ABVD + IFRT (30 Gy)
HD10 2 ABVD + IFRT (20 Gy)
4 ABVD + IFRT (30 Gy)
4 ABVD + IFRT (20 Gy)
Outcome
FFTF 75% OS 94% (5y)
FFTF 91% OS 94% (5y)
FFTF, 94% OS 98% (3y)
FFTF, 81% OS 96% (3y)
Results similar across all
4 arms with FFTF ~ 96%
and OS at 2 yrs ~ 99%.
Conclusions
 Combined modality approach reduces the number of
recurrences but the overall survival remains same when
compared to RT alone.
 Extended field radiotherapy is equivalent to involved field
radiotherapy in this group.
 2 - 4 cycles of ABVD with RT are enough to:
 Eliminate occult HL in the abdomen
 Prevent recurrence of HL in apparently uninvolved sites
adjacent to known HL
 Questions that remain to be answered are:
 Is the added benefit in terms of freedom from relapse
worthwhile in terms of the added toxicity of the additional CCT
 Are failures after CCT + IFRT more difficult to treat than
failures after RT alone.
 Was CCT alone better than combined modality approach
ABVD alone vs Combined
Modality
Author Design FFP OS
NCIC/ECOG HD61 ABVD x 4-6 88% (5 yrs)
NS
ABVD x 2 + STLI 95% (5 yrs)
MSKCC2 ABVD x 6 81% (5yrs)
NS
ABVD x 6 + EF/IF 86% (5yrs)
Laskar et al3 ABVD x 6 76% (8yrs) 89%
ABVD x 6 + IFRT 88% (8yrs) 100%
Conclusions
 One trial reported from India has shown that addition of
consolidation RT after CCT results in better OS also.
 However results were for all stages and like the Indian
scenario:
 Mixed cellularity is the most common histologic subtype
 Most patients were between 15-20 yrs age.
 Trial with shorter duration of F/U have failed to show a
benefit in OS ( ? Artifact of good results of salvage)
 However unquestionably 70-80% patient with early stage
disease don’t require additional RT after 6 cycles of CCT
with ABVD.
Unfavorable Early disease
 The 3 factors consistently identified to be
associated with a poor prognosis in HD are:
 Bulky Mediastinal Disease
 Presence of B symptoms
 Older age
 Approximately 20% patient relapse when treated
with EFRT alone.
 So CCT identified as a modality to treat these
patients.
Trial results
Author Regimen Outcome
EORTC H6U 3 MOPP + mantle RT + 3 MOPP FFP 76% (8 yrs)
3 ABVD + mantle RT + 3 ABVD FFP 88% (8 yrs)*
Milan 3 MOPP + STLI/TLI + 3 MOPP FFP 66% (5yrs)
3 ABVD + STLI/TLI + 3 ABVD FFP 72% (5yrs)
GALTA 3 CVPP + IFRT (30 Gy) + 3 CVPP EFS 85% (5yrs)
3 AOPE + IFRT (30 Gy) + 3 AOPE EFS 66% (5yrs)*
EORTC H7U 6 EBVP II + IFRT (36 GY) EFS 68% (6yrs)
6 MOPP/ABV + IFRT EFS 90% (6yrs)
GHSG HD11 4 ABVD + IFRT (30 Gy) Results equivalent
4 ABVD + IFRT (20 Gy) across all 4 arms at
2yrs with OS of 97%
4 BEACOPP + IFRT (30 Gy) and FFS at 90%
4 BEACOPP + IFRT (20 Gy)
Conclusions
 Addition of radiation to bulky sites is definitely a
good treatment option in those patients who
show a partial response to CCT.
 IFRT customized to the reduced bulk of the
disease and doses to the tune of 15-30 Gy are
adequate.
 Radiation alone is no longer a option.
 Chemotherapy when used alone may give poor
results as compared to Combination Rx as shown
by another GALTA trial.
 Chemotherapy in
Advanced Hodgkin’s
disease
Advanced Disease
 The role of Chemotherapy in advanced disease
has already been shown.
 ABVD alone results in good results in advanced
disease.
 The standard number of cycles is 6-8 cycles
(originally 2 more cycles after attaining CR as
recommended by Bonadonna et al)
 A recent CALGB (Canellos et al) trial found 6 - 8
cycles and 12 cycles to be comparable.
 The question is whether RT needs to be added to
CCT in advanced HD
Radiation in Advanced
Disease
 Loeffler et al in a metaanalysis of 14 trials
showed that
 Additional RT showed an 11% overall improvement in
tumor control rate after 10 years (P = .0001).
 No difference could be detected with respect to overall
survival (P = .57).
 Also they found an inferior survival if patients were
treated with RT instead of more CCT after completion of
a planned course of CCT (P = .045; 8% difference).
Radiation in Advanced
disease
 However there were several fallacies in this meta-
analysis as summarized by Prosnitz et al:
 Only 6 of the 14 trials were published as primary
manuscripts
 In the largest of the included trials conducted by SWOG:
 Patients were randomized to RT after CR but not after PR
 Patients with PR had similar OS and FFS as patients with
CR
 Other trials included in the meta-analysis were not
designed to evaluate the role of radiotherapy per se.
 Many trials also used MOPP based chemotherapy and
EFRT – no longer used.
Conclusions
 ABVD forms the standard CCT regimen for use in advanced
stages of Hodgkin’s Lymphoma as:
 Similar CR rates as hybrid regimens.
 Similar RFS and OS as hybrid regimens.
 60% to 70% of patients are free of disease at 5 year
 Salvage therapy is equally effective in failures.
 Acute as well as late toxicities reduced.
 Dose and schedule alterations due to toxicities reduced.
 Lesser leukemogenic risk.
 Reproductive function better maintained.
 Radiotherapy plays an adjunctive or additive role being
used in doses of 15-25 Gy as IFRT where partial response
is obtained after completion of course of CCT.
 More Intense
Chemotherapy: Is
more better?
More “Intense” regimens
 In an effort to improve the results seen with ABVD
attempts were made to:
 Increase the number of drugs given simultaneously
 Shorten the period of administration so that greater dose could
be given in a shorter period of time.
 One particular concern was bleomycin induced long term
pulmonary toxicity in children when combined with radiation
which could be circumvented by use of etoposide.
 Etoposide also had a 20-60% RR in refractory HL and hence
was used in all these regimens
 Dose Intensity: Increasing the dose or the frequency of
administration of CCT
 Dose Density: Increasing both the frequency and dose
together.
BEACOPP and variants
Drug Dose Days Drug Dose Days
BEACOPP 21 BEACOPP Increased Dose 22
Bleomycin 10 8 Bleomycin 10 8
Etoposide 100 1–3 Etoposide 200 1-3
Adriamycin 25 1 Adriamycin 35 1
Cyclophosphamide 650 1 Cyclophosphamide 1250 1
Oncovin (vincristine) 1.4 8 Oncovin 1.4 8
Procarbazine 100 1–7 Procarbazine 100 1-7
Prednisone 40 1–14 Prednisone 40 1-14
G-CSF —
Results BEACOPP
 The HD 9 trial evaluated BEACOPP vs COPP-ABVD and escalated
BEACOPP.
 Complete response rates were comparable:
 83% for COPP-ABVD,
 88% for BEACOPP
 96% for escalated BEACOPP
 Freedom from failure at 5yrs is improved with escalated
BEACOPP at 2 yrs p = 0.0001 as compared to COPP-ABVD (85%
vs 67%).
 Toxicity:
 Treatment related deaths were approximately 3%.
 16 of the 454 BEACOPP patients, including 11 who received escalated-
dose therapy, have developed myelodysplasia or acute leukemia.
 100% infertility in men
 100% infertility plus premature menopause in most women over the
age of 25 years
Stanford Regimen
Week M A V E O B P
Drug Dose
1    
Stanford
2   
Meclorethamine (M) 6
3    
Adriamycin (A) 25
4   
Vinblastine (V) 6
5    
Vincristine (O) 1.4
6   
Bleomycin (B) 5
7    
Etoposide (E) 60 x 2
Prednisone (P) 40 8   

G-CSF — 9    
10   
11   
12  
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
 Hospitalization for neutropenic fever occurred in 17% of
patients and for severe obstipation, 11%.
 Severe but reversible neurotoxicity was also common.
 1/3rd of the patients required blood transfusions.

 However most patients have retained fertility and acute

pulmonary toxicity was not seen.
Is ABVD inferior ?
 Gobbi et al compared ABVD with MOPPEBVCAD
against Stanford V regimen in 353 patients with
stage III or IV disease
 Radiotherapy was administered to bulky sites ABVD
or sites with partial response. MOPPEBVCAD
 Results Stanford V
 The CR with ABVD alone was 70% (compared to
38% and 56% for the other two regimens)
 RT was required more frequently for Stanford V
to assure CR than ABVD.
 Stastically significant severe myelotoxicity for
Stanford V and MOPPEBVCAD regimen (almost
doubled)
 3 treatment related deaths seen in MOPPEBVCAD
arm and 4 patients had to discontinue treatment
due to sever acute toxicity in Stanford V arm.
ABVD
 Dose intensity maintained best in ABVD arm
 Of the 12 patients who died in CR, 1 was in the MOPPEBVCAD
ABVD arm, 3 were in the modified Stanford V Stanford V
arm, and 8 were in the MOPPEBVCAD arm.
Chemotherapy in
special settings
Salvage Chemotherapy
 Most frequent ~ 2-5 yrs.
 3 types of failures known:
 Primary Progressive HL : ~ 10% of all diagnosed
 Early relapse ( < 12 months): 15% patients
 Late relapse: 15% patients
 Early recurrence usually implies resistance to the
original regimen.
 By proxy it also implies a very poor survival and
prognosis.
Treatment of recurrence
Type

Post RT Post CCT RT

CCT alone Late Relapse Early Relapse

with ABVD Primary Progressive HL

Salvage
CCT

High Dose CCT with

stem cell support
Regimens used
Regimen No. RR RFS
(%) (%)
CEP 58 54 16
CEVD 32 48 22
Dexa-BEAM 56 56 25
Mini-BEAM 44 84 36
MIME 47 63 8
DHAP 19 68 ne
ASHAP 56 70 40
MINE 100 75 46
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)
 No diff if TBI or CCT based preparative regimens are used.
 While diff exist in RFS these don’t translate into survival
differences
 Complications:
 Treatment related mortality : 14% -5%
 Infections: Early and delayed
 MDS / AML risk : 4% -15% within 5yrs.
 Cardiac and Pulmonary complications
 Sterility : Universal
Chemotherapy in Children
 ABVD remains the regimen of choice.
 However the pulmonary toxicity of bleomycin is a major
source of concern.
 While other regimens have been developed which replace
Bleomycin with etoposide the leukemogenic risk of the
latter is a potential concern.
 Radiotherapy is usually avoided to prevent late sequels
including growth disturbances and carcinogenesis.
 ABVD is associated with lesser gonadal toxicity than MOPP.
 Trials have found that reliable cure can be expected with
regimens like VBVP (vinblastine, bleomycin, etoposide, and
prednisone) in early stage disease while avoiding the
toxicity from alkylating agents and anthracycline.
 The VAMP regimen avoids bleomycin and uses
Methotrexate.
Conclusion: Primum non
nocere
 Unlike other malignancies HL can be cured.
 After living for 15-20 yrs many of the deaths will
be due to treatment related complications.
 ABVD given for 6 cycles holds the promise of
providing the best cure rates with the least
morbidity.
 Radiotherapy should be used only in selected
indications: Failure to attain CR and bulky
mediastinal disease.