Chemotherapy in Hodgkin’s Lymphoma

Moderator: Dr S C SharmaDept 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

Stage

Stage I & II A

Stage IIB, III & IV

Radiotherapy alone

Chemotherapy alone

Combined Modality

CCT + Consolidation Radiotherapy

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

Evolution of Rx1. Clinical Staging equal to Surgical staging2. 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 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.

S

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

Nitrogen Mustard Chlorambucil Cyclophosphamide

Vinca Alkaloids Vincristine Vinblastine

Non Classic Alkylating agents: Procarbazine Dacarbazine BCNU

Anthracyclines: Adriamycin

Platinum Analogues: Cisplatin

Podphyllotoxins: Etoposide (VP -16)

Bleomycin

Efficacy of Single Agents0 10 20 30 40 50 60 70 80

Nitrogen Mustard

Vincristine

Procarbazine

Prednisone

Cyclophosphamide

Chlorambucil

Vinblastine

BCNU

Doxorubicin

Bleomycin

DTIC

Etoposide

Cisplatin

% RR

%CR

Dose and AdministrationAgent 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

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 ; 06-Methylguanine mediated

cellular cytotoxicity.

Topoisomerase II inhibitors

DNA adducts and crosslinks

Direct DNA damage

ToxicityAgent Dose Limiting ToxicityNitrogen 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 1970s 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 28 days for 6 such cycles

Main features: 1st CCT regimen to be started with a

CURATIVE intent 6 month treatment program Sliding dosage scale devised to

combat bone marrow toxicity. All drugs had non overlapping

toxicities and mechanisms of action.

TLC Platelet(lacs)

Dose adjustment

> 4000 > 1.3 100% all drugs

≥ 3000 ≥ 1 100% VCR & PRED50% HN2 & PROC

≥ 2000 ≥ 0.8 100% PRED50% VCR25% HN2 & PROC

≥ 1500 ≥ 0.5 100% PRED25% VCR

< 1500 < 0.5 100% PRED

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 patients with Stage III / IV Hodgkin’s Disease.

Actuarial survival analysis of HD patients treated with MOPP

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

75% vs 76% in ABVD vs MOPP.

Toxicity was moderately lower with ABVD

Authors concluded ABVD was suitable for patients who had failure after MOPP and succeeded in proving it’s non cross resistance with MOPP.

Toxicity MOPP ABVD

Leucopenia 56% 45%

Thrombocytopenia

16% 15%

Paraesthesias 72% 5%

Loss of Hair 48% 75%

Skin Changes - 40%

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 et al –(CALGB)1

MOPP x 6 - 8 III A/BIV A/BRelapse

123 67% 51% 66%

ABVD x 6 - 8 115 82% 61% 73%

MOPP/ABVD x 12 123 83% 65% 75%

Somers et al2

MOPP x 8 IIIAIVA/B

96 57 % 43 % 57 %

MOPP (2) – ABVD (2) x 8 96 59 % 60 % 65 %

Anderson et al (NCI)3

MOPP x 6-8 III A/BIV A/BRelapse

69 % 48 % 66 %

ABVD x 6-8 81 % 64 % 74 %

MOPP /ABVD x 6-8 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 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

1st half of MOPP

2nd half of ABV

Hybrid Regimens: Results

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.

Author Regimen N Stage CR FFS OS

Connors et al

MOPP-ABV x 8-12 153 RelapseIIIB , IVA

80 % 71 % 81 %

MOPP/ABVD x 8-12 148 76 % 67 % 83 %

Glick et al MOPP-ABV x 6-12 347 RelapseIII & IV

83 % 64 % 77 %

MOPP x 6 ABVD x 3 344 75 % 54 % 69 %

Lessons from Alternate/Hybrid regimens Programs that include elements of ABVD are

associated with less toxicity and greater efficacy than MOPP alone

Little difference in efficacy between the programs that incorporated elements of both ABVD and MOPP

Hybrid regimens while increasing the response rates failed to increase the OS.

At the same time both hybrid and alternate administration is associated with significant toxicities.

Stage set for evaluation of single agent ABVD alone

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 : ToxicityToxicity 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

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.

Author Regimen Stage RFS OS

Longo et al (NCI)

MOPP x 6 I A/B , II A/BIII1A

86% (10 yr) 92% (10 yr)

EXRT 60% (10 yr) 75% (10 yr)

Cimino et al (Italy)

MOPP x 6 IA , IB, IIA 71% (8 yr) 56% (8 yr)

EXRT 70% (8 yr) 93% (8 yr)

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 al

CVPP x 6 I & II (A &B) 62% (7 yr) 82% (7 yr)

CVPP + RT 71% (7 yr) 89% (7 yr)

Zittoun et al MOPP + IFRT I & II (A & B)III A

90% (6 yr) 93% (6 yr)

MOPP + EFRT 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 cyclesTrial Design Outcome

GHSG HD7 EFRT 30 Gy (IFRT 40 Gy) FFTF 75% OS 94% (5y)

2 ABVD + EFRT 30 Gy (IFRT 40 Gy) FFTF 91% OS 94% (5y)

SWOG 9133

AV + STLI (S) (36–40 Gy) FFTF, 94% OS 98% (3y)

STLI (S) (36–40 Gy) FFTF, 81% OS 96% (3y)

GHSG HD10

2 ABVD + IFRT (30 Gy) Results similar across all 4 arms with FFTF ~ 96% and OS at 2 yrs ~ 99%.

2 ABVD + IFRT (20 Gy)

4 ABVD + IFRT (30 Gy)

4 ABVD + IFRT (20 Gy)

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 resultsAuthor 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 across all 4 arms at 2yrs with OS of 97% and FFS at 90%

4 ABVD + IFRT (20 Gy)

4 BEACOPP + IFRT (30 Gy)

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 variantsDrug 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 RegimenDrug Dose

Stanford

Meclorethamine (M) 6

Adriamycin (A) 25

Vinblastine (V) 6

Vincristine (O) 1.4

Bleomycin (B) 5

Etoposide (E) 60 x 2

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

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 or sites with partial response.

Results 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.

Dose intensity maintained best in ABVD arm Of the 12 patients who died in CR, 1 was in the

ABVD arm, 3 were in the modified Stanford V arm, and 8 were in the MOPPEBVCAD arm.

ABVD

MOPPEBVCAD

Stanford V

ABVD

MOPPEBVCAD

Stanford V

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 recurrenceType

Post RT Post CCT

CCT alone with ABVD

RT

Salvage CCT

High Dose CCT with stem cell support

Late Relapse Early RelapsePrimary Progressive HL

Regimens usedRegimen 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.