Chemotherapy In Hd

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

Stage IIB, III & IV

CCT + Consolidation Radiotherapy

Evolution of CCT 1st Generation 2nd Generation

Single agents

ABVD MOPP Alternating

MOPP variants

MOPP (USA) COPP (UK)

3rd Generation

ABVD

ABVD MOPP Hybrids

4th Generation

More intense therapy ??

Evolution of Rx 1. 2. 3.

4.

Clinical Staging equal to Surgical staging Extended field radiotherapy equivalent to IFRT in terms of overall survival. Use of combined modality therapy reduced the risk of failure but failed to improve the overall survival. 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   



Vinca Alkaloids  



Nitrogen Mustard Chlorambucil Cyclophosphamide Vincristine Vinblastine

Non Classic Alkylating agents:   

Procarbazine Dacarbazine BCNU



Anthracyclines: 



Platinum Analogues: 



Cisplatin

Podphyllotoxins: 



Adriamycin

Etoposide (VP -16)

Bleomycin

Efficacy of Single Agents 0

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 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

Class

Alkylating Agents

DNA alkylation & DNA cross linking

Vinca Alkaloids

Disruption of Microtubules with Mitotic arrest

Anthracyclines

Topoisomerase II dependant DNA cleavage

Non classic Alkylating agents

Single strand DNA breaks & premitotic G2 block ; 06-Methylguanine mediated 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 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 & PRED 50% HN2 & PROC

≥ 2000

≥ 0.8

100% PRED 50% VCR 25% HN2 & PROC

≥ 1500

≥ 0.5

100% PRED 25% 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

56%

45%

Thrombocytopenia 16%

15%

Paraesthesias

72%

5%

Loss of Hair

48%

75%

Skin Changes

-

40%

Leucopenia

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/B IV A/B Relapse

123

67%

51%

66%

115

82%

61%

73%

123

83%

65%

75%

Somers et al2

MOPP x 8

96

57 %

43 %

57 %

96

59 %

60 %

65 %

Anderson et al (NCI)3

MOPP x 6-8

69 %

48 %

66 %

81 %

64 %

74 %

82 %

64 %

76 %

ABVD x 6 - 8 MOPP/ABVD x 12

IIIA MOPP (2) – ABVD (2) x 8 IVA/B ABVD x 6-8 MOPP /ABVD x 6-8

III A/B IV A/B Relapse

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 Author

Regimen

N

Stage

CR

FFS

OS

Connors et al

MOPP-ABV x 8-12

153

80 %

71 %

81 %

MOPP/ABVD x 8-12

148

Relapse IIIB , IVA

76 %

67 %

83 %

Glick et al

MOPP-ABV x 6-12

347

83 %

64 %

77 %

MOPP x 6  ABVD x 3

344

Relapse 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 of both ABVD and evaluation MOPP single agent Hybrid regimensABVD while 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

6.6

7.5

NS

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

0

1.7

S

Cardiac (Gr II or more Hematological (Gr III or more)

Hypotension (Gr III or more)

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:  



Important features:    



Nonbulky Stage IA Nonbulky Stage IIA 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

Longo et al (NCI)

MOPP x 6

Cimino et al (Italy)





Stage

RFS

OS

86% (10 yr)

92% (10 yr)

EXRT

I A/B , II A/B III1A

60% (10 yr)

75% (10 yr)

MOPP x 6

IA , IB, IIA

71% (8 yr)

56% (8 yr)

70% (8 yr)

93% (8 yr)

EXRT

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

Pavalovsky et al

CVPP x 6

Zittoun et al

MOPP + IFRT



I & II (A &B)

CVPP + RT MOPP + EFRT



Stage

I & II (A & B) III A

RFS

OS

62% (7 yr)

82% (7 yr)

71% (7 yr)

89% (7 yr)

90% (6 yr)

93% (6 yr)

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 GHSG HD7

Design

Outcome

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 NCIC/ECOG HD61 MSKCC2 Laskar et al3

Design

FFP

OS

ABVD x 4-6

88% (5 yrs)

ABVD x 2 + STLI

95% (5 yrs)

ABVD x 6

81% (5yrs)

ABVD x 6 + EF/IF

86% (5yrs)

ABVD x 6

76% (8yrs)

89%

ABVD x 6 + IFRT

88% (8yrs)

100%

NS NS

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 EORTC H6U Milan GALTA EORTC H7U GHSG HD11

Regimen

Outcome

3 MOPP + mantle RT + 3 MOPP

FFP 76% (8 yrs)

3 ABVD + mantle RT + 3 ABVD

FFP 88% (8 yrs)*

3 MOPP + STLI/TLI + 3 MOPP

FFP 66% (5yrs)

3 ABVD + STLI/TLI + 3 ABVD

FFP 72% (5yrs)

3 CVPP + IFRT (30 Gy) + 3 CVPP

EFS 85% (5yrs)

3 AOPE + IFRT (30 Gy) + 3 AOPE

EFS 66% (5yrs)*

6 EBVP II + IFRT (36 GY)

EFS 68% (6yrs)

6 MOPP/ABV + IFRT

EFS 90% (6yrs)

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 metaanalysis 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

BEACOPP

Days 21

Drug

Dose

Days

BEACOPP Increased Dose

22

Bleomycin

10

8

Bleomycin

10

Etoposide

100

1–3

Etoposide

200

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

40

1–14

Prednisone

40

G-CSF

—

Prednisone

8 1-3

1-14

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 escalateddose 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 Drug

Dose

Stanford Meclorethamine (M)

6

Adriamycin (A)

25

Vinblastine (V)

6

Vincristine (O)

1.4

Bleomycin (B)

5

Etoposide (E)

60 x 2

Week

M

A

V

1







E



3





Prednisone (P)

40

8

G-CSF

—

9





12





  





 

10 11



 





 







6 7

P

 







4 

B



2

5

O













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 recurrence Type Post RT

CCT alone with ABVD

Post CCT

Late Relapse

RT

Early Relapse 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.