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BEACOPP (escalated x4 + baseline x4 cycles) vs. ABVD (x8 cycles) in stage III & IV Hodgkin Lymphoma high-risk (IPS ≥3) Intergroup study 20012 led by the EORTC Lymphoma Group Patrice Carde, Mathias Karrasch, Catherine Fortpied, Pauline Brice, H. Khaled, D. Caillot, I. Gaillard, S. Bologna, C. Fermé, P. Lugtenburg, F. Morschhauser, I. Aurer, B. Coiffier, R. Meyer, M. Seftel, M. Wolf, B. Glimelius, A. Sureda, Nicolas Mounier

Nordic Lymphoma Group


HD9 (GHSG) BEACOPP escalated x8 cycles: a double challenge • is conventional chemotherapy dose escalation beneficial?  a dream suggested by retrospective HL studies (Frei EIII AJM 69:585-94, 1980; Carde P JCO 1:146-153, 1983)

 rendered possible by simply using granulocytic GF (w/o stem cell grafting)

• does escalated BEACOPP become a new standard of care?  MOPP vs. ABVD vs. M/A (Canellos NEJM 327:147884, 1992)

 escalated BEACOPP vs. baseline BEACOPP vs. COPP/ABVD (Diehl V JCO 1998, NEJM 348:238695, 2003; Engert A, JCO 27:4548-4554, 2009)


eligibility => stage III-IV poor risk • • • • • • • •

histologically documented untreated Hodgkin Lymphoma clinical stage III or IV 1 bi-dimensionally measurable target lesion at least International Prognostic Score* (IPS) ≥ 3 age 16-60 years inclusively WHO performance status ≤ 2 no prior therapy for Hodgkin's lymphoma leukocytes > 2.0 *109/l and platelets > 100 *109/l

* amounts 42% of patients (predicted 5y FFP 55 ±2%, OS 70 ±2%) according to IPS study Hasenclever D, Diehl V NEJM 339:1506-14, 1998


study design HL stages III-IV IPS ≥3 randomized phase III trial

ABVD x8 4 cycles ABVD

2 cycles ABVD

2 cycles ABVD if ≥ PR 50%

4 cycles BEACOPP escalated

2 cycles BEACOPP baseline

if ≥ PR 75% /CRu

no 2 cycles RT BEACOPP baseline

BEACOPP 4+4 * stratified for institution and IPS (3 versus 4+)


primary endpoint and statistical design Event free survival (EFS) defined as the time from randomization until date of the first of these events 

  

discontinuation of the protocol therapy for any reason, including early discontinuation due to not achieving adequate response (minimum PR 50% after 4 cycles or PR 75%/CRu after 6 cycles) absence of CR/CRu after 8 cycles relapse or progression at any time death from any cause

152 events are required to have 80 % power to detect a hazard ratio of 0.62 (from 70% to 80% in EFS rate at 3 years), with a 2-sided log-rank test with alpha = 5% and one interim analysis after 50 events  planned accrual = 550 patients 


results: patient characteristics • • • • • •

stage IV : 74% WHO PS 0, 1, 2: 34, 48 & 17% B-symptoms : 81% median age : 35.2y males : 75% IPS was 4 or higher : 59%

accrual 550 patients jan 2003- jan 2010 only stages III-IV & high risk International Prognostic Score ≥3 histology reviewed no HL : 4 pts


flow of patients 550 patients randomized 549 patients (1 informed consent missing)

275 assigned to ABVD

274 assigned to BEACOPP

272 started ABVD

267 started BEACOPP (+2*)

 229 completers (84%)

 218 completers (81%)

 43 discontinued

 49 discontinued * 2 pts with no timely follow-up data


treatment discontinuations (all) reason

relapse/PD

ABVD (N=43/272) n (%)

8 (2.9)

BEACOPP (N=49/269) n (%)

1 (0.4)

Time to discontinuation - cycles

ABVD ABVD

100 90 80

BEACOPP BEACOPP

70 60 50 40 30 20 10

< PR at C4 or < CRu at C6

9 (3.3)

11 (4.1)

0

(weeks) cycle 0

O N 43 272 49 269

1

2

3

4

Number of patients at risk : 272 270 269 266 267 257 253 250

5

6

7

260 241

256 238

242 226

8 Treatment ABVD BEACOPP

protocol rules were not strictly applied, most particularly at cycle 6, where a significant of patients (50%) continued toxicity (incl. number toxic death) 10 (3.7) 28 (10.4) treatment beyond cycle 6 although failing to report restaging (37%) or with PR/SD (13%)


response to treatment*

Complete Response (CR/CRu) 95% CI

ABVD (N=275) n (%)

BEACOPP (N=274) n (%)

227 (82.5 %)

227 (82.8 %)

(78.1;87.0)

(78.4;87.3)

* sensitivity analysis, after review of responses & progressions by the study coordinators, final restaging 4 to 6 weeks after completion of study treatment. If no additional treatment was given after non-CR and there was no progression of disease within 6 months, the final treatment outcome was retrospectively redefined as CRu » in accordance to Borschmann P et al JCO 29:4234-4242, 2011 (HD12 study)

primary analysis: CR/Cru 202 (73.5 %) vs. 189 (69.0%)

95% CI (68.2;78.7) & (63.5;74.5)

response at C4/C6 and early discontinuation:  185/494 pts (37%) did not report restaging at C6  62/494 pts (13%) where assessed as PR and nevertheless continued beyond C6


Tx discontinuations for toxicity reasons ABVD (N=272) nb pts

TOXICITY respiratory related (not including infections) hematological infection/meningitis/septicemia septic/toxic shock hepatic cardiac neurological allergy to etoposide

10

BEACOPP (N=269) nb pts

28 7 1 2

5 4 10 4 2 1 1 1


primary endpoint* – Event-Free Survival first event

ABVD (N=275) n 98 (%)

BEACOPP (N=274) n 81 (%)

early discontinuation

29 (10.5)

38 (13.9)

no CR/CRu after 8 cycles

25 ( 9.1)

13 ( 4.7)

progression/relapse

35 (12.7)

21 ( 7.7) • sensitivity analysis

death

9 ( 3.3)

9 ( 3.3)


primary endpoint â&#x20AC;&#x201C; Event-Free Survival sensitivity analysis, after review of responses & progressions by the study coordinators

100 90 80

69.3% BEACOPP 4+4

70 60

63.7% ABVD x8

50 40 30 20

Hazard Ratio (95% CI) = 0.86 (0.64 to 1.15)

10

Overall Logrank test: p=0.313

0

(years) 0

O N 98 275 81 274

1

2

3

4

Number of patients at risk : 186 147 113 84 196 161 118 87

5 58 55

6 26 29

7

8

8 7

Treatment ABVD BEACOPP


Progression Free Survival* * not defined explicitly as an endpoint of the study

84.0% BEACOPP 100

84.0% BEACOPP 4+4

90 80

PFS at 4 yrs

70

69.4%ABVD ABVD x8 69.4%

60 50

Hazard Ratio (95% CI) Ratio (95% CI) =Hazard 0.50 (0.34 to 0.73) = 0.50 (0.34 to 0.73)

40 30 20

Overall Logrank test: p=0.0003

10 0

(years) 0

1

2

3

4

5

6

7

8

O N 75 275

Number of patients at risk : 216 164 121 87

61

28

8

Treatment ABVD

39 274

229

61

32

7

BEACOPP

184

137

99


cause of death ABVD (N=275) n (%)

ALL DEATHS

HL

33 (12.0 %)

BEACOPP (N=274) n (%)

23 (8.4%)

15 (5.5)

7 (2.6)

secondary hematological or solid tumor

2 (0.7)

4 (1.5)

toxicity including toxic death*

9 (3.3)

6 (2.2)

intercurrent infectious disease

2 (0.7)

3 (1.1)


second malignancies (no RT) Cumulative Incidence of Secondary Malignancies

secondary tumor

ABVD (N=275) n (%)

BEACOPP (N=274) n (%)

8 (2.9%)

10 (3.6%)

Death = Competing Event

100 90 80 70 60

cumulative incidence incidence at at 44 yrs yrs cumulative

50 40

4.7% 4.7% BEACOPP BEACOPP 4+4 3.4% ABVD x8 3.4% ABVD

30 20 10

lung

2 (0.7)

1 (0.4)

0

(years) 0

O N 8 275 10 274

1

2

3 (1.1)

2 (0.7)

4

Number of patients at risk : 245 197 147 105 241 195 145 104

Gray test: p-value=0.584

NHL

3

5

6

7

8

71 63

33 34

8 7

treatment ABVD BEACOP


Overall Survival 90.3% BEACOPP 4+4

100 90 80

OS at 4 yrs

86.7% ABVD x8

70 60

86.7% ABVD

50

20

Hazard Ratio (95% CI) Hazard (95% = 0.71Ratio (0.42 toCI) 1.21) 90.3% BEACOPP

10

Overall Logrank test: p=0.208

40 30

= 0.71 (0.42 to 1.21)

0

(years) 0

1

2

3

4

5

6

7

8

O N 33 275

Number of patients at risk : 246 200 150 107

72

34

9

Treatment ABVD

23 274

241

65

34

7

BEACOPP

198

149

108


Cumulative Incidence Curves deaths due to HL

deaths NOT due to HL

Deaths due to HL

Deaths not due to HL

Competing risk = Deaths due to other causes

100 90

90

80

80

at 4 yrs: 6.6% ABVD x8 3.4% BEACOPP 4+4

70 60 50 40 30 20

Competing risk = Deaths due to HL

100

at 4 yrs: 6.7% ABVD x8 6.3% BEACOPP 4+4

70 60 50 40 30 20

10

10

0

(years) 0

O N 15 275 7 274

1

2

3

4

Number of patients at risk : 246 200 150 107 241 198 149 108

5 72 65

6 34 34

7

8

9 7

Treatment ABVD BEACOPP

0

(years) 0

O N 18 275 16 274

1

2

3

4

Number of patients at risk : 246 200 150 107 241 198 149 108

5

6

7

8

72 65

34 34

9 7

Treatment ABVD BEACOPP


Conclusions • EFS (primary endpoint) is similar between treatment arms. However, more progressions/ relapses were observed with ABVD, while early discontinuations were more frequent with BEACOPP • in this high-risk group, conventional dose escalation with BEACOPP 4+4 provides a better PFS compared to ABVD, yet not good enough to improve overall survival • additional considerations (treatment burden & cost, fertility issues, risk of relapse, risk of salvage, immediate & late morbidities) may guide physician / patient decisions toward ABVD or BEACOPP, which currently may share the claim for “current standard of care”


to

Gianni BONNADONNA (1975) & Volker DIEHL (1998) thank YOU for thinking NOT standard… to patients, site investigators, EORTC HQ team, especially our statistician Catherine Fortpied, participating groups especially the GELA / LYSA and their staff for their hard work & action; to Amgen, Chugaï & the DRC of APHP (PHRC) for their generous grants

Nordic Lymphoma Group

BEACOPP  

cancer, tratamiento para el cancer

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