Early chemotherapy intensification with BEACOPP in high-risk,
interim-PET positive, advanced-stage Hodgkin lymphoma, improves
the overall treatment outcome of ABVD.
Gallamini A, Patti C, Viviani S., Rossi A, Fiore F, Di Raimondo F, Cantonetti M, Stelitano C, Feldman T, Gavarotti P, Sorasio R, Mulè A, Leone
M, Rambaldi A, Biggi A, Barrington S., Fallanca F., Ficola U, Chauvie S, Gianni AM, for the Gruppo Italiano Terapie Innovative nei Linfomi
(GITIL).
GITIL
Gallamini, JCO 25:3746-52, 2007
?
Ziakas PD: Eur J Nucl Med Mol Imaging 2008; 35:1573–1575
Treatment plan
High-risk HL
IIB-IVB or
IIA with more than 3
nodal sites, ESR > 50,
bulky lesion
PET-0
ABVD x2
PET-2
PET-2 +ve HL
PET-2 -ve HL
escalated BEACOPP x4
standard BEACOPP x4
ABVD x4
Consolidation RxT
Consolidation RxT
End-therapy PET
Early chemotherapy intensification with BEACOPP in PET-2 positive,
ABVD-treated HL pts.
Study registration number
Clinical trisals.gov: NCT00795613
Study characteristics
Clinical retrospective
Primary endpoint
2-y PFS of the entire cohort of patients ≥ 80%
Secondary endpoint
2-y PFS of PET-2 positive patients > 50%
Participating centers
8 Italian GITIL centers and 1 US center
Accrual time
January 1st 2006- December 31th - 2007
Enrolled patients
162
Mean follow-up
26 months (10-44)
PET review panel
S. Barrington°, A Biggi*, A Bianchi*, F. Fallanca§
Criteria for PET interpretation
5-point semi-quantitative score
Inclusion criteria
(a)
(b)
(c)
(d)
(e)
(f)
(g)
(h)
advanced stage HL (Ann Arbor stages IIB-IVB) or stage IIA with adverse
prognostic factors (three or more nodal regions affected, bulky mediastinal
lesion, erythrocyte sedimentation rate higher than 50 mm.);
treatment starting with ABVD chemotherapy per two courses followed by
interim PET scan;
patients with a negative PET-2 allowed to continue ABVD therapy for a total
of six cycles, followed by consolidation radiotherapy on the nodal sites with
bulky disease recorded at baseline;
patients with a positive PET-2 treated with escalated BEACOPP for 4
courses, followed by baseline BEACOPP for 4 courses;
both PET scans performed in the same PET centre;
minimum follow-up of one year;
PET-0 and PET-2 images available for central PET reviewing;
retrospective written informed consent to participate in the trial.
Patient characteristics N= 162
Variable
Number of patients (%)
Histological definition, n (%):
-Lymphocyte predominance
-Nodular sclerosis
-mixed cellularity
-lymphocyte depletion
-classical
-not specified
PET2
positive
PET2
negative
27 (17)
135 (83)
p
0.48
4 (15)
19 (70)
1 (4)
0
2 (7)
1 (4)
21 (16)
83 (61.5)
15 (11)
2 (1.5)
3 (2)
11 (8)
34
34
0.94
Male sex, n (%)
15 (56)
57 (42)
0.20
IPS ≥3, n (%)
6 (22)
38 (29)
0.49
Stage ≥ III, n (%)
13 (48)
74 (55)
0.53
Bulky disease, n (%)
17 (63)
75 (56)
0.48
Extra nodal disease, n (%)
7 (26)
45 (33)
0.45
Consolidation Radiotherapy (%)
15 (55)
63 (46)
Mean age (years)
5-point scale for interim-PET interpretation
1.
No uptake
2.
Uptake ≤ mediastinum
3.
Uptake > mediastinum but ≤ liver
4.
Moderately increased uptake compared to liver
5.
Markedly increased uptake compared to liver or new areas of FDG uptake
Negative
scan
Positive
scan
Meignan M: Leukemia & Lymphoma, 2009; 50: 1257–1260
PET scan review: reviewers concordance .
Reviewer 1
Reviewer 2
Reviewer 3
Cases (N°)
Positive
Positive
--
27
Negative
Negative
--
132
Positive
Negative
Negative
1
Negative
Positive
Negative
Positive
2
Total
162
Discordance between 2 reviewers was observed in 3 case. Discrepancies has
been resolved by the third reviewer. Cohen’s Kappa = 0.94
PET-2 scan review local center vs. review panel
Local PET
report
Positive
Review PET
report
Positive
Cases
(N°)
24
3 patients continued ABVD for treating
physician decision
Patient 1: in CCR treated with ABVD for
treating physician decision.
Patient 2: in CCR post BEACOPP.
Patient 3: in CCR post BEACOPP
Positive
Negative
3
Negative
Negative
130
Negative
Positive
Notes
5
All patients in clinical progression: rescue
with IGEV +ASCT (N=4) or HDS + ASCT
(N=1)
Discordance between local Center and reviewers was observed in 8 cases.
Cohen’s Kappa = 0.84. The clinical history of the patients is reported.
Multivariate analysis for prognostic
factors associated with FFS
Variable
HR
95% CI
P
Age as continuous variable
0.98
0.94-1.02
0.39
Interim PET positive
4.57
1.83-11.4
0.001
IPS ≥ 3
1.86
0.66-5.27
0.24
Stage ≥ III
1.31
0.44-3.89
0.63
Bulky disease
2.11
0.76-5.85
0.15
Extranodal disease
0.96
0.32-2.85
0.94
Trial results (162 pts.)
162 pts.
ABVD x 2
4 pts.
CT-PET
ABVD x 4
(Medical decision)
-
+
CT-PET
23 pts.
BEACOPP-esc. x 4
ABVD x 4
135 pts.
BEACOPP-bas. x 4
CCR
Rel-Pro
2 pts.
2 pts.
Rxt. IF
Rxt. IF
CT-PET
CT-PET
CCR
Rel-Pro
CCR
Rel-Pro
15 pts.
8 pts.
123 pts.
12 pts.
FFS according to PET-2 results reported
by the local PET centers.
Cohort of 158 patients
correctly treated
All patients
Subgroup of 141 patients with
stage IIB-IVB disease
PET-2 negative
PET-2 positive
FFS curves of the 152 patients correctly treated
according to PET review
All patients
PET-2 negative
PET-2 positive
Conclusions
• In advanced-stage, ABVD-treated HL patients in which chemotherapy
was intensified with BEACOPP only in PET-2 +-ve patients, the overall
treatment outcome of the entire cohort of patients was comparable to
that of BEACOPP given from the onset in all patients
• An undue toxicity from more aggressive chemotherapy was spared in
four fifths of the patients;
• The efficacy of this therapeutic strategy, currently being tested in a
prospective way in several multi-centre clinical trials, has been
retrospectively demonstrated;
• A very good concordance rate, using the 5-point semi-quantitative scale,
was found among reviewers.
Acknowledgements
P. Gavarotti, Hematology Chair, University of Turin - Torino
S. Viviani, V. Bonfante, Medical Oncology, Istituto Tumori, Milano
C. Stelitano, Hematology Dept., Poloiclinico A. Melacrino, Reggio Calabria
R. Sorasio, F. Fiore, Hematology Dept., S. Croce e Carle Hospital , Cuneo
A. Rossi, Hematology Dept., Ospedali Riuniti di Bergamo - Bergamo
L. Trentin, R. Zambello; Experimental medicine, Hematology and Immunology Dept., Padoa University, Padova
M. Cantonetti. Hematology Chair University Tor Vergata - Roma
K. Patti, S. Mrito : Hematology Dept. , Ospedale “ A. Cervello”, Palermo, Palermo
G. Di Raimondo, Hematology Dept. and BMT Unit, University of Catania, Catania
T. Feldman , Hackensack Medical Center, Hackensack University , N.Y. - USA
S. Barrington PET Imaging Centre, St Thomas’ Kings College Division of Imaging, London, UK.
U. Ficola. PET Imaging Department. Ospedale La Maddalena. Palermo A. Biggi, Chauvie S. . PET Imaging Department. S. Croce e Carle Hospital Cuneo.
D. Panush . Hackensack Medical Center, Hackensack University , N.Y. - USA