Early chemotherapy intensification with BEACOPP in advanced-stage Hodgkin lymphoma patients with a...

Early chemotherapy intensification with BEACOPP in advanced-stage Hodgkin lymphoma patients with a interim-PET positiveafter two ABVD courses

Andrea Gallamini,1 Caterina Patti,2

Simonetta Viviani,3 Andrea Rossi,4

Francesca Fiore,1 Francesco Di

Raimondo,5 Maria Cantonetti,6 Caterina

Stelitano,7 Tatyana Feldman,8 Paolo

Gavarotti,9 Roberto Sorasio,1

Antonino Mule,2 Monica Leone,2

Alessandro Rambaldi,4 Alberto Biggi,10

Sally Barrington,11 Federico Fallanca,12

Umberto Ficola,13 Stephane Chauvie10

and Alessandro Massimo Gianni,3 for the

Gruppo Italiano Terapie Innovative nei

Linfomi (GITIL)1Department of Hematology, S. Croce Hospital,

Cuneo, 2Department of Hematology, V. Cervello

Hospital, Palermo, 3Department of Onco-

Hematology, Istituto Nazionale Tumori, Milan,4Department of Hematology, Ospedali Riuniti di

Bergamo, Bergamo, 5Department of Hematology,

University of Catania, Catania, 6Department of

Hematology, University Tor Vergata, Rome,7Department of Hematology, Bianchi & Melacrino

Hospital, Reggio Calabria, Italy, 8Department of

Hematology, Hackensack University Medical

Center, Hackensack, NY, USA, 9Department of

Hematology, S. Giovanni Battista Hospital, Turin,10Department of Nuclear Medicine, S. Croce

Hospital, Cuneo, Italy, 11PET Imaging Centre, St

Thomas’ Kings College Division of Imaging,

London, UK, 12Department of Nuclear Medicine,

S. Raffaele Hospital, Milan, and 13Department of

Nuclear Medicine, La Maddalena Hospital,

Palermo, Italy

Received 15 August 2010; accepted for

publication 1 October 2010

Correspondence: Dr Andrea Gallamini,

Hematology Department and BMT Unit,

Azienda Ospedaliera S. Croce e Carle, Via M.

Coppino, 26 – 12100 Cuneo, Italy.

E-mail: [email protected]

Summary

Interim 2-[18F]Fluoro-2-deoxy-D-glucose Positron Emission Tomography

performed after two chemotherapy cycles (PET-2) is the most reliable

predictor of treatment outcome in ABVD-treated Hodgkin Lymphoma (HL)

patients. We retrospectively analysed the treatment outcome of a therapeutic

strategy based on PET-2 results: positive patients switched to BEACOPP,

while negative patients continued with ABVD. Between January 2006 and

December 2007, 219 newly diagnosed HL patients admitted to nine centres

were enrolled; 54 patients, unfit to receive this treatment were excluded from

the analysis. PET-2 scans were reviewed by a central panel of nuclear

medicine experts, according to the Deauville score (Meignan, 2009). After a

median follow up of 34 months (12–52) the 2-year failure free survival (FFS)

and overall survival for the entire cohort of 165 patients were 88% and 98%;

the FFS was 65% for PET-2 positive and 92% for PET-2 negative patients. For

154 patients in which treatment was correctly given according to PET-2

review, the 2-year FFS was 91%: 62% for PET-2 positive and 95% for PET-2

negative patients. Conclusions: this strategy, with BEACOPP intensification

only in PET-2 positive patients, showed better results than ABVD-treated

historic controls, sparing BEACOPP toxicity to the majority of patients

(Clinical Trials.gov Identifier NCT00877747).

Keywords: Hodgkin lymphoma, positron emission tomography, review

panel, ABVD, BEACOPP.

research paper

First published online 20 December 2010ª 2011 Blackwell Publishing Ltd, British Journal of Haematology, 152, 551–560 doi:10.1111/j.1365-2141.2010.08485.x

Hodgkin lymphoma (HL) has been considered a curable

disease, since more than 90% of patients are still alive, and

80% are cured after a minimum follow-up of 6 years. The

combination of doxorubicin, bleomycin, vinblastine and

dacarbazine (ABVD) has been considered for a long time

the standard treatment for advanced-stage HL patients to

date (Canellos & Niedzwiecki, 2002). However, 20–30% of

the advanced-stage patients fail to achieve durable remis-

sions, and ultimately die of recurrent/resistant lymphoma

(Bonadonna et al, 2005). Recently, more aggressive regimens,

based on the combination of bleomycin, etoposide, doxoru-

bicin, cyclophosphamide, vincristine, procarbazine and pred-

nisone (baseline and escalated BEACOPP) (Diehl et al,

2003), or mechlorethamine, vincristine, procarbazine, pred-

nisone, epidoxirubicin, bleomycin, vinblastine and doxoru-

bicin (MOPPEBVCAD) (Gobbi et al, 1993) have been

proposed. BEACOPP has achieved impressive progression-

free survival rates in several comparative studies in respect to

ABVD (Diehl et al, 2005; Federico et al, 2009; Gianni et al,

2008). Diehl and colleagues, for the German Hodgkin

Lymphoma Study Group (GHSG), demonstrated a superi-

ority of escalated BEACOPP versus the COPP/ABVD regi-

men, with a 8-year progression-free survival (PFS) of 85%

for the former, and of 69% for the latter. However, concerns

about the early and late toxicity of these aggressive

chemotherapy regimens prompted clinicians and investiga-

tors to search for new prognostic factors able to identify

patients at risk for treatment failure, to be selected for an

aggressive treatment.

Positron Emission Tomography using [18F]-Fluoro-

2-Deoxy-D-Glucose (FDG-PET) has been proposed as a

reliable tool to predict treatment outcome in HL patients

when performed very early during traditional ABVD chemo-

therapy (PET-2) (Rigacci et al, 2002; Hutchings et al 2005;

Hutchings et al, 2006; Gallamini et al, 2006; Kostakoglu et al,

2002, 2006; Zinzani et al, 2006; Gallamini et al, 2007). In the

joint Italian and Danish study, the 2-year PFS for advanced-

stage, ABVD-treated HL patients with a interim negative and

positive PET after two ABVD courses was 95% and 12%,

respectively (Gallamini et al, 2007). Starting from this

premise, several clinical projects aimed at exploring the role

of PET-response adapted flexible chemotherapy in advanced-

stage HL have been planned worldwide (Hutchings &

Barrington, 2009). We report here, on behalf of GITIL

(Gruppo Italiano Terapie Innovative nei Linfomi) the results

of a retrospective study from eight Italian and one north-

American onco-haematological centres sharing the same

strategy of PET-response adapted treatment for HL patients.

In brief, advanced-stage HL patients were treated with

ABVD · 2 courses, and an interim PET restaging performed:

patients with a positive PET-2 underwent treatment intensi-

fication with BEACOPP; patients with a negative PET-2

continued their therapy with ABVD for a total of six courses,

followed by consolidation radiotherapy on nodal site(s) of

bulky disease recorded at diagnosis.

Patients and methods

Study design

The present study was planned and performed with the

cooperation of the eight Italian Hematology Centers sharing

the same therapeutic strategy, selected from a survey conducted

among GITIL affiliations and inquired about the therapeutic

options used in advanced-stage HL patients. Subsequently, the

North-American Hackensack University Medical Centre joined

the study. Centres were asked to participate in the present

retrospective study, provided they had treated patients in the

period between January 1st 2006 till December 31st 2007 with

the following characteristics: (i) 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) staged at

baseline with traditional radiological techniques and PET scan;

(ii) treatment starting with ABVD chemotherapy per two

courses followed by interim PET scan; (iii) patients with a

negative PET-2 were 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; (iv) patients

with a positive PET-2 were treated with escalated BEACOPP for

four courses, followed by baseline BEACOPP for four courses;

(v) both PET scans were performed in the same PET centre; (vi)

minimum follow-up of 1 year; (vii) retrospective informed

consent to analyse patient charts. According to the present

hypothesis generation we could expect a 2-year failure-free

survival (2-year FFS) of the entire cohort of patients equal or

superior to 85%, and a 2-year FFS of PET-2 positive patients

equal or higher than 50%. Patients were staged according to the

Cotswold criteria (Lister et al, 1989), with the exception of bulky

disease definition. For study purposes, bulky disease was defined

as a thoracic mass of at least 6 cm in diameter on a computed

tomography (CT) scan or being >33% of the transverse diameter

of the thorax at the level of T5 or T6 or any extra mediastinal

mass larger than 10 cm in diameter. Staging included the

diagnostic procedures recommended in the Cotswold meeting

plus PET-0. ABVD chemotherapy was given according the

original schedule (Bonadonna et al, 2005). International Prog-

nostic Score (IPS) was calculated in all the patients, as originally

described (Hasenclever & Diehl, 1998). Patients with a positive

PET-2 underwent chemotherapy intensification with BEA-

COPP, according to the original schedule (Diehl et al, 2005);

no changes in radiotherapy schedule was planned for PET-

positive patients. Patients with a negative PET-2 continued with

ABVD chemotherapy for a total of six courses. In both patient

cohorts, after completion of chemotherapy, consolidation

radiotherapy was given, either on the nodal sites of bulky

mediastinal or extra mediastinal disease (retroperitoneal or

superficial nodes) recorded at baseline to a total dose of 30 or

36 Gy, or as irradiation of a residual mass to a total dose of

36 Gy. At the end of treatment patients underwent a complete

restaging with the standard diagnostic tools plus CT-PET scan.

A. Gallamini et al

552 ª 2011 Blackwell Publishing Ltd, British Journal of Haematology, 152, 551–560

Treatment response was defined according to the revised

response criteria for malignant lymphoma (Cheson et al,

2007). Every clinical Institution participating to the trial got

retrospective informed consensus from the patients treated by

the same centre to analyse his data.

PET scanning

PET scanning was performed according to a standard proce-

dure, following the international guidelines (Cheson et al,

2007; Bombardieri et al, 2003). Clinical scanning was

performed using the local quality control programme in place

for calibration and scanner performance. All patients fasted for

at least 6 h before [18F]FDG tracer injection. Serum glucose

level measured at the time of injection was below 170 mg/dl in

all patients. Half-body emission scans were performed approx-

imately 60 min after injection. The activity of FDG to be

injected was determined locally depending on the PET-CT

system type and acquisition mode (2D vs. 3D). Non contrast-

enhanced CT scan was acquired immediately before the PET

scan for attenuation correction and localization of PET uptake.

Patients were asked to relax during the uptake period to

minimize muscular activity. To reduce the accumulation of

FDG activity in the urinary bladder, patients were asked to

void just before the start of the scan. Transaxial, coronal and

sagittal images were reconstructed by means of iterative

methods using locally determined reconstructed algorithms.

PET-0 was performed just before therapy, PET-2 after the

second ABVD course, a few days before the third course, final

PET no <3 months after the end of chemotherapy or, if

indicated, of consolidation radiotherapy. PET-2 and

end-therapy PET scans were interpreted by the local PET

centres according to standard FDG-PET interpretation criteria,

with background as reference FDG uptake (Bombardieri et al,

2003; Delbeke et al, 2006). PET-CT images of the baseline and

interim scan were converted to DICOM (Digital Imaging and

Communications in Medicine) format.

Central PET reviewing

After anonymization, images were uploaded by local PET

centres to a dedicated WEB site (https://magic5.to.infn.it/

pet_escalation) at the National Institute of Nuclear Physics

(INFN) of Turin, Italy (Chauvie et al, 2009). PET reviewers

had access to clinical information such as G-CSF adminis-

tration, known infection/inflammation, venous catheter

present or recently removed at the time of PET scan. Two

independent Nuclear Medicine experts (S.B. and F.F.)

reviewed the scans. In case of disagreement in interpretation

between reviewers, the discrepancy was resolved by a third

reviewer (A.B.).

The criteria for PET-2 interpretation adopted by the

reviewers were based on visual assessment of FDG uptake,

and scored for intensity of FDG uptake according to the

‘Deauville rules’, as originally proposed by a group of

international experts at a meeting at St. Thomas Hospital in

London (Barrington et al, 2010), and subsequently accepted in

the international consensus meeting of Deauville, in April 2009

(Meignan et al, 2009). In brief, the following rules were used to

interpretate and score the PET-2 scans:

1 Consider the number of residual lesions detectable in PET-2

that were already recorded in PET-0, select the site with the

most intense metabolic activity, and consider the axial slices

where the FDG uptake is highest.

2 If no residual FDG uptake is observed in PET-2, the scan

score is 1.

3 Compare the FDG uptake of the selected hottest residual

lesion with (i) the FDG uptake in an homogeneous and

central region of the liver, steering clear of lesions (using

sagittal/coronal slices); (ii) the FDG uptake in mediasti-

num, trying to include large vessels and avoiding area of

uptake in the aorta’s wall, myocardium, thymus and

residual lesions (using sagittal/coronal slices).

4 Score PET-2 scan using mediastinal and liver as reference

organs according to the 5-point scale, as follows

i Score 1 No uptake

ii Score 2 Uptake £mediastinum

iii Score 3 Uptake >mediastinum and £liver

iv Score 4 Uptake moderately increased above liver at any

site

v Score 5 Markedly increased uptake at any site including

new sites of disease

5 PET-2 scans with score 1–3 are considered negative; score

4–5 are considered positive.

Statistical analysis

Two-sample T-test and chi-square statistics or Fisher’s exact

text were used for continuous and categorical data analyses,

respectively. Failure Free Survival (FFS), chosen as end point,

was defined as the time from diagnosis to either disease

progression or relapse, or to death as a result of any cause.

Data were censored if the patients were alive and free of

progression/relapse at last follow-up. Overall survival (OS) was

defined as the time from diagnosis to death from any cause.

Data were censored if the patients were alive at last follow-up.

Survival curves were calculated using the method of Kaplan

and Meier (1958). The association between clinical prognostic

factors and the probability of treatment failure was assessed by

log-rank and univariate regression analyses (Mantel, 1966). To

investigate the contribution of individual prognostic factors, a

multivariate analysis based on the Cox proportional hazards

regression model was performed (Cox, 1972). All data analyses

were performed using SPSS package for Windows (Landau &

Everitt, 2004). Inter-rater reliability was scored with Cohen’s

kappa (Cohen, 1960). An high kappa demonstrate that the

agreement between reviewers does not occur through chance.

Values of kappa ranging form 0.60 to 0.80 demonstrate

BEACOPP Intensification in Interim PET Positive HL

ª 2011 Blackwell Publishing Ltd, British Journal of Haematology, 152, 551–560 553

substantial agreement, if kappa is above 0.8 reliability is

considered almost perfect (Landis & Koch, 1977).

Results

Demographics

Two-hundred and nineteen patients consecutively admitted to

the nine institutions participating to the study from January

2006 till December 31st, 2007 fulfilled the inclusion criteria.

However, 54 were excluded from the analysis for the following

reasons: PET-0 or PET-2 images not evaluable (18), patients

unable to be treated with aggressive chemotherapy for

co-morbidity (9), age >65 years (18), psychiatric disorder:

dementia senile (2), schizophrenia (1) and severe depressive

syndrome (1), other therapy (4), lost to follow-up (1). No

patient showed a positive antibody test for HIV. The clinical

characteristics of the 165 patients included in the study are

depicted in Table I. PET-2 was negative in 137 (83%) and

positive in 28 patients (17%). No difference was observed

between the two cohorts according to age, sex distribution,

percentage of patients with high risk IPS, stage ‡III, bulky

disease, or extranodal localization of disease. Notably, IPS

score ‡3 was recorded in 21% of PET-2 positive and 28% of

PET-2 negative patients, respectively. Radiotherapy was

administered to the sites of bulky disease at diagnosis and to

residual enlarged nodes in 82/165 (50%) patients: in 75

patients the irradiated site was mediastinum, in two the

retroperitoneal nodes, in one the latero-cervical region.

All patients were scanned with FDG PET at baseline and

after two ABVD courses. One hundred and thirty-seven

patients (83%) had a negative PET-2; the treatment, in this

patient cohort, was completed with a further four ABVD

courses. Twenty-eight patients (17%) had a positive PET-2:

23 were treated with BEACOPP, four escalated and four

baseline courses. Five out of 28 PET-2 positive patients were

treated with ABVD · 4 courses, plus involved-field radio-

therapy, for decision of the treating physicians. ABVD

chemotherapy was given in time with a 100% dose during

the first two ABVD courses in 158/165 (96%); we have no

data for the remaining cycles both in ABVD and BEACOPP

cohorts. Eighty-two patients were treated with consolidation

radiotherapy in the sites of previous bulky lesions: 13 in the

ABVD and 69 in the BEACOPP cohorts. In no patient with a

positive PET-2 a supplemental radiotherapy was given either

as consolidation in new bulky lesion or with involved field

technique (Fig 1). [Corrections added on 14 January 2011

after first online publication: In the Results section, ‘‘13 in

the ABVD and 69 in the BEACOPP cohorts’’ should be

substituted with ‘‘69 in the ABVD and 13 in the BEACOPP

cohorts’’.]

PET reviewing

Twenty-one patients (13%) were scanned with C-PET, 144

(87) with CT-PET. All the scans were available for central

review; the results of central PET-2 review are reported in

Table II.

Discordance between the two expert Nuclear Physicians

(S.B. and F.F.) was observed in three cases (2%), with a Cohen

Kappa coefficient of concordance of 0Æ98; a third reviewer

(A.B.) was therefore asked to resolve these differences. In one

Table I. Patients’ characteristics.

Variable

PET-2

positive

PET-2

negative P

Number of patients (%) 28 (17) 137 (83)

Histological definition, n (%):

Lymphocyte predominance 4 (14) 21 (15) 0Æ41

Nodular sclerosis 20 (71) 83 (61)

Mixed cellularity 1 (4) 17 (12Æ5)

Lymphocyte depletion 0 2 (1Æ5)

Classical 2 (7) 3 (2)

Not specified 1 (4) 11 (8)

Median age (years) 34 34 0Æ89

Male sex, n (%) 15 (54) 58 (42) 0Æ27

IPS ‡3, n (%) 6 (21) 38 (28) 0Æ49

Stage ‡III, n (%) 13 (46) 74 (54) 0Æ46

Bulky disease, n (%) 18 (64) 75 (55) 0Æ35

Extra nodal disease, n (%) 7 (25) 45 (33) 0Æ41

Fig 1. Results of the retrospective analysis.

Table II. PET scan review. Discordance between two reviewers was

observed in three case. Discrepancies has been resolved by the third

reviewer. Cohen’s Kappa = 0Æ98.

Reviewer 1 Reviewer 2 Reviewer 3 Cases (no.)

Positive Positive – 27

Negative Negative – 135

Positive Negative Negative 1

Negative Positive Negative

Positive

2

Total 165

A. Gallamini et al


patient, uptake in the neck was interpreted as nodal by

reviewer 1 but reviewer 2 interpreted it as vascular. The third

reviewer decided the uptake was vascular (negative). In the

second patient, uptake in the pelvis was interpreted as brown

fat by reviewer 1, but reviewer 2 interpreted it as nodal; the

third reviewer agreed with reviewer 1, and interpreted the FDG

uptake as unspecific in brown fat. In the third case the two

reviewers disagreed about the intensity of residual uptake: the

third reviewer considered the uptake to be slightly higher than

liver (positive). We then compared the results of the central

analysis of the reviewers with respect to the one originally done

by the local nuclear medicine physicians at the referring

centres. The five patients with a negative PET-2 according to

the local PET centre interpretation, reclassified as PET-2

positive by reviewers, showed treatment failure with relapse/

progression after a median of 7Æ7 months after diagnosis. Four

underwent rescue treatment with Ifosfamide Vinorelbine and

Gemcytabine (IGEV) x four courses, and one with high dose

Cyclophosphamide and Cytarabine, followed by Carmustine,

Etoposide, Cytarabine, Melphalan (BEAM) myeloablative

chemotherapy and autologous stem cell transplantation. Four

of them are in continuous complete remission (CCR) and one

showed no response at the time of writing. On the other hand,

the three patients with a positive PET-2 according to the local

PET centre and a negative scan by the review panel are still in

CCR after salvage treatment. The first patient underwent

biopsy of a residual upper left cervical node just after PET-2

restaging. The histological picture was inconclusive and

showed necrotic areas alternating with massive sclerosis and

scattered foci of T-lymphocytes. No Reed Sternberg cells were

observed. The patient was treated with escalated BEACOPP

and is now in CCR 35 months after diagnosis. The second

patient was treated with escalated BEACOPP and is now in CCR

30 months after diagnosis. The third patient continued with

ABVD therapy despite the positive PET-2, as a result of the

treating clinician’s decision. He remains in CCR 28 months after

diagnosis. Other four patients were treated with ABVD despite a

‘true’ positive PET-2 scan (confirmed by the review panel, all

with a score 4): three patients relapsed 4, 5 and 6 months after

diagnosis, one is in CCR 33 months after diagnosis.

Outcome

After a median follow-up of 34 months (12–52) 157 out of 165

patients are alive and eight have died. Twenty-four showed

treatment failure, both for progression or relapse: 13/137 in the

PET-2 negative arm and 11/28 in the PET-2 positive arm.

Considering only the 160 patients out of 165 enrolled in the

trial, in which treatment was adapted to PET-2 results as

reported by the local PET centre, the 2-year overall and failure

free survival were 98% and 88%, respectively. The 2-years FFS

for PET-2 negative patients was 92%, significantly higher than

that of the 23 patients with a positive PET-2 (2-years FFS 65%,

P = 0Æ0006) (Fig 2A).

There was no difference in FFS between 141 patients in stage

IIB-IVB and 19 patients in stage IIA (88% and 89%,

respectively). Considering only ‘truly’ advanced stage patients

(stage IIB–IVB) FFS was 92% in PET-2 negative and 64% in

PET-2 positive patients (P = 0Æ0004) (Fig 2B).

By multivariate analysis PET-2 was the only prognostic

factor significantly associated with FFS (HR 4Æ18, range

1Æ7–10Æ2, P = 0Æ001).

After PET review, 154/165 patients resulted to have received

a correct therapy, according to the proposals of this analysis:

(A) (B)

Fig 2. FFS according to PET-2 results reported by the local PET centres. Panel A represents the cohort of 160 patients correctly treated according to

local PET centre interpretation and panel B the subgroup of this cohort with stage IIB–IVB disease (N = 141). In both panels solid line represents all

patients of the cohort, dashed line PET-2 negative and dash-dotted line PET-2 positive patients; percentages indicate 2-year FFS.



133 patients with a negative PET-2 scan were treated with six

ABVD courses plus IF RT (132 patients originally negative and

one patients whose PET-2 scan was considered positive by the

local nuclear medicine physician, who didn’t change therapy

for clinical decision, and reclassified as PET-2 negative by the

central review panel) and 21 out of 24 patients with a positive

PET-2 who were treated with BEACOPP. The FFS of this

cohort was 91%, 95% in PET-2 negative and 62% in PET-2

positive patients, respectively (P < 0Æ0001) (Fig 3).

The overall toxicity for the entire patient population was

limited: one patient with grade 1 stipsis and two patients with

grade 3 dyspnoea in the ABVD cohort and one toxic death for

pneumonia in a patient with evidence of progressing

lymphoma during BEACOPP treatment.

Discussion

The role of prognostic factors in HL has been a matter of

debate for years. Ten years ago IPS (Hasenclever & Diehl,

1998) and other prognostic models (Gobbi et al, 2001) have

been constructed by a retrospective appraisal of a set of clinical

variables with a known prognostic meaning in a large cohort of

homogeneously-treated, advanced-stage HL patients. How-

ever, these prognostic models have proved to be of limited

clinical value, and their predictive power for treatment

outcome has been questioned (Gobbi et al, 2001; Hasenclever,

2002). ABVD treatment has been considered for long the ‘gold

standard’ treatment for advanced-stage HL; however, in at

least three randomized studies, BEACOPP escalated has been

definitely proven superior to ABVD, both in terms of

progression-free survival and overall survival (Diehl et al,

2005; Federico et al, 2009; Gianni et al, 2008), with nearly 90%

of the patients in continuous complete remission 8 year from

diagnosis (Diehl et al, 2005). Prognostic factors seemed no

longer necessary, as treatment was successfully adapted to

disease burden (Hasenclever, 2002). However, these high-

performance results have been achieved at a cost early and late

toxicity such as severe cytopenias, infections, amenorrhea and

secondary tumours (Behringer et al, 2005; Josting et al, 2003;

Engert et al, 2009). Moreover, more than two-thirds of the

patients who would have responded to less intensive chemo-

therapy regimes, were exposed to the risk of overtreatment.

In recent years a novel class of prognostic factor in

lymphoma has been proposed, based on a early individual

risk assessment of chemo resistance during treatment, either by

the evaluation of minimal residual disease (MRD) with

molecular biology techniques (Freedman et al, 1999; Rambaldi

et al, 2005) or by assessing the chemosensitivity to treatment

with PET scanning. Interim FDG-PET, performed after a one

to three cycles of chemotherapy, has been proven to reliably

predict treatment outcome in more than 90% of HL patients

(Rigacci et al, 2002; Hutchings et al 2005; Hutchings et al,

2006; Gallamini et al, 2006; Kostakoglu et al, 2002, 2006;

Zinzani et al, 2006; Gallamini et al, 2007), with a sensitivity

and a specificity ranging between 43% and 100%, and 67% and

100%, respectively (Terasawa et al, 2009). Since 2007 onward,

based on these results, a number of clinical trials have been

planned worldwide, aimed at assessing the overall efficacy of a

PET response–adapted flexible chemotherapy. In these studies

interim PET scan is performed very early during treatment,

both in limited or advanced-stage HL (Hutchings & Barring-

ton, 2009; ClinicalTrials.gov 2007, 2008a,b,c, 2009). The

purpose of improving outcome of PET-2 positive, ABVD-

treated advanced-stage HL patients has been debated (Ziakas &

Poulou, 2008) but, to our knowledge, only two studies have

been published so far reporting the impact of PET response-

adapted therapy in advanced-stage HL (Dann et al, 2007;

Avigdor et al, 2010). In the first study patients were treated

according to IPS risk-class: those with IPS of 3 or higher

received two cycles of escalated BEACOPP, the others received

two cycles of standard BEACOPP. Subsequent therapy was

administered according to results of early interim Gallium-67

(67Ga) or PET scan. Baseline or escalated BEACOPP was given

in negative or positive interim scan patients, respectively. The

5-year event-free survival (EFS), and overall survival (OS) rates

were 85% and 90%, respectively (Dann et al, 2007). In the

second study, a small cohort of 44 high-risk, advanced-stage

HL patients with IPS score ‡3 underwent interim PET scan

after two escalated BEACOPP courses: Patients in CR or PR

were treated with ABVD · 4 courses whatever the PET-2

result; patients in less than PR were treated with high-dose

chemotherapy followed by autologous stem cell transplanta-

Fig 3. FFS curves of the 154 patients correctly treated according to

PET review: solid line represents all patients of the cohort, dashed line

PET-2 negative and dash-dotted line PET-2 positive patients;

percentages indicate 2-year FFS.

A. Gallamini et al


tion (ASCT) (Avigdor et al, 2010). Thirteen (29%) of the

patients showed a positive PET-2 scan and 31a negative PET-2

scan; all continued treatment with ABVD · 4 courses. After a

median follow-up of 48 months the PFS for the entire cohort

of patients was 78% and the OS 95%. These results seem quite

encouraging even though there may have been a number of

false positive results among positive PET-2 scans, as the

percentage of 29% seems to be higher than that reported after

ABVD (20%) (Hutchings et al, 2006; Zinzani et al, 2006;

Gallamini et al, 2007).

Moving from the preliminary reports presented in 2004 on

the role of PET-2 in predicting treatment outcome in HL

(Gallamini et al, 2004; Hutchings et al, 2004), several GITIL

clinical centres decided from 2006, to generate the following

working hypothesis: (i) if very poor-prognosis, PET-2 positive

patients after two ABVD cycles could be rescued with

BEACOPP in at least half of cases; (ii) if the overall outcome

of the entire cohort of patients could be improved. We report

here the results of a this therapeutic strategy in a cohort of 165

advanced-stage HL patients homogeneously treated, admitted

from January 2007 for 2 years in nine GITIL centres. Several

limitations due to the retrospective nature of this analysis

should be born in mind while interpreting its results; in fact, a

number of factors potentially affecting them could not be

controlled: (i) the criteria for excluding patients from the

analysis; (ii) the protocol for PET scanning; (iii) the Quality

Control policies of the different PET centres that, though

performed with standard rules were not shared from the study

onset; (iv) the rules for dose reduction of cytostatic drugs; (v)

the supportive care measures; (vi) the median follow-up

duration slightly inferior to 3 years (34 months). For all these

reason, once again, the present report refers to the results of a

‘generated working hypothesis’ that should be verified in

prospective way within a controlled clinical trial.

All that said, the overall efficacy of this therapeutic approach

in the cohort of advanced-stage HL patients correctly treated

according to PET-2 results was superior (2-year FFS 91%) to that

of the historical controls treated with front-line ABVD treatment

(2-year FFS 80%) (Canellos et al, 1992; Canellos & Niedzwiecki,

2002). Moreover, the 2-years PFS of PET-2 positive patients

moved from 12% in the prospective Italian-Danish study

(Gallamini et al, 2007) to 62% in the present report.

Although we can not exclude that some selection bias of the

patients may have occurred, a thorough analysis of the clinical

characteristics of all the HL patients consecutively admitted to

the nine Institutions participating to the study showed that the

patients excluded from the analysis, with the exception of cases

in whom PET images were unavailable, could not be treated

with standard ABVD treatment in the daily clinical practice.

Moreover, the percentage of patients showing a positive PET-2

(17%) was similar to the percentage reported in previous

studies (Zinzani et al, 2006; Gallamini et al, 2007); only five

patients with a positive PET-2 did not undergo therapy

intensification with BEACOPP, and no other protocol viola-

tions were known. The 2-year failure-free survival of 91% is

similar (Federico et al, 2009; Gianni et al, 2008) or slightly

inferior (Diehl et al, 2005) to that obtained for patients treated

front-line with escalated BEACOPP. However, four-fifths of

the patients enrolled in the study were spared procarbazine,

high-dose etoposide and high-dose cyclophosphamide, while

doxorubicin was given at lower doses. In the present patient

cohort, besides grade 3–4 haematological toxicity in 80% of

BEACOPP treated patients despite filgrastim administration, a

limited toxicity was reported, mainly grade 1 stipsis and grade

3 dyspnea in two patients in the ABVD arm and one toxic

death due to pneumonia in a patients progressing during

BEACOPP therapy. Different from the afore mentioned

randomized studies (Diehl et al, 2003; Federico et al, 2009;

Gianni et al, 2008) we included in our analysis stage IIA

patients with adverse prognostic factors, since in the previous

joint Italian and Danish experience the treatment outcome

PET-2-positive patients with IIA stage and adverse prognostic

factors was as dismal as that of stage IIB-IVB patients

(Gallamini et al, 2007). These results appear to be confirmed

in the present study, since the 2-year FFS of the entire cohort

of patients was very similar to the stage IIB-IV B patients (88%

vs. 89%).

PET scans have been reviewed according to the 5-point,

semi-quantitative Deauville score (Delbeke et al, 2006). In

most of the centrally reviewed scans the results of the PET-2

interpretation by the local PET centre were confirmed by the

central review panel (154/162: 95%). Moreover, the concor-

dance rate between the two reviewers of the central panel

showed a k coefficient of 0Æ98, and in only tree cases a review

by a third reviewer was required to resolve disagreements.

Similar concordance results among reviewers using the same

score in HL have been very recently published (Barrington

et al, 2010). As a result of PET-2 scan redefinition by central

review, even allowing for the slight change in the percentage of

positive versus negative scans, overall treatment outcome

results improved, and a 2-year FFS moving from 88% to

91%. In fact, five patients treated with ABVD according to a

negative local PET-2 scan and reclassified as PET-2-positive

had inadequate treatment: all experienced treatment failure.

Two out of three patients with a positive local PET-2

reclassified as negative, and treated with BEACOPP underwent

overtreatment, while the third had an appropriate treatment

since he was treated with ABVD despite the local scan report:

all three are in continuous clinical remission. Since an

international consensus on these rules is still lacking, these

data, taken together, confirm the need for a review panel for

interim scan interpretation in the several ongoing prospective

clinical trials adopting a PET response-adapted strategy.

With the limitations derived from a retrospective appraisal

of the results, the present study appears noteworthy since it

suggest that: (i) in advanced-stage, ABVD-treated HL patients

in which chemotherapy was intensified early with BEACOPP

only in the small subset of PET-2 positive patients the

treatment outcome was similar to that obtained with this

regimen from disease onset; (ii) these results could be achieved



for the entire cohort of patients while sparing undue toxicity

from more aggressive chemotherapy to four-fifths of patients;

(iii) the efficacy of BEACOPP intensification in PET-2-positive

advanced-stage HL patients during first-line ABVD therapy,

currently being tested in a prospective way in several multi-

centre clinical trials, has been retrospectively demonstrated;

(iv) the application of the Deauville interpretation reporting

criteria for interim PET seems warranted, with a very good

concordance rate among reviewers.

Acknowledgements

We thank PierGiorgio Cerello from the Istituto Nazionale di

Fisica Nucleare of Turin for having provided facilities and

knowledge for the website dedicated to central PET reviewing.

We thank Alex Stancu, from the Department of Nuclear

Medicine of S. Croce Hospital in Cuneo, for having created the

website dedicated to the central PET scan review.

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