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Early chemotherapy intensification with BEACOPP in advancedstage Hodgkin lymphoma patients with a interim-PET positive after 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 Ste´phane Chauvie10 and Alessandro Massimo Gianni,3 for the Gruppo Italiano Terapie Innovative nei Linfomi (GITIL) 1

Department of Hematology, S. Croce Hospital,

Cuneo, 2Department of Hematology, V. Cervello Hospital, Palermo, 3Department of OncoHematology, Istituto Nazionale Tumori, Milan, 4

Department of Hematology, Ospedali Riuniti di

Bergamo, Bergamo, 5Department of Hematology, University of Catania, Catania, 6Department of Hematology, University Tor Vergata, Rome, 7

Department of Hematology, Bianchi & Melacrino

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).

Hospital, Reggio Calabria, Italy, 8Department of Hematology, Hackensack University Medical Center, Hackensack, NY, USA, 9Department of

Keywords: Hodgkin lymphoma, positron emission tomography, review panel, ABVD, BEACOPP.

Hematology, S. Giovanni Battista Hospital, Turin, 10

Department of Nuclear Medicine, S. Croce

Hospital, Cuneo, Italy,

11

PET Imaging Centre, St

Thomas’ Kings College Division of Imaging, London, UK,

12

Department of Nuclear Medicine,

S. Raffaele Hospital, Milan, and

13

Department 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]

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

First published online 20 December 2010 doi:10.1111/j.1365-2141.2010.08485.x

A. Gallamini et al 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 remissions, and ultimately die of recurrent/resistant lymphoma (Bonadonna et al, 2005). Recently, more aggressive regimens, based on the combination of bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine and prednisone (baseline and escalated BEACOPP) (Diehl et al, 2003), or mechlorethamine, vincristine, procarbazine, prednisone, epidoxirubicin, bleomycin, vinblastine and doxorubicin (MOPPEBVCAD) (Gobbi et al, 1993) have been proposed. BEACOPP has achieved impressive progressionfree 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 superiority of escalated BEACOPP versus the COPP/ABVD regimen, 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 investigators 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]-Fluoro2-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 chemotherapy (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 advancedstage, 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 advancedstage 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 northAmerican 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 intensification 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. 552

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 Prognostic Score (IPS) was calculated in all the patients, as originally described (Hasenclever & Diehl, 1998). Patients with a positive PET-2 underwent chemotherapy intensification with BEACOPP, according to the original schedule (Diehl et al, 2005); no changes in radiotherapy schedule was planned for PETpositive 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.


BEACOPP Intensification in Interim PET Positive HL 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 procedure, 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 approximately 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 contrastenhanced 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 mediastinum and £liver 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


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A. Gallamini et al 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 Number of patients (%) Histological definition, n (%): Lymphocyte predominance Nodular sclerosis Mixed cellularity Lymphocyte depletion Classical Not specified Median age (years) Male sex, n (%) IPS ‡3, n (%) Stage ‡III, n (%) Bulky disease, n (%) Extra nodal disease, n (%)

554

PET-2 positive

PET-2 negative

28 (17)

137 (83)

P

Fig 1. Results of the retrospective analysis. 4 20 1 0 2 1 34 15 6 13 18 7

(14) (71) (4) (7) (4) (54) (21) (46) (64) (25)

21 83 17 2 3 11 34 58 38 74 75 45

(15) (61) (12Æ5) (1Æ5) (2) (8) (42) (28) (54) (55) (33)

0Æ41

0Æ89 0Æ27 0Æ49 0Æ46 0Æ35 0Æ41

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 Negative Positive Negative

Positive Negative Negative Positive

– – Negative Negative Positive

27 135 1 2

Total

165


BEACOPP Intensification in Interim PET Positive HL 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

(A)

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:

(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.


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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.

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. However, 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 556

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 highperformance 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 chemotherapy 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 & Barrington, 2009; ClinicalTrials.gov 2007, 2008a,b,c, 2009). The purpose of improving outcome of PET-2 positive, ABVDtreated 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 responseadapted 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-


BEACOPP Intensification in Interim PET Positive HL 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 violations 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 concordance 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


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A. Gallamini et al 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 multicentre 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.

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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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