Impact of high-dose chemotherapy followed by auto-sct for positive interim [ 18 F] FDG-PET diffuse large B-cell lymphoma patients

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1 (2011) 46, & 2011 Macmillan Publishers Limited All rights reserved /11 ORIGINAL ARTICLE Impact of high-dose chemotherapy followed by auto-sct for positive interim [ 18 F] FDG-PET diffuse large B-cell lymphoma patients V Roland 1,12, C Bodet-Milin 2,12, A Moreau 3, T Gastinne 1, B Mahé 1, V Dubruille 1, H Maisonneuve 4, N Juge-Morineau 5, P Moreau 6, H Jardel 7, L Planche 8, M Mohty 1,9,10, P Moreau 1, J-L Harousseau 11, F Kraeber-Bodéré 2,9,11 and S Le Gouill 1,9,10 1 Centre Hospitalier Universitaire de Nantes, Service d Hématologie Clinique, Nantes, France; 2 Centre Hospitalier Universitaire de Nantes, Service de Médecine Nucléaire, Nantes, France; 3 Centre Hospitalier Universitaire de Nantes, Service d Anatomopathologie, Nantes, France; 4 Centre Hospitalier Départemental Les Oudairies, Service d Onco-Hématologie, La Roche sur Yon, France; 5 Centre Catherine de Sienne, Service d Hématologie Clinique, Rezé, France; 6 Centre Hospitalier de Lorient, Service d Hématologie Clinique, Lorient, France; 7 Centre Hospitalier de Vannes, Service d Hématologie Clinique, Vannes, France; 8 Cellule de la Promotion et de la Recherche Clinique, CHU de Nantes, Nantes, France; 9 Centre de recherches en Cancérologie Nantes/Angers, INSERM, Équipe 10, UFR Médecine et Techniques Médicales, Université de Nantes, Nantes, France; 10 Centre d Investigation Clinique en Cancérologie, CHU de Nantes, Nantes, France and 11 Centre Régional de Lutte Contre le Cancer René Gauducheau, Saint-Herblain, France [ 18 F] fluoro-2-deoxy-d-glucose positron emission tomography (FDG-PET) is increasingly used for response assessment in diffuse large B-cell lymphoma (DLBCL). A positive interim FDG-PET was shown to be associated with an unfavorable outcome in high-grade non-hodgkin s lymphomas. For positive interim FDG-PET patients, the question of increasing the intensity of treatment using highdose chemotherapy followed by auto-sct (HDC-ASCT) remains unanswered. We retrospectively analyzed the prognostic value of FDG-PET in 42 DLBCL patients who were systematically evaluated at time of diagnosis, before and after HDC-ASCT. Of note, HDC-ASCT was part of the initial treatment strategy, while FDG-PET results did not influence the treatment approach. Results and outcome were analyzed according to FDG-PET results before and after HDC-ASCT. Patients were classified into three groups according to FDG-PET results before and after HDC-ASCT: those who were negative before and after ( / ; n ¼ 25), positive before and negative after ( þ / ; n ¼ 9) or positive before and after ( þ / þ ; n ¼ 8). The median follow-up was 34.5 (range, 19 74) months. The median EFS was significantly lower for the þ / þ group (27.4 months) as compared with other groups (median not reached; P ¼ 001). More importantly, there was no difference in term of EFS between the / group compared with the þ / group. These results suggest that HDC-ASCT can significantly improve the bad prognosis, otherwise indicated by a positive interim FDG-PET. (2011) 46, ; doi:1038/bmt.20130; published online 31 May 2010 Correspondence: Dr S Le Gouill, Centre Hospitalier Universitaire de Nantes, Hoˆtel-Dieu, Service d He matologie Clinique, 1 place Alexis Ricordeau, Nantes 44093, France. steven.legouill@chu-nantes.fr 12 These authors contributed equally to this work. Received 30 November 2009; revised 30 March 2010; accepted 4 April 2010; published online 31 May 2010 Keywords: Introduction FDG-PET; lymphoma; Auto-SCT In diffuse large B-cell lymphoma (DLBCL), [ 18 F] fluoro-2- deoxy-d-glucose positron emission tomography (FDG- PET) assessment has become mandatory for initial staging and final evaluation. According to Cheson s revised response criteria, patients are only considered in CR if FDG-PET result shows a normal FDG uptake. 1,2 One prospective study by Haioun et al. 3 including first-line DLBCL patients showed that a positive interim FDG-PET result performed after two cycles of CHOP or rituximab CHOP was correlated with a poorer outcome. This prospective study showed that additional cycles of CHOP were insufficient to cure positive interim FDG-PET patients. The GOELAMS group and others have shown that high-grade lymphoma patients with disseminated disease may benefit from high-dose chemotherapy followed by auto-sct (HDC-ASCT) upfront. 4 However, the role of HDC-ASCT upfront remains controversial. As a positive interim FDG-PET has been shown to have a dismal prognostic value, HDC-ASCT could be a therapeutic option for positive interim FDG-PET in DLBCL patients. The aim of this retrospective study was to assess whether HDC-ASCT can improve the bad prognosis or not, otherwise indicated by a positive interim FDG-PET. Material and methods Patient selection and study design The present report was a single-institution retrospective study. All patients underwent HDC-ASCT in the

2 394 Hematology Department of the University Hospital of Nantes (Nantes, France). Inclusion criteria included newly diagnosed DLBCL (according to the WHO classification) patients presenting with bulky disease (47 cm) and/or a stage III or IV disease and/or an international prognostic index (IPI) score 41; and relapsed DLBCL or patients with histological transformation. 5 Local expert pathologists analyzed all tissue specimens. Histological transformation was confirmed if the histological and immunophenotypical analysis showed DLBCL. Patients with meningeal or central nervous system involvement and positive serology for human immunodeficiency virus were excluded. HDC-ASCT was proposed for all patients presented with these criteria. It is to be noted that HDC-ASCT was planed before the start of induction chemotherapy, and the FDG-PET results before HDC-ASCT did not influence the scheduled strategy. Response assessment was classified according to Cheson s revised response criteria. 1 The initial staging included physical examination, biological markers, computed tomography (CT) scan of the thorax, abdominal and pelvis and BM biopsy. After completion of induction therapy (at least 3 weeks after completion of induction chemoimmunotherapy and 1 week before HDC-ASCT), a so-called interim evaluation including CT scan and FDG-PET (interim FDG-PET) was performed. Final evaluation included CT scan, FDG- PET and BM biopsy if positive at diagnosis. For the final evaluation, FDG-PET was performed at least 3 weeks after the ASCT or 12 weeks after radiation therapy. Post transplant follow-up consisted of a 3 monthly physical examination and CT scan every 6 months. A follow-up of at least 9 months after HDC-ASCT was required. The relatively small number of patients included during this 3.5- year time period was a result of the availability of PET imaging in our institution. It is to be noted that the studied patients who have pre- and post transplant FDG-PET imaging were not different from those who did not, and reflect the DLBCL population treated in our institution during this period. Therapeutic strategy Induction chemotherapy regimens consisted of four courses of rituximab CHOP, one cycle every 2 weeks, or high-dose CHOP plus rituximab (relapsed DLBCL and patients older than 60 years who received four courses of rituximab CHOP). 4,6,7 After completion of induction chemoimmunotherapy, patients with an insufficient response (opr) according to CT scan assessment received only three additional cycles of rituximab DHAP before HDC-ASCT. The conditioning regimen consisted of BEAM (except in one case). Radiation therapy was given to patients with bulky disease at diagnosis. Supportive care during HDC- ASCT was performed according to standard practice. FDG-PET/CT acquisition Imaging and data acquisitions were performed on an integrated PET/CT system (Discovery LS, GE Healthcare, Waukesha, WI, USA), using a single table for both the attenuation correction CT and FDG-PET elements. Patients had fasted for 4 h before PET/CT acquisitions and blood glucose had to be o7 mmol/l before injection of 7 MBq/kg of FDG (CIS bio international, Gif-sur-Yvette, France). Intravenous injection in the arm was followed by a period of B60 min, during which patients remained in a quiet room. No muscle relaxants were administered. During the image acquisition, patients maintained their arms above their head and no specific breathing instructions were given. FDG-PET data were acquired in two-dimensional mode and for 5 min per bed position. FDG-PET images were reconstructed using CT data, for attenuation correction; using the ordered-subsets expectation maximization algorithm; and without CT-based attenuation correction. FDG-PET/CT analysis [ 18 F] fluoro-2-deoxy-d-glucose-pet images were evaluated blindly by two nuclear medicine physicians experienced in hematology (CBM and FKB). FDG-PET/CT images were analyzed visually to localize abnormal foci and differentiate abnormal metabolic activity from physiological FDG uptake (kidneys, urethras, brain and myocardium). Abnormal FDG uptake was defined as greater than background activity in surrounding tissue and for the spleen, as FDG uptake greater than that in the liver. For initial staging, positive FDG-PET was defined as the existence of areas of increased uptake thought to be lymphoma-related and negative FDG-PET as the absence of all abnormal disease uptakes. After treatment, interim and final metabolic responses were defined according to international guidelines. 1,2,8 Statistical analysis A descriptive analysis of all variables was presented with the number of observations, mean, s.d., median, minimum and maximum for continuous variables, and the number and percentage per category for categorical data. Statistical analyses were performed using the SAS 9.1 software (SAS Institute Inc, Cary, NC, USA). Survival analysis was carried out from time of HDC-ASCT using the Kaplan Meier method. The log-rank test and Fisher s exact test were used for comparisons. OS was defined as the interval between time of HDC-ASCT and death. EFS was measured from the date of HDC-ASCT to the event (relapse or death). A P-value o5 was considered as significant. The negative predictive value (NPV) and positive predictive value (PPV) of FDG-PET to determine relapse or progression within 12 months after treatment were calculated. Results Patient characteristics are summarized in Table 1. All patients were diagnosed before June 2005 and underwent HDC-ASCT between April 2002 and December In all, 42 DLBCL patients were enrolled: DLBCL in 35 cases (newly diagnosed in 31 cases and at the time of first relapse in 4 cases) and histological transformation in 7 cases. Patient characteristics were as follows: 23 men; median age at diagnosis was 50 years (range, 16 65). Initial staging showed a stage III IV disease in 32 cases, a bulky

3 Table 1 Patient characteristics 395 Total [ 18 F] FDG-PET (Pos/Pos) [ 18 F] FDG-PET (Neg/Neg) [ 18 F] FDG-PET (Pos/Neg) P-value N Median age at HDC-ASCT (range), years 50 (16 65) 56 (38 65) 30 (19 58) 52 (17 65) 4 Male PS LDH4normal Ann Arbor stage I II III IV IPI Bulky (47 cm) Initial diagnosis DLBCL Histological transformation Induction chemotherapy R-CHOP R-CHOP+R-DHAP High-dose CHOP High-dose CHOP+R-DHAP HDC-ASCT Upfront At relapse CT status before HDC-ASCT CR PR Stable Progressive CT status after HDC-ASCT CR PR Stable Progressive Auto-SCT BEAM Melphalan alone Relapse Death Abbreviations: DLBCL ¼ diffuse large B-cell lymphoma; [ 18 F] FDG-PET ¼ [ 18 F] fluoro-2-deoxy-d-glucose positron emission tomography; HDC- ASCT ¼ high-dose chemotherapy followed by auto-sct; IPI ¼ international prognostic index; LDH ¼ lactate dehydrogenase; Neg/Neg ¼ patients with a negative FDG-PET before and after HDC-ASCT; Pos/Neg ¼ patients with a positive FDG-PET before and negative after HDC-ASCT; Pos/Pos ¼ patients with a positive FDG-PET before and after HDC-ASCT; PS ¼ performance status; R-CHOP ¼ rituximab CHOP; R-DHAP¼ rituximab DHAP. disease in 24 cases and an age-adjusted IPI score 41 in30 cases. Source of stem cell was peripheral blood in all cases. Conditioning regimen consisted of BEAM in all cases except for one who received high-dose melphalan alone. Median time from the start of induction chemotherapy to HDC-ASCT was 4.4 months. In all, 21 patients received radiotherapy after HDC-ASCT. A total of 38 patients with a chemosensitive (at least PR) disease received HDC-ASCT. According to first Cheson s criteria, 22 patients reached CR at final assessment after HDC-ASCT. According to Cheson s revised criteria including FDG-PET, disease status before HDC-ASCT was CR in 24 cases (57%), PR in 14 cases (33%), stable disease in 2 cases (5%) and progressive disease in 2 cases (5%). A total of 17 patients had a positive FDG-PET before HDC-ASCT. After HDC-ASCT, 33 patients reached CR (79%), 8 patients reached PR (19%) and 1 patient had a progressive disease (2%). Thus, 9 patients

4 396 Kaplan-meier estimate Figure 1 Kaplan-meier estimate Figure OS for all patients EFS for all patients. Kaplan-mejer estimate (22%) converted from a positive FDG-PET before HDC- ASCT to a negative FDG-PET after HDC-ASCT. EFS and OS curves are presented in Figures 1 and 2, respectively. The median follow-up (calculated from the time of HDC-ASCT) for surviving patients was 34.5 months (range, 19 74). The 2-year EFS and OS estimates were 80% (95% confidence interval (CI), %) and 9% (95% CI, 77 96%), respectively. No patient died because of HDC-ASCT-related toxicity. Eight patients experienced relapse, including one patient who presented with low-grade lymphoma at the time of relapse. Four patients died; the causes of death were sepsis in a context of relapse in one case, involvement of lymphoma of the spinal fluid at relapse in another case and respiratory failures in two cases due to lymphoma progression. Among the three positive FDG-PET after HDC-ASCT patients who did not relapse, biopsy was performed in two cases. The biopsy found a celiac disease in one case and an eosinophilic pneumonia in another case. We first divided patients according to their disease status after completion of HDC-ASCT. As expected, patients with a negative FDG-PET (patients in CR) after HDC-ASCT had a better outcome as compared with others. The 2-year EFS and OS estimates for positive vs negative FDG-PET patients were 57% (95% CI, 17 84%) vs 91% (95% CI, 74 97%) (Po001) and 75% (95% CI, %) vs 94% (95% CI, %) (P ¼ 9), respectively (see Figure 3). Interestingly, sites of relapse for negative FDG-PET patients after HDC-ASCT were BM (n ¼ 1) and spinal fluid (n ¼ 1). In contrast, the 2-year EFS and OS estimates for positive vs negative interim FDG-PET patients were 81% (95% CI, %) vs 88% (95% CI, 67 96%) (P ¼ 1) and 88% (95% CI, 61 97%) vs 92% (95% CI, 72 98%) (P ¼ 8), respectively. We then divided patients into three subgroups according FDG-PET results before and after HDC-ASCT: those who were positive before and after ( þ / þ ; n ¼ 8); positive before and negative after ( þ / ; n ¼ 9); and negative before and after ( / ; n ¼ 25). The median EFS was not reached for þ / and / groups vs 27.4 months for the þ / þ group (P ¼ 001; see Figure 4). Using the Fisher s exact test, we compared patient s outcome according to interim FDG-PET results (patients with a positive vs those with a negative interim FDG-PET) and observed no differences in term of EFS and OS (P ¼ ). Indeed, the NPV and PPV of interim FDG-PET performed before HDC-ASCT were 88 and 29%, respectively. In contrast, the NPV and PPV of final FDG-PET were 91 and 62%, respectively. Discussion Neg Pos P < Figure 3 EFS according to [ 18 F] fluoro-2-deoxy-d-glucose positron emission tomography (FDG-PET) results after high-dose chemotherapy followed by auto-sct (HDC-ASCT). Kaplan-mejer estimate P = 001 +/+ +/- -/ Figure 4 EFS according to [ 18 F] fluoro-2-deoxy-d-glucose positron emission tomography (FDG-PET) results before and after high-dose chemotherapy followed by auto-sct (HDC-ASCT). In this single-institution study, only DLBCL patients (with an age-adjusted IPI score 41 or bulky disease or a stage

5 III IV at diagnosis) who received a rituximab-containing regimen followed up by a scheduled HDC-ASCT were enrolled. HDC-ASCT was part of the initial treatment strategy, and interim FDG-PET results did not influence the scheduled therapeutic approach. Using this intensive strategy, the 2-year OS and EFS estimates were 9% (95% CI, 77 96%) and 79.6% (95% CI, 63 89%), respectively. As the goal of the present work was not to investigate the impact of HDC-ASCT in DLBCL upfront, we cannot conclude whether HDC-ASCT is required for all advanced DLBCL patients. Therefore, it is still questionable whether patients with a negative FDG-PET result after induction therapy would not have performed well without HDC-ASCT or whether patients with a positive FDG-PET result after induction therapy need to undergo HDC- ASCT. Indeed, part of the interim FDG-PET-positive DLBCL patients in Haioun s report reached prolonged CR without transplantation. 3 Herein, the aim of the study was to assess the predictive prognostic value of interim FDG- PET assessment performed systematically before HDC- ASCT in previously untreated advanced DLBCL patients. As expected, the statistical analysis confirmed the negative prognostic impact of a positive FDG-PET result after HDC-ASCT. In contrast, the PPV of interim FDG-PET before HDC-ASCT was only 29%. Furthermore, it is interesting to notice that two patients with negative FDG- PET results after HDC-ASCT experienced relapse in two sites (BM and spinal fluid) that are not well explored by FDG-PET. Therefore, FDG-PET cannot be used to replace BM or spinal fluid aspiration. Previous studies addressed the issue of interim FDG- PET in DLBCL patients treated with conventional chemotherapy alone without HDC-ASCT. The PPV of interim analysis varied from 60 to 100%. 3,9 14 The authors concluded that a positive interim FDG-PET result was highly predictive of early relapse and underlined the need for other therapeutic approach for these patients. Other reports investigated the prognostic value of interim FDG- PET results in transplanted patients (Table 2). In contrast with our findings, most studies concluded that positive interim FDG-PET patients experienced a high rate of relapse, despite the use of HDC-ASCT These results may suggest that the use of HDC-ASCT could not significantly improve the bad prognosis, otherwise indicated by a positive interim FDG-PET. Different reasons may explain discrepancies between these studies and the present report. First, most of studies included not only DLBCL but also Hodgkin s disease and other types of non- Hodgkin s lymphomas. Second, interim FDG-PET evaluation was performed at various time points and not systematically at 1 week before HDC-ASCT. Third and most importantly, HDC-ASCT was frequently performed at time of relapse and not upfront. Thus, it is interesting to note that few patients converted from a positive interim FDG-PET result to a negative FDG-PET result after HDC-ASCT ( þ / patients; Figure 5). In our series, 9 patients out of 17 converted from a positive interim FDG- PET before HDC-ASCT to a negative FDG-PET after HDC-ASCT. The outcome of the nine þ / patients was similar to the / patients. Interestingly, the nine þ / patients underwent HDC-ASCT upfront. The present series with untreated DLBCL patients cannot be compared with other reports that included only relapsed or refractory DLBCL patients. Indeed, the FDG-PET result before HDC-ASCT has to be taken into consideration also according to the number of line of treatment. The other important difference between studies is the type of chemotherapy regimen and number of courses of chemotherapy before HDC-ASCT. Herein, all patients received at least four courses of chemotherapy before transplantation and all reached CR or PR according to CT evaluation. 397 Table 2 Published reports evaluating the prognostic value of pre- and post-auto-sct FDG-PET Authors Study design n Disease Disease status Median follow-up Before and/or after FDG-PET Outcome according to FDG-PET results before ASCT (negative vs positive) Outcome according to FDG-PET results after ASCT (negative vs positive) Becherer R 16 NHL (n ¼ 10), et al. 15 including DLBCL (n ¼ 8) HD (n ¼ 6) Spaepen R 60 HD (n ¼ 19), NHL et al. 19 (n ¼ 41), including DLBCL (n ¼ 24) Shot et al. 18 R 39 NHL (n ¼ 28) and HD (n ¼ 11) Svoboda R 50 HD (n ¼ 19), et al. 20 DLBCL (n ¼ 21) and others Filmont et al. 17 P 60 NHL (n ¼ 50), including DLBCL (n ¼ 20) Crocchiolo R 53 HD (n ¼ 14) and et al. 16 NHL (n ¼ 39) Frontline (n ¼ 6) relapse/refractory (n ¼ 4) 13 months Before 1-year EFS 100 vs 18% (Po1) 1-year OS 100 vs 55% (Po1) Relapse or refractory 1510 days Before 2-year EFS 96 vs 23% (Po00001) 2-year OS 100 vs 55 (Po0002) Relapse 22 months Before 2-year PFS 58 vs 0% (Po019) Relapse or refractory Frontline, relapse or refractory 19 months Before Median EFS 19 months vs 5 months (Po01) median OS NR vs 19 months (Po4) 12 months Before and after 1-year EFS 80 vs 43% (Po002) Frontline and relapse 31 months Before 5-year OS 90 vs 55% (Po1) 1-year EFS 81 vs 25% (Po001) Abbreviations: DLBCL ¼ diffuse large B-cell lymphoma; FDG-PET ¼ [ 18 F] fluoro-2-deoxy-d-glucose positron emission tomography; HD ¼ Hodgkin s disease; NHL ¼ non-hodgkin s lymphoma; NR ¼ not reached; P ¼ prospective study; R ¼ retrospective study.

6 398 Figure 5 Patient with a positive [ 18 F] fluoro-2-deoxy-d-glucose positron emission tomography (FDG-PET) before and negative FDG-PET after high-dose chemotherapy followed by auto-sct (HDC-ASCT). Images a, b and c show FDG-PET coronal and transverse images recorded, respectively, at initial staging and before and after HDC-ASCT. Pre-treatment imaging shows bulky mediastinal disease (a). Response before HDC-ASCT was evaluated as incomplete by FDG-PET with positive residual masses in the mediastinum area (b). FDG-PET realized at the end of the treatment, after HDC-ASCT was negative without significative focus in the mediastinum (c). Despite the lack of international guidelines for interim FDG-PET interpretation, the use of interim FDG-PET is constantly increasing. Terasawa et al. 21 showed that the sensitivity and specificity of interim FDG-PET in DLBCL were only % and %, respectively. Lin et al. 22 established a standardized uptake value (SUV)-based assessment system that significantly improved the prognostic value of interim FDG-PET when performed after two cycles of chemotherapy. This SUV-based assessment system has been compared with the visual analysis after four cycles of chemotherapy. No differences in term of prognostic value were observed between the two methods. 23 Thus, the visual analysis method is the most accurate system for interim FDG-PET analysis to date. In the present work, we applied this visual method as recommended for final response assessment. 2 Recently, the first international workshop on interim FDG-PET took place in France and this meeting established bases to reach a consensus in years to come. 24 In conclusion, our report suggests that chemosensitive DLBCL patients with a positive interim FDG-PET result according to a visual analysis are likely eligible candidates for HDC-ASCT. The issue of optimal chemotherapy regimen before HDC-ASCT is yet to be addressed. This should be addressed through prospective clinical trials and international guidelines for interim FDG-PET interpretation. Conflict of interest The authors declare no conflict of interest.

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