before, during and after treatment in mature T/NK lymphomas: a study from the GOELAMS group

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1 Annals of Oncology 22: , 2011 doi: /annonc/mdq415 Published online 25 August F-fluorodeoxyglucose positron emission tomography before, during and after treatment in mature T/NK lymphomas: a study from the GOELAMS group X. Cahu 1, C. Bodet-Milin 2, E. Brissot 1, H. Maisonneuve 3, R. Houot 4, N. Morineau 5, P. Solal-Celigny 6, P. Godmer 7, T. Gastinne 1, P. Moreau 1, A. Moreau 8, T. Lamy 4,9, F. Kraber-Bodere 2,10,11 & S. Le Gouill 1,10,12 * Departments of 1 Hematology; 2 Nuclear Medicine, Centre Hospitalier Universitaire Nantes; 3 Department of Hematology, Centre Hospitalier De partemental La Roche-sur-Yon; 4 Department of Hematology, Hoˆpital Pontchaillou, Centre Hospitalier Universitaire Rennes, Rennes; 5 Department of Hematology, Centre Catherine de Sienne, Nantes; 6 Department of Hematology and Oncology, Centre Jean Bernard, Clinique Victor Hugo, Le Mans; 7 Department of Hematology, Centre Hospitalier De partemental Vannes, Vannes; 8 Department of Pathology, Centre Hospitalier Universitaire Nantes, Nantes; 9 Research Unit, Inserm U917, Universite de Rennes I, Rennes; 10 Center for Oncology Research Nantes/Angers, Inserm UMR 892, Nantes; 11 Department of Nuclear Medicine, Centre Rene Gauducheau, Saint-Herblain; 12 Center for Clinical Investigation in Oncology (CI2C), Centre Hospitalier Universitaire Nantes, France Received 24 February 2010; revised 25 June 2010; accepted 28 June 2010 Background: In non-cutaneous T-cell/natural killer (T/NK) lymphomas, the prognostic value of 18 F-fluorodeoxyglucose positron emission tomography (FDG PET) during or after therapy is unknown. Patients and methods: In this retrospective study, 54 T/NK lymphoma patients were assessed using FDG PET before (n = 40), during (n = 44) and/or after therapy (n = 31). Results: FDG PET showed an abnormal FDG uptake in all cases. Interim FDG PET was negative in 25 of 44 cases. After completion of therapy, 19 of 31 patients reached complete remission with negative FDG PET. In ALK+ anaplastic large cell lymphomas, the 4-year progression-free survival (PFS) was 80% and the negative predictive value of posttherapy FDG PET was 83% (n = 9). In ALK2 T/NK lymphomas, the 4-year PFS was 59% for patients with a negative interim FDG PET versus 46% for patients with a positive interim FDG PET (P = 0.28, n = 35). Similarly, there was no statistical difference in 4-year PFS between negative and positive post-therapy FDG PET in these lymphomas (51% and 67%, respectively, P = 0.96). The 4-year cumulative incidence of relapse from a negative post-therapy FDG PET was 53% in ALK2 T/NK lymphomas. Conclusions: Although T/NK lymphomas are FDG-avid at diagnosis, a negative interim or post-therapy FDG PET does not translate into an improved PFS in ALK2 T/NK lymphomas. Key words: 18 F-fluorodeoxyglucose, positron emission tomography, T-cell lymphoma, T/NK neoplasm original article introduction Mature T-cell and natural killer (NK) neoplasms are rare and heterogeneous. Except for ALK+ anaplastic large cell lymphoma (ALCL), their outcome is poor [1]. Strategies such as combination chemotherapy with cyclophosphamide, doxorubicin, vincristine and prednisone (CHOP)-based chemotherapy regimen, immunochemotherapy [2], autologous bone marrow transplantation (ABMT) [3 5] or allogeneic stem cell transplantation (allo-sct) [6] have been proposed. However, no consensual strategy has emerged and the CHOP *Correspondence to: Dr S. Le Gouill, Department of Hematology, Centre Hospitalier Universitaire Nantes, Place Alexis Ricordeau, Nantes Cedex 1, France. Tel: ; Fax: ; steven.legouill@chu-nantes.fr Present address: Department of Hematology, Hôpital Pontchaillou, Centre Hospitalier Universitaire Rennes, France. regimen can still be considered as the gold standard. Using conventional chemotherapy regimens, the 5-year overall survival (OS) of non-cutaneous ALK2 T/NK lymphomas ranges between 7% and 64% [1]. New compounds and innovative therapeutic strategies are therefore highly warranted in T/NK lymphomas. Over the past years, 18 F-fluorodeoxyglucose positron emission tomography (FDG PET) has emerged as an efficient tool to assess Hodgkin s lymphoma (HL) and diffuse large B- cell lymphoma s (DLBCL) response to treatment. Furthermore, it has been demonstrated that results of interim FDG PET predict HL patients outcome [7]. After therapy, FDG PET refines the evaluation of computed tomography (CT scan) [8]. Recent studies suggest that FDG PET is both sensitive and specific for initial staging in T/NK lymphomas [9 16]. However, the predictive value of early (so called interim) or post-therapy FDG PET remains unknown. We investigated ª The Author Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For permissions, please journals.permissions@oxfordjournals.org

2 the prognostic value of interim and post-therapy FDG PET in T/NK lymphomas in a retrospective and multicentric study. patients and methods patients and treatments In this retrospective study, patients were recruited in five institutions from the GOELAMS (Groupe Ouest-Est des Leucémies Aiguës et autres Maladies du Sang) group (Centre Hospitalier Universitaire Nantes and Centre Catherine de Sienne, Nantes, France; Hôpital La Roche-sur-Yon, France; Clinique Victor Hugo, Le Mans, France and Centre Hospitalier Universitaire Rennes, France) between February 2003 and June All adult patients with a previously untreated and histology proven noncutaneous mature T/NK neoplasm evaluated with FDG PET at any time of the treatment baseline, interim (after three or four cycles of chemotherapy) and/or post-therapy FDG PET were eligible for the purpose of the study [17]. FDG PET and CT assessment conventional evaluation. At baseline and after completion of treatment, conventional evaluation included the following assessment: a complete history and physical examination, blood cell counts, complete biochemical profile including lactate dehydrogenase level, bone marrow biopsy and CT scan (thorax, abdomen and pelvis). Ann Arbor stage was determined from clinical, biological, radiological and histological data including bone marrow evaluation. The international prognostic index and the simplified two-class prognostic index for peripheral T-cell lymphoma unspecified (spit) were calculated according to standard criteria [2, 18]. FDG PET imaging. FDG PET was carried out at baseline, after three or four cycles of chemotherapy (interim FDG PET) and/or after completion of treatment (post-therapy FDG PET). Post-therapy FDG PET was evaluated after completion of all first-line therapies (after chemotherapy, radiotherapy, ABMT and/or allo-sct when carried out as first-line therapy). Post-therapy FDG PET scans were recorded at least 3 weeks after the last course of chemotherapy and at least 8 weeks after radiotherapy. Before each FDG PET, patients fasted for at least 4 h and had capillary glucose levels measured with a glucometer. FDG PET was acquired min after injecting 7 MBq/kg using local systems (Centre Hospitalier Universitaire Nantes and Centre Hospitalier Départemental La Roche-sur- Yon, Discovery LS, General Electric Healthcare; Centre Catherine de Sienne, Discovery STE, General Electric Healthcare; Centre Hospitalier Universitaire Rennes, Discovery ST, General Electric Healthcare and Clinique Victor Hugo, Gemini, Philips Healthcare). FDG PET images were reconstructed by an iterative algorithm (ordered subset expectation maximisation) with and without correction. Images were interpreted by a local nuclear medicine physician and detailed reports were elaborated. For initial staging, positive FDG PET was defined as the existence of areas of increased uptake related to lymphoma. FDG PET was considered negative in the absence of abnormal uptake. All interim and post-therapy FDG PET reports were retrospectively interpreted in the light of the International Harmonization Project (IHP) criteria by XC and further approved by FK-B, without knowledge of outcome [8]. Of note, whenever feasible, FDG uptake was interpreted in the light of baseline FDG PET [19]. Equivocal areas were considered positive if described as positive on initial FDG PET reports. Conversely, equivocal areas were considered negative if described as negative on initial FDG PET reports. Differences between XC and FKB were discussed and an agreement could be found in all cases on the basis on the above criteria. As no validated and standardised criteria exist for interim FDG PET, reports were also interpreted according to a less stringent method, namely a three-point scale method [20, 21]. Every FDG uptake was ranked on a three-level scale (1 = low, 2 = moderate and 3 = high). The designation of low, intermediate or high uptake was based on a pure visual assessment by the local nuclear medicine physician without any more specification. Interim FDG PET was considered negative if no pathological FDG uptake or one grade 1 lesion was reported. Conversely, interim FDG PET was classified as positive if at least one grade 2 or two grade 1 lesions were reported. statistical analysis Except for relapse, all time-related data were measured from the diagnosis. OS and progression-free survival (PFS) were evaluated by the Kaplan Meier method. Comparisons between subgroups were assessed by the log-rank test. The cumulative incidence of relapse from a negative FDG PET was evaluated from the time of achieving a negative FDG PET. All data were computed using R Package [R Development Core Team (2006). R: A language and environment for statistical computing. R Foundation for Statistical Computing, Vienna, Austria. ISBN , URL results Annals of Oncology patient characteristics and outcome Patient characteristics are described in Table 1. Treatment regimens were heterogeneous (Table 1). Induction therapy usually consisted of three to five cycles of a CHOP-like regimen. In case of partial or complete responses, consolidation therapy was administered. Consolidation therapy included anthracyclin-based chemotherapy (n = 25), cisplatin- and aracytine-based regimen (n = 6), pentostatin (n = 3), frontline ABMT (n = 14) and/or allo-sct (n = 10). After relapse or progressive disease, salvage chemotherapy included cisplatinand aracytine-based regimen, pentostatin, alemtuzumab, ABMT and/or allo-sct. Interim FDG PET results modified the course of treatment in six patients with a switch to a cisplatin- and aracytine-based regimen. The median follow-up of surviving patients was 24 months (range 6 74). In the whole study population, 35 of 54 patients were still alive at the time of analysis, translating into a 4-year OS of 54% (95% CI 39 74) and a 4-year PFS of 50% (95% CI 37 68). ALK+ ALCL patients displayed a better 4-year OS (89%) and PFS (80%) than patients with other histologies (ALK2 T/NK lymphomas) (4-year OS and PFS of 47% and 44%, respectively) (Figure 1A). ALK2 ALCL patients (n = 14) displayed a 4-year OS of 62% and a 4-year PFS of 47%. Overall, allografted patients (n = 14) had a 4-year OS of 71%, a 4-year PFS of 73% and a relapse incidence of 9%. Patients receiving ABMT (n = 14) had a 4-year OS of 75%, a 4-year PFS of 60% and a relapse incidence of 40%. Patients who received standard chemotherapy excluding patients receiving ABMT or allo- SCT (n = 29) displayed a 4-year OS of 47%, a 4-year PFS of 48% and a relapse incidence of 49%. spit analysis According to spit, 22 patients had 0 or 1 adverse factor (group 1) and 29 patients had 2, 3 or 4 adverse factors (group 2) (Table 1) [2]. The 4-year OS was 81% for group 1 and 36% for group 2(P = 0.004). The 4-year PFS was 75% for group 1 versus 33% for group 2 (P = 0.004) (Figure 2A). In ALK2 T/NK lymphomas, the 4-year OS was 77% for group 1 versus 31% for 706 Cahu et al. Volume 22 No. 3 March 2011

3 Annals of Oncology Table 1. Patient characteristics and treatment ALK+ anaplastic large cell lymphoma ALK2 T/NK lymphoma a Total Number of patients Gender (male) Median age (17 77) Age <65 years, n (%) 10 (100) 35 (79) 45 (83) Performance status >1, n (%) 3 (30) 12 (44) 15 (28) LDH >N, n (%) 6 (60) 26 b (60) 32 (60) Positive bone marrow biopsy, 2 b (22) 15 b (35) 17 (33) n (%) CT scan stage b I II III IV IPI PIT c Group 1: 0-1 factor Group 2: factors First-line therapy, induction therapy, n (%) Anthracyclin based 10 (100) 42 (95) 52 (96) First-line therapy, consolidation therapy d Anthracyclin based Cisplatin based Pentostatin Radiotherapy ABMT Allo-SCT Salvage therapy d, n (%) 2 (20) 18 (41) 20 (37) Anthracyclin based Cisplatin based Pentostatin Alemtuzumab ABMT Allo-SCT a ALK2 T/NK lymphomas include 14 ALK2 anaplastic large cell lymphomas, 15 peripheral T-cell lymphomas unspecified, 11 AILT, 1 case of subcutaneous panniculitis-like T-cell lymphoma, 2 cases of extranodal NK/ T-cell lymphomas (nasal type and extranasal) and 1 indeterminate NK/T neoplasm (cd T-cell lymphoma or NK neoplasm). b Missing data: LDH level for one patient with ALK2 ALCL; bone marrow biopsy for one patient with AILT and one patient with ALK+ ALCL; CT scan for one patient with ALK+ ALCL, two patients with AILT and one patient with indeterminate T/NK neoplasm. c PIT could not be evaluated for three patients due to missing data. d Consolidation therapy and salvage therapy are missing for one patient. NK, natural killer; LDH, lactate dehydrogenase; IPI, international prognostic index; ABMT, autologous bone marrow transplantation; Allo- SCT, allogeneic stem cell transplantation; AILT, angioimmunoblastic T-cell lymphomas; ALCL, ALK+ anaplastic large cell lymphoma. group 2 (P = 0.01) and 4-year PFS was 68% for group 1 versus 30% for group 2 (P = 0.02) (Figure 2B). When focussing on ALK2 T/NK lymphoma patients who underwent an interim FDG PET, the 4-year OS was 92% (n = 13) for patients from group 1 versus 40% (n = 20) for patients from group 2 (P = 0.01) and the 4-year PFS was 75% for group 1 versus 42% for group 2 (P = 0.06). For ALK2 T/NK lymphoma patients who underwent a post-therapy FDG PET, the 4-year OS was 89% for group 1 (n = 9) versus 42% for group 2 (n = 12, P = 0.20) and the 4-year PFS was 78% for group 1 versus 52% for group 2 (P = 0.45). FDG PET analysis original article Initial FDG PET was carried out in 40 of the 54 patients (74%) (Table 2) and showed abnormal FDG uptake in all cases. Before therapy, 35 patients underwent both CT scan and FDG PET evaluations. These two imaging devices agreed on Ann Arbor staging in 28 cases (80%). In seven instances (20%), FDG PET upgraded Ann Arbor staging by finding lesions in various sites such as cervical, thoracic, abdominal regions or bone marrow. According to histological subgroups, FDG PET increased Ann Arbor stage in 4 of 7 ALK+ ALCL, 1 of 10 ALK2 ALCL, 0 of 7 angioimmunoblastic T-cell lymphoma, 1 of 10 PTCL-U and in 1 case of nasal NK/T lymphoma. Forty-four (81%) interim FDG PET scans were performed (Table 2). In seven instances, the three-point scale method and IHP criteria disagreed. There were 31 (57%) post-therapy FDG PET scans (Table 2). Interim and post-therapy FDG PET analysis is described in Table 2. statistical analysis interim FDG PET. With the three-point scale method, the 4-year OS was 76% for patients with a negative interim FDG PET versus 47% for patients with a positive interim FDG PET (P = 0.16). With the same method, the 4-year PFS estimate was 69% for patients with a negative interim FDG PET and 49% for patients with a positive interim FDG PET, respectively (P = 0.10). Results were similar with IHP criteria (4-year OS for negative versus positive FDG PET: 78% vresus 57%, P = 0.21). Clinical outcome was also studied according to ALK status (ALK+ ALCL and ALK2 T/NK lymphomas) and interim FDG PET results were interpreted using the three-point scale method. In ALK+ ALCL (n = 9), none of the six cases with a negative interim FDG PET relapsed as compared with one of the three cases with a positive interim FDG PET. The negative predictive value was 100% in ALK+ ALCL. In ALK2 T/NK lymphomas (n = 35), there were eight relapses among the 19 cases with a negative interim evaluation. The negative predictive value was 58% and the 4-year cumulative incidence of relapse from a negative interim FDG PET was 41% in ALK2 T/NK lymphomas. The 4-year OS estimate was 69% for patients with a negative interim FDG PET (n = 19) and 42% for patients with a positive interim FDG PET (n = 16, P = 0.24). At 4 years, PFS was not statistically different between ALK2 T/NK lymphomas with a negative or a positive interim FDG PET (59% versus 46%, P = 0.28) (Figure 1B). Results were similar with IHP criteria (4-year PFS for negative versus positive FDG PET in ALK2 T/NK lymphomas: 58% versus 50%, P = 0.39; negative predictive value: 57%). Interim FDG PET results modified the course of treatment in six patients. All the present results were similar when excluding these six patients from analysis (data not shown). IHP criteria and the three-point scale method disagreed in seven instances. Results Volume 22 No. 3 March 2011 doi: /annonc/mdq

4 Annals of Oncology Figure 1. Outcome of patients with T/NK lymphomas. (A) PFS of T/NK lymphomas: ALK+ ALCL (solid line) and ALK T/NK lymphomas (dashed line). (B) PFS in T/NK ALK2 lymphomas with a negative (dashed line) or positive (solid line) interim FDG PET (three-point scale method). (C) Cumulative incidence of relapse in T/NK ALK2 lymphomas with a negative post-therapy FDG PET. (D) PFS in T/NK ALK2 lymphomas with a negative (dashed line) or positive (solid line) post-therapy FDG PET. NK, natural killer; PFS, progression-free survival; ALCL, ALK+ anaplastic large cell lymphoma; FDG PET, 18 F-fluorodeoxyglucose positron emission tomography. were similar when excluding these seven patients from analysis (data not shown). post-therapy FDG PET. The 4-year OS was 62% for patients with a negative post-therapy FDG PET (n = 19) and 75% for patients with a positive FDG PET (n = 12, P = 0.71). The 4-year PFS was not statistically different in these two groups (61% and 67% for negative and positive evaluations, respectively) (P = 0.73). In ALK+ ALCL, one of the six patients with a negative posttherapy FDG PET relapsed as compared with one of the three patients who had a positive post-therapy FDG PET. The negative predictive value was 83% for post-therapy FDG PET in ALK+ ALCL. In ALK2 T/NK lymphomas, 5 of 13 patients relapsed after a negative FDG PET evaluation (negative predictive value: 61%). The 4-year cumulative incidence of relapse from a negative FDG PET was 53% in ALK2 T/NK lymphomas (Figure 1C). Conversely, six of nine patients with a positive post-therapy FDG PET did not relapse during follow-up (positive predictive value: 33%). In ALK2 T/NK lymphomas, the estimated 4-year OS rates were 50% and 67% in the negative and positive post-therapy subgroups, respectively (P = 0.64). The 4-year PFS estimates were not statistically different in these two groups (51% versus 67% for negative versus positive FDG PET, P = 0.96, Figure 1D). discussion Reports focusing on the value of FDG PET during or after therapy in non-cutaneous T/NK neoplasms are scarce and have brought conflicting results [22 24]. In the present article, we address the issue of the value of FDG PET results at diagnosis, during (interim FDG PET) or after completion of therapy according to the histological entity. At diagnosis, FDG PET was positive in all cases. Our results confirm the sensitivity of FDG PET in T/NK lymphomas [9, 10, 13 16]. FDG PET upgraded Ann Arbor stage in seven instances (20%), which shows the ability of FDG PET to reveal involved areas not detected by conventional imaging. In stage I II extranodal NK/T-cell lymphoma, nasal type, FDG PET may reveal valuable as the delineation of involved areas is paramount to achieve high-quality radiotherapy [10]. Moreover, PET carried out before therapy helps interpreting interim and post-therapy FDG PET [8, 25]. Importantly, our study focused on non-cutaneous T/NK lymphomas and did not 708 Cahu et al. Volume 22 No. 3 March 2011

5 Annals of Oncology original article Table 2. Diagnostic, interim and post-therapy FDG PET analysis ALK+ anaplastic large cell lymphoma ALK2 T/NK lymphoma Patients Diagnostic FDG PET Interim FDG PET Three-point scale method Positive FDG PET Negative FDG PET IHP criteria Positive FDG PET Negative FDG PET Post-therapy FDG PET IHP criteria Positive FDG PET Negative FDG PET FDG PET, 18 F-fluorodeoxyglucose positron emission tomography; NK, natural killer; IHP, International Harmonization Project; ALCL, ALK+ anaplastic large cell lymphoma. Total Figure 2. PFS according to the simplified two-class prognostic index for peripheral T-cell lymphoma unspecified. (A) PFS in group 1 (0 or 1 adverse prognostic factor) (dashed line) or group 2 (2, 3 or 4 adverse prognostic factors) (solid line) in T/NK lymphomas. (B) PFS in group 1 (dashed line) or 2 (solid line) in ALK2 T/NK lymphomas. PFS, progression-free survival; NK, natural killer. address the ability of FDG PET to detect cutaneous involvement, which has previously been reported as variable. A recent study showed that maximum standardised uptake values are low in aggressive peripheral T-cell lymphomas similar to that of grade 1 2 follicular lymphomas [26]. The potential interest of interim FDG PET is twofold. First, it may carry a prognostic and predictive value. Second, it may guide the treatment strategy according to FDG PET results. Choosing the most appropriate therapy in T/NK lymphomas is all the more important as many therapeutic options e.g. conventional chemotherapy, immunotherapy, ABMT or allo- SCT are being used without any consensual strategy. Some therapies such as ABMT are controversial and their specific indication remains to be determined [3, 27, 28]. Unlike posttherapy FDG PET, there are no standardised and validated criteria for interpreting interim FDG PET. Separate criteria have been recently proposed in DLBCL and HL [19] but they still need to be validated. Furthermore, the latter do not apply to T/NK malignancies. This lack of standardised criteria legitimated the use of two interpretation methods in our study. Both methods disagreed in a significant number of cases (16%), stressing the need to standardise interim FDG PET interpretation criteria. Whatever the method, OS and PFS were not statistically different in positive and negative subgroups either in T/NK neoplasms or in ALK2 T/NK lymphomas. We agree that this lack of difference should be taken with caution since a statistical difference may have emerged from larger cohorts. Although a clear cut can hardly be defined, any statistical difference if it exists should be significant enough to be clinically relevant. Moreover, both histology and treatment strategies are heterogeneous in the present study. The heterogeneity of treatments is all the more important as OS, PFS and relapse rates vary depending on therapy. Therefore, FDG PET should ideally be evaluated in the context of a specific therapy (e.g. ABMT, allo-sct or standard chemotherapy). Due to our rather small cohort, stratification according to therapy could not be carried out. After completion of therapy, we did not find any significant difference in terms of OS or PFS for patients with a positive or negative FDG PET. As we underlined for interim FDG PET, a statistical difference could emerge from larger cohorts. Our data show a trend in a higher OS/PFS for patients with a positive FDG PET compared with patients with a negative FDG PET, although not significant. A few patients (n = 4) with clinical progressive disease during first-line therapy were not evaluated by post-therapy FDG PET and went on directly to second-line therapy. This selection bias may participate in the unintuitive result described above. In ALK+ ALCL, the negative predictive value was high for interim and post-therapy FDG PET. However, this data does not permit to draw any definitive conclusion because of the small size of our cohort and the low incidence of relapse in this histology. Further studies are warranted in ALK+ ALCL. A significant rate of relapse (53%) occurred in ALK2 T/NK lymphomas after a negative posttherapy FDG PET. It suggests that the negative predictive value Volume 22 No. 3 March 2011 doi: /annonc/mdq

6 of FDG PET is low for ALK2 T/NK lymphomas. Residual disease may persist in ALK2 T/NK lymphomas despite a negative interim or post-therapy FDG PET. More generally, we found a high incidence of relapse after a negative FDG PET when carried out either during or after therapy. Obtaining complete metabolic response appears not to be sufficient to achieve a long-term PFS. Our results suggest that metabolic complete response should not be considered as a primary goal in T/NK neoplasms trials. Conversely, the positive predictive value of post-therapy FDG PET was low (33%). Since no treatment was administered after post-therapy FDG PET until relapse or progression, there are many false-positive post-therapy FDG FDG in ALK2 T/NK lymphomas. Positive lesions were biopsied in one single instance and showed inflammatory tissue without tumour (Figure 3). Although other positive lesions were not Annals of Oncology biopsied, non-tumoral inflammatory processes may explain this poor positive predictive value. Moreover, small foci <2 cm showing uptake higher than the neighbouring background are considered positive in IHP criteria, which may increase the rate of false-positive results. In our study, FDG PET interpretation may not be optimal for two reasons. First, baseline FDG PET was available for 77% and 71% of patients with an interim or post-therapy FDG PET, respectively. The systematic implementation of a baseline FDG PET may facilitate the interpretation of interim and post-therapy FDG PET [8, 19], although interim and post-therapy analysis did not reach any significant difference when focusing on patients with a baseline FDG PET (data not shown). Secondly, the present results are based on visual assessments by local nuclear medicine physicians. Visual assessments have been Figure 3. A false-positive case of T/NK lymphoma. (A) Initial FDG PET of a patient with ALK+ ALCL. (B) Interim FDG PET (after four cycles of a CHOP-like regimen). (C) Post-therapy FDG PET (after four cycles of a CHOP-like regimen, cisplatin-based chemotherapy, radiation therapy and autologous bone marrow transplantation). After the post-therapy FDG PET, the positive lesion was biopsied and showed inflammatory tissue without tumour. The patient is still in complete remission at last follow-up (4 years after post-therapy FDG PET). NK, natural killer; FDG PET, 18 F-fluorodeoxyglucose positron emission tomography; ALCL, anaplastic large cell lymphoma; CHOP, combination chemotherapy with cyclophosphamide, doxorubicin, vincristine and prednisone. 710 Cahu et al. Volume 22 No. 3 March 2011

7 Annals of Oncology shown to be moderately reproducible among nuclear experts in interim FDG PET [29]. The three-point scale method may be all the more variable among nuclear physicians as low, intermediate and high were not precisely pre-defined among nuclear physicians. The reproducibility of IHP criteria remains also to be proven. The rationale for these interpretation methods is low and relies more on expert s expertise and consensus than on evidence-based medicine [8]. Therefore, there is a place for improving interpretation methods in T/NK lymphomas, e.g. by using quantitative assessment [30]. Despite these limitations, FDG PET exhibited low positive and negative predictive values in ALK2 T/NK lymphomas. This poor result has to be put in parallel to spit, which could discriminate patients with good or poor prognosis in the whole study population and in ALK2 T/NK lymphomas. In conclusion, our study shows the sensibility of FDG PET at diagnosis in non-cutaneous T/NK malignancies. However, a significant incidence of relapse occurs in ALK2 T/NK lymphomas despite a negative interim or post-therapy FDG PET. Therefore, complete metabolic response does not necessarily translate into prolonged PFS in ALK2 T/NK lymphomas. funding SLG is supported by a grant from Pays de la Loire (Nouvelles équipes, nouvelles thématique ) and a grant from INCa, France (PAIRMCL R09011NN). disclosure The authors declare no conflict of interest. references 1. Vose J, Armitage J, Weisenburger D. International peripheral T-cell and natural killer/t-cell lymphoma study: pathology findings and clinical outcomes. J Clin Oncol 2008; 26: Gallamini A, Stelitano C, Calvi R et al. Peripheral T-cell lymphoma unspecified (PTCL-U): a new prognostic model from a retrospective multicentric clinical study. Blood 2004; 103: Rodriguez J, Conde E, Gutierrez A et al. The results of consolidation with autologous stem-cell transplantation in patients with peripheral T-cell lymphoma (PTCL) in first complete remission: the Spanish Lymphoma and Autologous Transplantation Group experience. Ann Oncol 2007; 18: Chen AI, McMillan A, Negrin RS et al. Long-term results of autologous hematopoietic cell transplantation for peripheral T cell lymphoma: the Stanford experience. Biol Blood Marrow Transplant 2008; 14: Reimer P, Rudiger T, Geissinger E et al. Autologous stem-cell transplantation as first-line therapy in peripheral T-cell lymphomas: results of a prospective multicenter study. J Clin Oncol 2009; 27: Le Gouill S, Milpied N, Buzyn A et al. Graft-versus-lymphoma effect for aggressive T-cell lymphomas in adults: a study by the Societe Francaise de Greffe de Moelle et de Therapie Cellulaire. J Clin Oncol 2008; 26: Terasawa T, Lau J, Bardet S et al. Fluorine-18-fluorodeoxyglucose positron emission tomography for interim response assessment of advanced-stage Hodgkin s lymphoma and diffuse large B-cell lymphoma: a systematic review. J Clin Oncol 2009; 27: Juweid ME, Stroobants S, Hoekstra OS et al. Use of positron emission tomography for response assessment of lymphoma: consensus of the Imaging Subcommittee of International Harmonization Project in Lymphoma. J Clin Oncol 2007; 25: original article 9. Suh C, Kang YK, Roh JL et al. Prognostic value of tumor 18F-FDG uptake in patients with untreated extranodal natural killer/t-cell lymphomas of the head and neck. J Nucl Med 2008; 49: Khong PL, Pang CB, Liang R et al. Fluorine-18 fluorodeoxyglucose positron emission tomography in mature T-cell and natural killer cell malignancies. Ann Hematol 2008; 87: Karantanis D, Subramaniam RM, Peller PJ et al. The value of [(18)F]fluorodeoxyglucose positron emission tomography/computed tomography in extranodal natural killer/t-cell lymphoma. Clin Lymphoma Myeloma 2008; 8: Berk V, Yildiz R, Akdemir UO et al. Disseminated extranodal NK/T-cell lymphoma, nasal type, with multiple subcutaneous nodules: utility of 18F-FDG PET in staging. Clin Nucl Med 2008; 33: Kako S, Izutsu K, Ota Y et al. FDG-PET in T-cell and NK-cell neoplasms. Ann Oncol 2007; 18: Bishu S, Quigley JM, Schmitz J et al. F-18-fluoro-deoxy-glucose positron emission tomography in the assessment of peripheral T-cell lymphomas. Leuk Lymphoma 2007; 48: Hu-Bing W, Quan-Shi W, Ming-Fang W et al. Utility of 18F-FDG PET/CT for staging NK/T-cell lymphomas. Nucl Med Commun 2010; 31: Hadithi M, Mallant M, Oudejans J et al. 18F-FDG PET versus CT for the detection of enteropathy-associated T-cell lymphoma in refractory celiac disease. J Nucl Med 2006; 47: Swerdlow SH, Campo E, Lee Harris N et al. WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues, 4th edition. Lyon, France: International Agency for Research on Cancer A Predictive Model for Aggressive non-hodgkin s Lymphoma. The international non-hodgkin s lymphoma prognostic factors project. N Engl J Med 1993; 329: Meignan M, Itti E, Bardet S et al. Development and application of a real-time on-line blinded independent central review of interim PET scans to determine treatment allocation in lymphoma trials. J Clin Oncol 2009; 27: Haioun C, Itti E, Rahmouni A et al. [18F]fluoro-2-deoxy-D-glucose positron emission tomography (FDG-PET) in aggressive lymphoma: an early prognostic tool for predicting patient outcome. Blood 2005; 106: Mikhaeel NG, Timothy AR, O Doherty MJ et al. 18-FDG-PET as a prognostic indicator in the treatment of aggressive Non-Hodgkin s Lymphoma-comparison with CT. Leuk Lymphoma 2000; 39: Choi YH, Kang BW, Hong HS et al. The role of an early interim 18 F-FDG PET/CT for prediction of outcomes of patients with peripheral T cell lymphoma. ASH Annu Meet Abstr 2008; 112: Kircher SM, Gurbuxani S, Smith SM. CHOP plus alemtuzumab can induce metabolic response by FDG-PET but has minimal long-term benefits: a case report and literature review. J Gastrointest Cancer 2007; 38: Pro B, Nunez RF, Romaguera J et al. Achievement of FDG-PET negativity does not predict durable responses in T-cell lymphoma. ASH Annu Meet Abstr 2006; 108: Meignan M, Gallamini A, Haioun C. Report on the first international workshop on interim-pet scan in lymphoma. Leuk Lymphoma 2009; 50: Tang B, Douglas-Nikitin V, Balon H et al. Exceptionally low metabolic activity in aggressive peripheral T-cell lymphoma. Nucl Med Commun 2009; 30: Mercadal S, Briones J, Xicoy B et al. Intensive chemotherapy (high-dose CHOP/ ESHAP regimen) followed by autologous stem-cell transplantation in previously untreated patients with peripheral T-cell lymphoma. Ann Oncol 2008; 19: Nickelsen M, Ziepert M, Zeynalova S et al. High-dose CHOP plus etoposide (MegaCHOEP) in T-cell lymphoma: a comparative analysis of patients treated within trials of the German High-Grade Non-Hodgkin Lymphoma Study Group (DSHNHL). Ann Oncol 2009; 20: Horning SJ, Juweid ME, Schöder H et al. Interim positron tomography scans in diffuse large B-cell lymphoma: an independent expert nuclear medicine evaluation of the Eastern Cooperative Group E3404 study. Blood 2010; 115: Lin C, Itti E, Haioun C et al. Early 18F-FDG PET for prediction of prognosis in patients with diffuse large B-cell lymphoma: SUV-based assessment versus visual analysis. J Nucl Med 2007; 48: Volume 22 No. 3 March 2011 doi: /annonc/mdq