The predictive value of interim FDG-PET in early-stage Hodgkin lymphoma is not well established

The predictive value of interim FDG-PET in early-stage Hodgkin lymphoma is not well established A recent study by Zaucha et al. [1] included 106 patients with early-stage Hodgkin lymphoma. These patients were treated with 2–4 cycles of adriamycin, bleomycin, vinblastine, and dacarbazine (ABVD) followed by radiation therapy (RT) or with six cycles of ABVD. These patients underwent interim FDG-PET scans after one cycle of ABVD in all 106 cases, whereas 57 (53.8%) underwent FDG-PET imaging both after one and two cycles of ABVD. After one cycle of ABVD, FDG-PET scans of 87/106 (82%) patients were scored negative (i.e. Deauville score 1–3), whereas 19/106 (18%) were scored positive (i.e. Deauville score 4–5), of whom four were excluded from further analysis because of progression and treatment escalation. Of the patients with negative interim FDG-PET results, 4/87 had an event (one progression, three relapses), whereas in the group of patients with positive interim FDG-PET results, 5/15 experienced an event (three progressions, two relapses), resulting in a negative predictive value (NPV) and positive predictive value (PPV) of 95% and 33%, respective. Of the 56 patients with FDG-PET scans performed after two cycles of ABVD, 50 (89.3%) had negative and 6 (10.7%) had positive results. Three of these latter six patients were excluded because of progression and treatment escalation. Consequently, only three patients with positive results at interim FDG-PET after two cycles were evaluable. Each of these three patients (100%) experienced an event (one progression, two relapses), whereas only 2/50 patients with negative interim FDG-PET results (4%) experienced an event (two progressions). Zaucha et al. [1] concluded FDG-PET after two cycles of ABVD to be the optimal tool that can distinguish very well between responders and non-responders. However, we disagree with their conclusion that is based on their very small number of FDG-PET-positive patients, since several important and larger studies evaluating the value of interim FDG-PET after two or more cycles of ABVD that reported contrasting results remained unreported in their discussion (Table 1). Note that results on the predictive value of interim FDG-PET in early-stage Hodgkin lymphoma are heterogeneous (relapse rates ranging from 0% to 100%), with several large-scale studies showing a very low PPV of positive interim FDG-PET results, contradicting the results of Zaucha et al. [1]. In particular, the large-scale EORTC/LYSA/FIL H10 trial [2] is important. This study included 1925 patients with early-stage Hodgkin lymphoma and FDG-PET after two cycles of ABVD. Of 1925 patients, 361 (18.8%) patients had positive FDG-PET results of whom 192 (53.2%) were randomized to standard ABVD with RT. Remarkably, these patients had a very good prognosis, with only 36/192 (18.8%) of these patients developing disease relapse after therapy. Even more striking are the results of Radford et al. [3] who included 565 early-stage Hodgkin lymphoma who had an FDG-PET scan after three cycles of ABVD, of whom 145 (25.7%) had positive results. Of these 145 patients who were resistant to three cycles of ABVD according to FDG-PET, only 15 (10.3%) developed disease relapse after being additionally treated with only one cycle of ABVD and RT, resulting in a low PPV of only 10.3%. Table 1 Studies on the prognostic value of interim FDG-PET in early-stage Hodgkin lymphoma patients treated with ABVD therapy Study (year)  Number of therapy cycles before interim FDG-PET  Number of interim FDG-PET-positive patients/total number of patients included  Standard, non-intensified therapy in interim FDG-PET-positive patients  Proportion of interim FDG- PET-positive patients experiencing treatment failure  Proportion of interim FDG-PET- positive patients experiencing death  PFS of interim FDG-PET patients  OS of interim FDG-PET-positive patients  Studies applying interim FDG-PET after one cycle of ABVD   Hutchings et al. [4] (2014)  1  10/44 (22.7%)  2–4× ABVD + RT or 6× ABVD  6/10 (60%)  NR  NR  NR   Zaucha et al. [1] (2017)  1  19/106 (82%) of whom 15/19 (78.9%) evaluable  2–4× ABVD + RT or 6× ABVD  5/15 (33%)  1/15 (6.7%)  NR  NR    Studies applying interim FDG-PET after two cycles of ABVD   Andre et al. [2] (2017)  2  361/1925 (18.8%), of whom 192/361 (53.2%) randomized to standard ABVD therapy  3–4× ABVD + RT  36/192 (18.8%)  NR  5-year PFS: 77.4%  5-year OS: 89.3%   Filippi et al. [5] (2013)  2  10/80 (12.5%)  3× ABVD + RT: 9  0/10 (0.0%)  0/10 (0%)  3-year PFS: 100%  3-year OS: 100%  4× ABVD + RT: 71   Rigacci et al. [6] (2015)  2  36/246 (14.6%)  4× ABVD + RT  19/36 (52.8%)  6/36 (16.7%)  2-year PFS: 30%  NR   Simontacchi et al. [7] (2015)  2  43/257 (16.7%)  4× ABVD + RT: 24  6/43 (14.0%)  3/43 (7.0%)  5-year PFS: 83.7%  5-year OS: 93.0%  6× ABVD + RT: 12  2× ABVD + other regimen + RT: 5  2× ABVD + HDT + ASCT: 2   Zaucha et al. [1] (2017)  2  6/56, of whom 3/6 treated with standard ABVD therapy  2–4× ABVD + RT or 6× ABVD  3/3 (100%)  1/3 (33%)  NR  NR   Zinzani et al. [8] (2012)  2  19/147  4× ABVD + RT or 6× ABVD  15/19 (78.9%)  2/19 (10.5%)  9-year PFS: 31.3%  9-year OS: 85.2%    Studies applying interim FDG-PET after three cycles of ABVD   Radford et al. [3] (2015)  3  145/565 (25.7%)  4× ABVD + RT  15/145 (10.3%)  8/145 (5.5%)  NR  NR  Study (year)  Number of therapy cycles before interim FDG-PET  Number of interim FDG-PET-positive patients/total number of patients included  Standard, non-intensified therapy in interim FDG-PET-positive patients  Proportion of interim FDG- PET-positive patients experiencing treatment failure  Proportion of interim FDG-PET- positive patients experiencing death  PFS of interim FDG-PET patients  OS of interim FDG-PET-positive patients  Studies applying interim FDG-PET after one cycle of ABVD   Hutchings et al. [4] (2014)  1  10/44 (22.7%)  2–4× ABVD + RT or 6× ABVD  6/10 (60%)  NR  NR  NR   Zaucha et al. [1] (2017)  1  19/106 (82%) of whom 15/19 (78.9%) evaluable  2–4× ABVD + RT or 6× ABVD  5/15 (33%)  1/15 (6.7%)  NR  NR    Studies applying interim FDG-PET after two cycles of ABVD   Andre et al. [2] (2017)  2  361/1925 (18.8%), of whom 192/361 (53.2%) randomized to standard ABVD therapy  3–4× ABVD + RT  36/192 (18.8%)  NR  5-year PFS: 77.4%  5-year OS: 89.3%   Filippi et al. [5] (2013)  2  10/80 (12.5%)  3× ABVD + RT: 9  0/10 (0.0%)  0/10 (0%)  3-year PFS: 100%  3-year OS: 100%  4× ABVD + RT: 71   Rigacci et al. [6] (2015)  2  36/246 (14.6%)  4× ABVD + RT  19/36 (52.8%)  6/36 (16.7%)  2-year PFS: 30%  NR   Simontacchi et al. [7] (2015)  2  43/257 (16.7%)  4× ABVD + RT: 24  6/43 (14.0%)  3/43 (7.0%)  5-year PFS: 83.7%  5-year OS: 93.0%  6× ABVD + RT: 12  2× ABVD + other regimen + RT: 5  2× ABVD + HDT + ASCT: 2   Zaucha et al. [1] (2017)  2  6/56, of whom 3/6 treated with standard ABVD therapy  2–4× ABVD + RT or 6× ABVD  3/3 (100%)  1/3 (33%)  NR  NR   Zinzani et al. [8] (2012)  2  19/147  4× ABVD + RT or 6× ABVD  15/19 (78.9%)  2/19 (10.5%)  9-year PFS: 31.3%  9-year OS: 85.2%    Studies applying interim FDG-PET after three cycles of ABVD   Radford et al. [3] (2015)  3  145/565 (25.7%)  4× ABVD + RT  15/145 (10.3%)  8/145 (5.5%)  NR  NR  ABVD, adriamycin, bleomycin, vinblastine, and dacarbazine; ASCT, autologous stem cell transplantation; HDT, high-dose chemotherapy; OS, overall survival; PFS, progression-free survival; RT, radiation therapy. In conclusion, several large-scale studies have shown early-stage Hodgkin lymphoma patients with positive interim FDG-PET results after two or more cycles of ABVD to have a good prognosis, contradicting the results and conclusion of Zaucha et al. [1]. Consequently, interim FDG-PET may not be an adequate tool to distinguish responders from non-responders. Acknowledgments This article does not contain any studies with human participants or animals performed by any of the authors. Funding None declared. Disclosure The authors have declared no conflicts of interest. References 1 Zaucha JM, Małkowski B, Chauvie S et al.   The predictive role of interim PET after the first chemotherapy cycle and sequential evaluation of response to ABVD in Hodgkin’s lymphoma patients—the Polish Lymphoma Research Group (PLRG) Observational Study. Ann Oncol  2017; 28( 12): 3051– 3057. Google Scholar CrossRef Search ADS PubMed  2 Andre MP, Girinsky T, Federico M et al.   Early positron emission tomography response-adapted treatment in stage I and II Hodgkin lymphoma: final results of the randomized EORTC/LYSA/FIL H10 Trial. J Clin Oncol  2017; 35: 1786– 1794. Google Scholar CrossRef Search ADS PubMed  3 Radford J, Illidge T, Counsell N et al.   Results of a trial of PET-directed therapy for early-stage Hodgkin’s lymphoma. N Engl J Med  2015; 372( 17): 1598– 1607. Google Scholar CrossRef Search ADS PubMed  4 Hutchings M, Kostakoglu L, Zaucha JM et al.   In vivo treatment sensitivity testing with positron emission tomography/computed tomography after one cycle of chemotherapy for Hodgkin lymphoma. J ClinOncol  2014; 32: 2705– 2711. Google Scholar CrossRef Search ADS   5 Filippi AR, Botticella A, Bello M et al.   Interim positron emission tomography and clinical outcome in patients with early stage Hodgkin lymphoma treated with combined modality therapy. Leuk Lymphoma  2013; 54( 6): 1183– 1187. Google Scholar CrossRef Search ADS PubMed  6 Rigacci L, Puccini B, Zinzani PL et al.   The prognostic value of positron emission tomography performed after two courses (INTERIM-PET) of standard therapy on treatment outcome in early stage Hodgkin lymphoma: A multicentric study by the fondazione italiana linfomi (FIL). Am J Hematol  2015; 90( 6): 499– 503. Google Scholar CrossRef Search ADS PubMed  7 Simontacchi G, Filippi AR, Ciammella P et al.   Interim PET after two ABVD cycles in early-stage Hodgkin lymphoma: outcomes following the continuation of chemotherapy plus radiotherapy. Int J Radiat Oncol Biol Phys  2015; 92( 5): 1077– 1083. Google Scholar CrossRef Search ADS PubMed  8 Zinzani PL, Rigacci L, Stefoni V et al.   Early interim 18F-FDG PET in Hodgkin's lymphoma: evaluation on 304 patients. Eur J Nucl Med Mol Imaging  2012; 39( 1): 4– 12. Google Scholar CrossRef Search ADS PubMed  © The Author(s) 2017. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For Permissions, please email: journals.permissions@oup.com. http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Annals of Oncology Oxford University Press

The predictive value of interim FDG-PET in early-stage Hodgkin lymphoma is not well established

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Abstract

A recent study by Zaucha et al. [1] included 106 patients with early-stage Hodgkin lymphoma. These patients were treated with 2–4 cycles of adriamycin, bleomycin, vinblastine, and dacarbazine (ABVD) followed by radiation therapy (RT) or with six cycles of ABVD. These patients underwent interim FDG-PET scans after one cycle of ABVD in all 106 cases, whereas 57 (53.8%) underwent FDG-PET imaging both after one and two cycles of ABVD. After one cycle of ABVD, FDG-PET scans of 87/106 (82%) patients were scored negative (i.e. Deauville score 1–3), whereas 19/106 (18%) were scored positive (i.e. Deauville score 4–5), of whom four were excluded from further analysis because of progression and treatment escalation. Of the patients with negative interim FDG-PET results, 4/87 had an event (one progression, three relapses), whereas in the group of patients with positive interim FDG-PET results, 5/15 experienced an event (three progressions, two relapses), resulting in a negative predictive value (NPV) and positive predictive value (PPV) of 95% and 33%, respective. Of the 56 patients with FDG-PET scans performed after two cycles of ABVD, 50 (89.3%) had negative and 6 (10.7%) had positive results. Three of these latter six patients were excluded because of progression and treatment escalation. Consequently, only three patients with positive results at interim FDG-PET after two cycles were evaluable. Each of these three patients (100%) experienced an event (one progression, two relapses), whereas only 2/50 patients with negative interim FDG-PET results (4%) experienced an event (two progressions). Zaucha et al. [1] concluded FDG-PET after two cycles of ABVD to be the optimal tool that can distinguish very well between responders and non-responders. However, we disagree with their conclusion that is based on their very small number of FDG-PET-positive patients, since several important and larger studies evaluating the value of interim FDG-PET after two or more cycles of ABVD that reported contrasting results remained unreported in their discussion (Table 1). Note that results on the predictive value of interim FDG-PET in early-stage Hodgkin lymphoma are heterogeneous (relapse rates ranging from 0% to 100%), with several large-scale studies showing a very low PPV of positive interim FDG-PET results, contradicting the results of Zaucha et al. [1]. In particular, the large-scale EORTC/LYSA/FIL H10 trial [2] is important. This study included 1925 patients with early-stage Hodgkin lymphoma and FDG-PET after two cycles of ABVD. Of 1925 patients, 361 (18.8%) patients had positive FDG-PET results of whom 192 (53.2%) were randomized to standard ABVD with RT. Remarkably, these patients had a very good prognosis, with only 36/192 (18.8%) of these patients developing disease relapse after therapy. Even more striking are the results of Radford et al. [3] who included 565 early-stage Hodgkin lymphoma who had an FDG-PET scan after three cycles of ABVD, of whom 145 (25.7%) had positive results. Of these 145 patients who were resistant to three cycles of ABVD according to FDG-PET, only 15 (10.3%) developed disease relapse after being additionally treated with only one cycle of ABVD and RT, resulting in a low PPV of only 10.3%. Table 1 Studies on the prognostic value of interim FDG-PET in early-stage Hodgkin lymphoma patients treated with ABVD therapy Study (year)  Number of therapy cycles before interim FDG-PET  Number of interim FDG-PET-positive patients/total number of patients included  Standard, non-intensified therapy in interim FDG-PET-positive patients  Proportion of interim FDG- PET-positive patients experiencing treatment failure  Proportion of interim FDG-PET- positive patients experiencing death  PFS of interim FDG-PET patients  OS of interim FDG-PET-positive patients  Studies applying interim FDG-PET after one cycle of ABVD   Hutchings et al. [4] (2014)  1  10/44 (22.7%)  2–4× ABVD + RT or 6× ABVD  6/10 (60%)  NR  NR  NR   Zaucha et al. [1] (2017)  1  19/106 (82%) of whom 15/19 (78.9%) evaluable  2–4× ABVD + RT or 6× ABVD  5/15 (33%)  1/15 (6.7%)  NR  NR    Studies applying interim FDG-PET after two cycles of ABVD   Andre et al. [2] (2017)  2  361/1925 (18.8%), of whom 192/361 (53.2%) randomized to standard ABVD therapy  3–4× ABVD + RT  36/192 (18.8%)  NR  5-year PFS: 77.4%  5-year OS: 89.3%   Filippi et al. [5] (2013)  2  10/80 (12.5%)  3× ABVD + RT: 9  0/10 (0.0%)  0/10 (0%)  3-year PFS: 100%  3-year OS: 100%  4× ABVD + RT: 71   Rigacci et al. [6] (2015)  2  36/246 (14.6%)  4× ABVD + RT  19/36 (52.8%)  6/36 (16.7%)  2-year PFS: 30%  NR   Simontacchi et al. [7] (2015)  2  43/257 (16.7%)  4× ABVD + RT: 24  6/43 (14.0%)  3/43 (7.0%)  5-year PFS: 83.7%  5-year OS: 93.0%  6× ABVD + RT: 12  2× ABVD + other regimen + RT: 5  2× ABVD + HDT + ASCT: 2   Zaucha et al. [1] (2017)  2  6/56, of whom 3/6 treated with standard ABVD therapy  2–4× ABVD + RT or 6× ABVD  3/3 (100%)  1/3 (33%)  NR  NR   Zinzani et al. [8] (2012)  2  19/147  4× ABVD + RT or 6× ABVD  15/19 (78.9%)  2/19 (10.5%)  9-year PFS: 31.3%  9-year OS: 85.2%    Studies applying interim FDG-PET after three cycles of ABVD   Radford et al. [3] (2015)  3  145/565 (25.7%)  4× ABVD + RT  15/145 (10.3%)  8/145 (5.5%)  NR  NR  Study (year)  Number of therapy cycles before interim FDG-PET  Number of interim FDG-PET-positive patients/total number of patients included  Standard, non-intensified therapy in interim FDG-PET-positive patients  Proportion of interim FDG- PET-positive patients experiencing treatment failure  Proportion of interim FDG-PET- positive patients experiencing death  PFS of interim FDG-PET patients  OS of interim FDG-PET-positive patients  Studies applying interim FDG-PET after one cycle of ABVD   Hutchings et al. [4] (2014)  1  10/44 (22.7%)  2–4× ABVD + RT or 6× ABVD  6/10 (60%)  NR  NR  NR   Zaucha et al. [1] (2017)  1  19/106 (82%) of whom 15/19 (78.9%) evaluable  2–4× ABVD + RT or 6× ABVD  5/15 (33%)  1/15 (6.7%)  NR  NR    Studies applying interim FDG-PET after two cycles of ABVD   Andre et al. [2] (2017)  2  361/1925 (18.8%), of whom 192/361 (53.2%) randomized to standard ABVD therapy  3–4× ABVD + RT  36/192 (18.8%)  NR  5-year PFS: 77.4%  5-year OS: 89.3%   Filippi et al. [5] (2013)  2  10/80 (12.5%)  3× ABVD + RT: 9  0/10 (0.0%)  0/10 (0%)  3-year PFS: 100%  3-year OS: 100%  4× ABVD + RT: 71   Rigacci et al. [6] (2015)  2  36/246 (14.6%)  4× ABVD + RT  19/36 (52.8%)  6/36 (16.7%)  2-year PFS: 30%  NR   Simontacchi et al. [7] (2015)  2  43/257 (16.7%)  4× ABVD + RT: 24  6/43 (14.0%)  3/43 (7.0%)  5-year PFS: 83.7%  5-year OS: 93.0%  6× ABVD + RT: 12  2× ABVD + other regimen + RT: 5  2× ABVD + HDT + ASCT: 2   Zaucha et al. [1] (2017)  2  6/56, of whom 3/6 treated with standard ABVD therapy  2–4× ABVD + RT or 6× ABVD  3/3 (100%)  1/3 (33%)  NR  NR   Zinzani et al. [8] (2012)  2  19/147  4× ABVD + RT or 6× ABVD  15/19 (78.9%)  2/19 (10.5%)  9-year PFS: 31.3%  9-year OS: 85.2%    Studies applying interim FDG-PET after three cycles of ABVD   Radford et al. [3] (2015)  3  145/565 (25.7%)  4× ABVD + RT  15/145 (10.3%)  8/145 (5.5%)  NR  NR  ABVD, adriamycin, bleomycin, vinblastine, and dacarbazine; ASCT, autologous stem cell transplantation; HDT, high-dose chemotherapy; OS, overall survival; PFS, progression-free survival; RT, radiation therapy. In conclusion, several large-scale studies have shown early-stage Hodgkin lymphoma patients with positive interim FDG-PET results after two or more cycles of ABVD to have a good prognosis, contradicting the results and conclusion of Zaucha et al. [1]. Consequently, interim FDG-PET may not be an adequate tool to distinguish responders from non-responders. Acknowledgments This article does not contain any studies with human participants or animals performed by any of the authors. Funding None declared. Disclosure The authors have declared no conflicts of interest. References 1 Zaucha JM, Małkowski B, Chauvie S et al.   The predictive role of interim PET after the first chemotherapy cycle and sequential evaluation of response to ABVD in Hodgkin’s lymphoma patients—the Polish Lymphoma Research Group (PLRG) Observational Study. Ann Oncol  2017; 28( 12): 3051– 3057. Google Scholar CrossRef Search ADS PubMed  2 Andre MP, Girinsky T, Federico M et al.   Early positron emission tomography response-adapted treatment in stage I and II Hodgkin lymphoma: final results of the randomized EORTC/LYSA/FIL H10 Trial. J Clin Oncol  2017; 35: 1786– 1794. Google Scholar CrossRef Search ADS PubMed  3 Radford J, Illidge T, Counsell N et al.   Results of a trial of PET-directed therapy for early-stage Hodgkin’s lymphoma. N Engl J Med  2015; 372( 17): 1598– 1607. Google Scholar CrossRef Search ADS PubMed  4 Hutchings M, Kostakoglu L, Zaucha JM et al.   In vivo treatment sensitivity testing with positron emission tomography/computed tomography after one cycle of chemotherapy for Hodgkin lymphoma. J ClinOncol  2014; 32: 2705– 2711. Google Scholar CrossRef Search ADS   5 Filippi AR, Botticella A, Bello M et al.   Interim positron emission tomography and clinical outcome in patients with early stage Hodgkin lymphoma treated with combined modality therapy. Leuk Lymphoma  2013; 54( 6): 1183– 1187. Google Scholar CrossRef Search ADS PubMed  6 Rigacci L, Puccini B, Zinzani PL et al.   The prognostic value of positron emission tomography performed after two courses (INTERIM-PET) of standard therapy on treatment outcome in early stage Hodgkin lymphoma: A multicentric study by the fondazione italiana linfomi (FIL). Am J Hematol  2015; 90( 6): 499– 503. Google Scholar CrossRef Search ADS PubMed  7 Simontacchi G, Filippi AR, Ciammella P et al.   Interim PET after two ABVD cycles in early-stage Hodgkin lymphoma: outcomes following the continuation of chemotherapy plus radiotherapy. Int J Radiat Oncol Biol Phys  2015; 92( 5): 1077– 1083. Google Scholar CrossRef Search ADS PubMed  8 Zinzani PL, Rigacci L, Stefoni V et al.   Early interim 18F-FDG PET in Hodgkin's lymphoma: evaluation on 304 patients. Eur J Nucl Med Mol Imaging  2012; 39( 1): 4– 12. Google Scholar CrossRef Search ADS PubMed  © The Author(s) 2017. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

Journal

Annals of OncologyOxford University Press

Published: Feb 1, 2018

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