Re: Richard T. Hoppe, Ranjana H. Advani, Weiyun A. Ai, et al. Hodgkin Lymphoma Version 1.2017, NCCN Clinical Practice Guidelines in Oncology. J Natl Compr Canc Netw 2017;15(5):608–638.
The updated NCCN Clinical Practice Guidelines in Oncology for Hodgkin Lymphoma (HL)1 promote the application of interim fluorodeoxyglucose (FDG)-PET–adapted therapy in both early- and advanced-stage HL. Unfortunately, this approach is not supported by the studies cited.1 In early-stage HL, treatment escalation in interim FDG-PET–positive patients may not be justified, because these patients have an excellent prognosis following standard, nonintensified therapies.2 On the other hand, treatment de-escalation in patients with early-stage HL with negative interim FDG-PET results demonstrated markedly increased relapse rates in all available studies.3 In patients with advanced-stage HL with positive interim FDG-PET results, treatment escalation has not proven to be beneficial, because studies showing favorable results lacked a randomization arm of patients treated with nonintensified therapies. On the contrary, the only available randomized trial on treatment escalation in advanced-stage HL showed that interim FDG-PET–adapted treatment approaches had no benefit at all.4 Finally, treatment de-escalation in patients with advanced-stage HL with negative interim FDG-PET results is controversial, because most patients with therapy-resistant disease have negative interim FDG-PET results.5 Consequently, a negative interim FDG-PET result has low value in ruling out residual disease.
The low value of interim FDG-PET in selecting the appropriate therapy regimen is most likely due to its limited sensitivity and specificity. FDG-PET images have a spatial resolution of 6 to 9 mm, and lymphomatous deposits below this threshold are missed. This theoretical underpinning is reflected by several observations: (1) a combination of lymphoma-positive bone marrow biopsies and no increased FDG uptake in the marrow6; (2) a high relapse rate during follow-up in patients with HL who initially experienced FDG-PET–based complete remission (CR) after treatment7; (3) additional radiation therapy reduces relapse rates despite achieving FDG-PET–based CR3; and (4) patients receiving palliative care and those with indolent non-Hodgkin's lymphoma (NHL) treated with noncurative therapies can experience an FDG-PET–based CR. Meanwhile, the histopathologic substrate of FDG-avid lesions at interim FDG-PET in HL is currently still unknown. Importantly, studies in NHL reported a strikingly high number of false–positive FDG-avid lesions at interim FDG-PET that were histologically verified.8 These results can very likely be translated to HL. Note that HL comprises only 0.1 to 10 of malignant Reed-Sternberg tumor cells9 and that virtually all FDG-avidity is caused by the associated inflammatory substrate, even before treatment has started.
In conclusion, the current evidence does not support the application of interim FDG-PET–adapted treatment in both early- and advanced-stage HL. Theoretical underpinnings suggest that results of future trials on interim FDG-PET will be unlikely to show benefit.
Hoppe RT, Advani RH, Ai WZ et al.. NCCN Clinical Practice Guidelines in Oncology for Hodgkin Lymphoma, Version 1.2017. J Natl Compr Canc Netw 2017;15:608–638.
Adams HJ, Kwee TC. Will treatment intensification in early-stage Hodgkin lymphoma patients with a positive interim FDG-PET improve outcome? Pediatr Hematol Oncol 2016;33:1–4.
Sickinger MT, von Tresckow B, Kobe C et al.. PET-adapted omission of radiotherapy in early stage Hodgkin lymphoma—a systematic review and meta-analysis. Crit Rev Oncol Hematol 2016;101:86–92.
Borchmann P, Haverkamp H, Lohri A et al.. Progression-free survival of early interim PET-positive patients with advanced stage Hodgkin's lymphoma treated with BEACOPPescalated alone or in combination with rituximab (HD18): an open-label, international, randomised phase 3 study by the German Hodgkin Study Group. Lancet Oncol 2017;18:454–463.
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. Borchmann P Haverkamp H Lohri A Progression-free survival of early interim PET-positive patients with advanced stage Hodgkin's lymphoma treated with BEACOPPescalated alone or in combination with rituximab (HD18): an open-label, international, randomised phase 3 study by the German Hodgkin Study Group. Lancet Oncol 2017; 18: 454– 463.
Adams HJ, Kwee TC. Controversies on the prognostic value of interim FDG-PET in advanced-stage Hodgkin lymphoma. Eur J Haematol 2016;97:491–498.
Adams HJ, Nievelstein RA, Kwee TC. Opportunities and limitations of bone marrow biopsy and bone marrow FDG-PET in lymphoma. Blood Rev 2015;29:417–425.
Adams HJ, Nievelstein RA, Kwee TC. Systematic review and meta-analysis on the prognostic value of complete remission status at FDG-PET in Hodgkin lymphoma after completion of first-line therapy. Ann Hematol 2016;95:1–9.
Adams HJ, Kwee TC. Proportion of false-positive lesions at interim and end-of-treatment FDG-PET in lymphoma as determined by histology: systematic review and meta-analysis. Eur J Radiol 2016;85:1963–1970.