Hodgkin lymphoma: is there really a need for interim and end‐of‐treatment FDG‐PET evaluations? – Response to Adams & Kwee

We thank our colleagues for their interest in and extensive evaluation of our article (Mesguich et al, 2016), which pointed out that, in Hodgkin lymphoma (HL), interim fluorodeoxyglucose positron emission tomography (FDG-PET) has a lower sensitivity than end-of-treatment PET (46 7% vs. 80%; P = 0 0078), i.e., a negative interim FDG-PET study cannot obviate the need for end-PET examination. We realize that this subject raises questions, and we tried to answer most of them in our article. However, Adams and Kwee stress some additional points that we will try to address. We restrict discussion to ABVD (adriamycin, bleomycin, vinblastine and dacarbazine)-treated patients, as in our report. The first point raised by Adams and Kwee is that we did not sufficiently address how these unsatisfactory results of interim FDG-PET evaluation should be interpreted for routine clinical management. They state that the sensitivity of 46 7% and the PPV of 43 8% seriously question whether interim FDG-PET results should be used for prognostication in this disease, and undermines the feasibility of FDG-PET adapted trials. We agree with Adams and Kwee that the sensitivity of interim PET is suboptimal. This calls for maintaining FDG-PET evaluation at the end of the treatment in order to identify patients who require further therapy (Mesguich et al, 2016). Our results are in agreement with findings from recent trials in advanced HL patients (Johnson et al, 2016; Press et al, 2016), which showed that the relapse rates in interim-PET-negative patients are higher than previously thought (Gallamini et al, 2014). Unfortunately, results from end-of-chemotherapy PET are not available in these reports (Johnson et al, 2016; Press et al, 2016). Despite the limited sensitivity of interim PET, early identification of some patients with resistance to therapy is an important issue, particularly in patients with advanced HL. The positive predictive value of interim PET varies with disease stage and risk factors. A recent retrospective analysis found that 3-year progression-free survival (PFS) rates in interim PET-positive patients ranged between 76 9% and 20% depending on initial risk group (Oki et al, 2014). A retrospective multicentre study found a 3-year PFS rate of 28% for patients with advanced HL and positive interim PET (Gallamini et al, 2014). Based on these results, prospective multicentre trials of PET-adapted therapy have found it unethical to randomise advanced HL patients with positive interim PET after two cycles of ABVD; all these patients were switched to intensified regimens (Johnson et al, 2016; Press et al, 2016). These trials showed encouraging PFS rates in patients offered escalated therapy. We, however, agree with Adams and Kwee that, in the absence of randomisation, the positive predictive value cannot be assessed from these trials (Johnson et al, 2016; Press et al, 2016). Adams and Kwee question why the sensitivity of FDGPET was higher at end of treatment than at interim analysis. Indeed, six patients who were interim PET negative showed FDG-avid lesions on end-of-treatment PET, which might be the result of different reasons. Some tumours might initially respond to chemotherapy but refractory clones are selected that show late resurgence. Also, interim PET is performed shortly after a chemotherapy cycle (e.g. c. 10 days after the second cycle). With this short timing there might be a ‘stunning effect’. In contrast, end-of-treatment PET is usually performed 6–8 weeks after the end of therapy. Finally, for interim PET we used liver as reference (Deauville score ≥4 is positive) based on Lugano guidelines (Cheson et al, 2014), while for end-of-treatment we used mediastinal blood pool (Deauville score ≥3 is positive), the traditional reference region for end-of-treatment PET interpretation (Juweid et al, 2007). Indeed, current guidelines are unclear whether a Deauville score of 3 on end-of-treatment PET should be considered negative or positive (Cheson et al, 2014). This has received little prospective evaluation and validation. We agree with Adams and Kwee that prospective studies can be of importance to define the optimal criteria for end-of-treatment PET positivity (>mediastinal blood pool or >liver). The sensitivity of end-of-treatment FDG-PET in our series (80%) is within the range (50–100%) reported in a metaanalysis (Terasawa et al, 2008). Our findings on superiority of end-PET are in agreement with those from Barnes et al (2011). Our reading of this paper (Barnes et al 2011) could not find the figures quoted in the table presented by Adams and Kwee. Finally, Adams and Kwee state that it might not be at all helpful to assess response to chemotherapy in HL patients, whether by interim or end-of-treatment evaluations. They raised the fact that HL is a highly curable disease and that the number of end-of-treatment FDG-PET scans required to detect one case with residual disease is very high. They also Correspondence