Pretherapeutic FDG-PET total metabolic tumor volume predicts response to induction therapy in pediatric Hodgkin’s lymphoma

Hodgkin’s lymphoma (HL) accounts for about 7% of pediatric malignancies and about 1% of childhood cancer-related deaths in the United States [1]. Treatment intensity within standardized treatment protocols is based on different treatment groups/treatment levels (TG/TL) defined by the clinical stages I to IV, the presence of extranodal lesions, elevated erythrocyte sedimentation rate (ESR, ≥ 30 mm/h) or a tumor bulk ≥ 200 ml [2, 3]. F18-fluorodesoxyglucose-positron emission tomography/computed tomography (FDG-PET/CT) allows for combined functional-metabolic and morphological imaging both at initial staging to define the patient’s clinical stage [4] and during treatment to assess the presence or absence of remaining vital lymphoma tissue [5–7]. In particular, FDG-PET/CT has become essential for early response assessment (ERA) performed after 2 cycles of induction therapy [2, 3, 5]; only if FDG-avid tissue is still present in initially involved sites (semi-quantified as Deauville score > 3 or quantified with qPET [6]) or bulky lesions show < 50% volume reduction in CT, patients in all TG/TL are currently eligible for radiotherapy (RT) dependent on late response assessment following further chemotherapy. In patients with adequate response (AR), RT can be omitted irrespective of the TG/TL – and late effects due to radiotherapy, especially secondary malignancies, are avoided [8, 9]. Nevertheless, prediction of OS by ERA may inferior to late response assessment (LRA) [10]. Furthermore, initial prediction of response to induction therapy could even allow individualized treatment intensification to prevent IR a priori.

Despite this important role of FDG-PET/CT, no initial PET based parameter has been identified so far to predict response at ERA in pediatric HL patients – including the standardized uptake value (SUV) as the most common quantitative FDG-PET parameter [11]. Nevertheless, Meignan et al. recently showed in adult patients with follicular lymphoma (mostly stage III or IV disease) that a high initial metabolic tumor volume (MTV) can predict progression-free survival (PFS) and overall survival (OS) [12]. Moreover, Ben Bouallègue et al. demonstrated that heterogeneity parameters derived from the delineated MTV can serve as additional predictors of early metabolic response in adults with bulky Hodgkin and non-Hodgkin lymphomas [13].

Accordingly, the aim of this study was to identify metabolic or heterogeneity parameters from pretherapeutic FDG-PET/CT to predict inadequate response (IR) in pediatric patients with HL. PFS or OS were not selected as endpoints in this study because both are not only determined by initial characteristics/risk profile (which was the main focus of this study) but also by the extent of treatment (and namely the performance of RT).

The aim of the present study was to investigate the predictive value of several quantitative parameters derived from pretherapeutic FDG-PET in pediatric HL regarding the occurrence of IR at ERA after induction therapy.

The total MTV of all nodal and extranodal HL lesions of the patients predicted IR with high but varying accuracy within all three TG/TL (AUC, 0.71 to 0.92). Furthermore, the optimal cut-off to distinguish patients with IR or AR was distinctly different between either stages I/II versus III/IV (cut-off, > 80 ml vs. > 410 ml) or between the three TG/TL (> 80 ml vs. > 160 ml vs. > 410 ml). This reflects an increasing average MTV especially between stage I/II and stage III/IV disease as one expects given the supposed increase in involved regions – while, interestingly, the average MTV in stage III and stage IV was similar (Fig. 2).

This study shows that quantitative parameters from pretherapeutic FDG-PET can predict IR to induction therapy in pediatric HL. This could help to further improve the established risk stratification. Patients with a high risk for IR could benefit from more intense induction therapy to increase their probability of achieving AR and avoid additional radiation therapy. Vice versa, patients with a priori especially low risk for IR might be the best candidates for the pursued treatment de-escalation. With regard to the patient’s outcome, Cottereau et al. demonstrated that the baseline MTV in adult patients with peripheral T-cell lymphoma (PTCL) helps to predict PFS and OS [24]. Both Cottereau et al. and Meignan et al. [12] delineated the MTV based on 41% of the maximum activity (i.e. t41 in the Supplementary material of the present study). However, Cottereau et al. further showed that a fixed threshold of 41% of maximum activity and different adaptive thresholds render highly correlative MTV and equally predict PFS and OS in patients with PTCL [25]. In the current study, the MTV was primarily defined using a background-adapted semi-automated algorithm (BG) but comparison with t41 confirmed this high inter-method agreement in measured MTV and ASP (see Additional file 1). In contrast, agreement with an absolute threshold of SUV = 2.5 was lower. However, larger patient samples would be required to evaluate if one of the methods is significantly more accurate to predict the patient’s outcome. In a study by Kanoun et al. with 59 mainly adult HL patients, MTV delineated with a 41% relative threshold or a fixed SUV of 2.5 equally allowed to identify patients with impaired PFS despite considerable inter-method MTV differences [26]. Nevertheless, advantageous practicality or robustness might favor one of the delineation approaches. Only BG and t41 allow for a differentiated delineation of lesions taking into account their intralesional and interlesional uptake heterogeneity – which is especially true for BG (see [16] for details). However, this might prolongate the delineation process if neighboring lesions within a subvolume (e.g. the mediastinum) are especially heterogeneous. An absolute SUV threshold disregards such heterogeneities which can facilitate lesion delineation despite the necessity to adjust the absolute SUV level in high background activity (e.g. spleen or bones) or to manually exclude background voxels from the MTV. For background-adapted MTV delineation, we used an algorithm developed at our site, but several other viable automated algorithms have been published [27–35]. It can be assumed that these algorithms perform similar to the algorithm used here.

Further metabolic parameters performed slightly (TLG) or considerably worse (different SUVs) compared to the MTV. This is in accordance with a study by Bouallègue et al. who did not find an association between SUVmax, SUVmean or SUVpeak with the early metabolic response in 57 patients (mostly adults) with HL or non-Hodgkin lymphoma [13]. The observation that the FDG uptake intensity in HL lesions is of less relevance than the anatomical distribution or volumetric extent of the lesions might be attributed to the multifocal/systemic nature of HL in contrast to other childhood malignancies such as Ewing’s sarcoma [36] or osteosarcoma [37] in which the pre-treatment SUVmax is a prognostic factor. Furthermore, the examined heterogeneity parameters – among which the ASP still performed best – showed lower predictive accuracy on average than the MTV. Except for the ASP, none of the heterogeneity parameters provided consistent predictive value sufficient for clinical application. Similarly, in the study by Ben Bouallègue et al., entropy, contrast and CSH were no significant predictors of early metabolic response (neither was the ASP) [13]. To estimate why certain heterogeneity parameters are especially relevant in different tumor entities requires thorough consideration of methodological (spatial resolution, voxel size), biological (lesion number and sizes), and metabolic features (intralesional heterogeneity of FDG uptake intensity). The examined heterogeneity parameters are differently susceptible to these factors. More specifically, the ASP is a priori independent not only from the size of the MTV itself but also from the heterogeneity of the intralesional activity distribution (it only depends on the MTV’s surface complexity). Thus, it could in principal be valuable as an additional quantitative parameter to the MTV to improve the predictive value of pretherapeutic PET in pediatric HL in all or only some of the different TG/TL. This combined risk assessment could especially help to increase the sensitivity to identify patients at risk for IR which is likely the primary clinical goal. Both parameters were significantly related to the response to induction therapy when evaluated in separate models (log-linear analysis); however, the evaluation of an independent predictive relevance of both parameters in a combined analysis would require a larger sample size. This is also true for the relationship between MTV and ASP with the tumor stage or TG/TL.

This retrospective explorative study is limited by the investigation of only 50 patients (although treated consecutively) which necessitates a larger study with an independent patient cohort to validate the presented results and to further elucidate the predictive value of single parameters within the relevant subgroups. Furthermore, as only one patient had stage I, no specific conclusions can be drawn for this stage in particular.

The response to induction therapy at ERA was used as endpoint in the current study but is only a surrogate for patient outcome – as opposed to the PFS or OS. Indeed, the predictive value of a high pretherapeutic MTV independent from the German Hodgkin Study Group (GHSG) risk group has been recently demonstrated retrospectively in 267 adult patients with early stage HL [38]. Nevertheless, one must be aware that a long-term endpoint as PFS or OS implies a certain bias of response-dependent treatment intensification (namely radiotherapy) that can only be avoided by a prospective study design or an early universal surrogate parameter such as the IR to a uniform induction treatment.

In this explorative study, a high total MTV best predicted IR to induction therapy in pediatric HL of all pretherapeutic FDG-PET parameters. This was true in both low and high stages as well as the three different TG/TL. Among the investigated heterogeneity parameters, only ASP may be sufficiently predictive of IR to serve as a supplemental parameter to the MTV and further improve the predictive accuracy. The influence of inter-method MTV variability of different delineation approaches on their predictive accuracy requires further investigation.