Despite the consolidated role of [18F]FDG PET/CT in the treatment response evaluation of HNSCC, there is no clear consensus regarding the optimal interpretation criteria to be used in this clinical scenario. Semi-quantitative PET parameters, such as the well-known SUVmax, did not prove to be reliable indicators probably due to the numerous technical and patient variables that could influence this value, especially in the investigated population (e.g. inflammation and post-treatment effects) [4, 15, 16].
Over the last years, consistent efforts towards standardizing the reporting system in surveillance of HNSCC have been done and a number of different qualitative assessment methods for predicting regional disease control have been proposed in order to find out the best [18F]FDG PET visual scale. However, none of them were approved and routinely used up to date. As known, one of the major limits remains the low sensitivity and PPV.
In our study, the head-to-head comparison between scales showed good sensitivity, specificity, and PPV (87%, 86%, and 76% respectively) and a high NPV (92%) of the first introduced Hopkins scale. Comparing our results with the reference one, published by Marcus and colleagues, we reported almost similar specificity and NPV (92.2% and 91.1%, respectively), but a higher sensitivity and PPV compared to 68.1% and 71.1% in the reference study [12].
Similarly, a 2017 study by Kendi et al. on 69 HNSCC patients showed a sensitivity, specificity, PPV and NPV of the overall therapy assessment of 66.7%, 87.3%, 33%, 96.5% respectively, underlining the higher sensitivity and PPV reached in our study [17]. Diagnostic accuracy of response assessment PET/CT in our study could be affected by the time interval between treatment and follow-up imaging; the later median time point of imaging post-therapy (20 weeks) compared to other studies may account for the slightly higher PPV[18].
More recently, other authors proposed to apply to HNSCC post-treatment PET evaluation the Deauville score, the most famous standardized 5-point Likert scale used for Hodgkin and Non-Hodgkin lymphoma [19]. Benjamin et al. conducted a retrospective analysis on 43 HNSCC patients who underwent organ preservation radiotherapy and applied the DS to [18F]FDG PET/CT scan. Their study results showed a higher PPV than ours (100% vs 70%), but only 4/43 patients have experimented disease progression (4 or 5 DS) in the mentioned study [4].
Another study by Zhong et al., on a larger cohort of 562 patients, compared the diagnostic performance of the Hopkins and Deauville score for predicting locoregional control and PFS. The study confirmed on a larger sample the high NPV of both visual criteria, reaching also a very high PPV compared to our results as well as to the existing literature (51–78%). Although the authors ascribed this higher value to the later median time point of imaging post-therapy (17 weeks) [20].
To deal with these conflicting results, in 2020 an Italian Multicentric study introduced a novel 6-point visual system called Cuneo score to find out a higher PPV [14]. The reference article compared the three different PET visual scores, reporting the best PPV for Cuneo score (with scores 3 and 4 clustered with 1 and 2, indicative of the absence of disease) for all categories: 42.9% for the primary tumor, 100% for the nodal involvement, and 50% for the cumulative score. In our cohort, the primary tumor, lymph node involvement, and the cumulative Cuneo score reached higher PPV values (86%, 83% and 78% respectively), at the expense of lower values of sensitivity and NPV, when compared to Hopkins and Deauville scores.
Our results support the hypothesis proposed by Bonomo et al. of considering 6-point visual criteria to minimize false positive PET findings in post-treatment evaluation of HNSCC, reaching a better PPV. More prospective studies with a larger sample are warranted to support Cuneo criteria. However, because none of the mentioned criteria demonstrated to be able to solve undetermined cases (e.g., Fig. 4), minimizing both false positive and false negative results, a further repeat PET/CT 4–6 weeks later is still necessary.
The survival analysis was consistent with the current literature [21]. All the studied scores once again showed their high prognostic value both in terms of PFS and OS, underlining the reliability of a prognostic score system in HNSCC patients. Two clinical examples extracted from our sample are shown in Fig. 5 and Fig. 6, supporting the prognostic role of each visual score.
Regarding the secondary endpoint of the study, both SUVmax extracted from restaging PET and ΔSUVmax were able to discriminate lymph node persistent disease from treatment-related changes, showing a good performance in predicting outcome. However, their cutoff value found (2.75 for SUVmax, -6.6 for ΔSUVmax) needs to be considered with caution, confirming the debated role of semiquantitative analysis in literature.
The added value of our study was the proof that hybrid imaging, combining morphological and metabolic imaging, could improve the interpretation of [18F]FDG PET/CT in treatment response evaluation. We demonstrated that the Cuneo criteria and the product of diameters of the lymph node with the highest uptake at restaging PET scan could be considered prognostic factors for PFS. To the best of our knowledge, only another 2016 study try to consider lymph node diameters (the short-axis ones) in the restaging PET scan but failed to assess its usefulness [21]. These results could help the visual interpretation of [18F]FDG PET/CT in order to clarify indeterminate cases, and assign new risk classes. The use of contrast enhancement CT on PET/CT exams could strengthen our hypothesis to better discriminate lymph node involvement [22].
One of the major limits of our study is the knowledge of HPV status in more than half of the patients which limits further consideration. HPV status is a well-known prognostic factor in HNSCC. HPV-related HNSCCs, which primarily arise in the oropharynx, have a markedly better prognosis compared to HPV-unrelated [15]. A study suggests that nodal disease may take longer to involute in patients with HPV-positive disease [23]. It is therefore possible that HPV-positive patients with equivocal findings at 3-month [18F]FDG PET/CT assessment, might have achieved a cure without neck dissection if they had undergone a further later PET/CT exam. Accordingly, we can suppose that the slightly higher PPV reached in our study than reported rates, could be related to the HPV status as well as the time between the restaging PET/CT and the end of radiotherapy [7, 24, 25]. Moreover, the retrospective nature of the study and the relatively small sample size has to be also considered.