What is the prognostic impact of FDG PET in locally advanced head and neck squamous cell carcinoma treated with concomitant chemo-radiotherapy? A systematic review and meta-analysis

Head and neck cancer is the sixth most common malignant tumour, with increasing incidence worldwide [1]. In over 95% of cases, the disease arises from the epithelial layer of the mucosa lining the upper aerodigestive tract. Due to the absence of anatomical barriers, the abundant lymphatic drainage of the neck and the usually infiltrative pattern of growth of head and neck squamous cell carcinoma (HNSCC), in about 60% of patients the diagnosis is made at an advanced locoregional stage. In order to maximize the likelihood of disease cure, multimodality treatment is usually needed. Therapeutic management is often challenging: both primary radical surgery and concurrent chemoradiotherapy are burdened with a high rate of posttreatment complications, acute and long-term toxicities [2] and a marked detrimental effect on quality of life. Notwithstanding the refinement of treatment strategies that has taken place in last 20 years, the prognosis of HNSCC remains severe, with a cumulative 5-year overall survival (OS) rate of 45–55% [3] in patients with locally advanced disease. The prevalent pattern of failure in the overall population is locoregional: about 50% of first events of relapse occur at the primary tumour site and/or in the neck, in the vast majority (about 90%) within the first 2 years after treatment.

Taking into account that the patient’s outlook can be substantially influenced by clinical factors with large variability existing among the different subsites of disease, a series of common features contribute to the severe prognosis of locally advanced HNSCC; these include the suboptimal efficacy of the standard “one size fits all” multimodal approach, the large proportion of frail patients who are noncompliant with intensive therapy, and the absence of biomarkers. In this regard, the only notable exception is the human papillomavirus (HPV). In the last 15 years, a major epidemiological shift has taken place in western countries due to the rising incidence of HPV-associated oropharyngeal cancer [4], reducing the dominance of the classical phenotype of HNSCC resulting from alcohol and tobacco-induced field cancerization. A positive HPV status was recognized as an independent favourable prognostic factor in a series of correlative prospective studies and in an unplanned secondary analysis of the randomized phase 3 RTOG 0129 trial [5]. Overall, HPV positivity is associated with a reduction in the risk of death and disease progression of about 60%.

Although major progress has been achieved in unravelling key molecular pathways involved in HNSCC pathogenesis [6], at present no biomarkers are available in clinical practice apart from HPV status. Prognostic information is therefore critically lacking in the management of patients affected by HNSCC. Next to individual genomic profiling, an alternative strategy which has been explored in recent years is to integrate molecular imaging into precision oncology care, exploiting the potential of imaging as a biomarker. The possibility of linking the information obtained from medical images with personalized treatment forms the core of “theragnostics”, an term that has been used particularly in the context of radiation therapy [7]. In a hallmark review published in 2000, Ling et al. [8] suggested that the evolution of molecular imaging could facilitate the development of customized dose delivery in the era of intensity-modulated radiotherapy (IMRT). As foreseen by Ling and colleagues, in the last 15 years molecular imaging has been increasingly implemented in the management of HNSCC, in particular ¹⁸F-fluorodeoxyglucose (FDG) positron emission tomography (PET). The fundamental prerequisite is the ability to image physiopathological processes occurring within a tumour or its microenvironment. The use of FDG allows the characterization of the metabolic activity of a defined tumour burden. In HNSCC, available evidence supports the role of FDG PET in primary target definition for radiotherapy planning [9], staging [10] and posttreatment response assessment [11]. However, its potential impact on patient outcomes is an unresolved issue. The aim of this work was to define the relevance of semiquantitative and qualitative FDG PET features as prognostic biomarkers in the curative setting of locally advanced head and neck cancer.

In accordance with the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) statement [12], a systematic review of the literature was conducted. Relevant articles were identified in two databases (MEDLINE and Embase) over a 10-year period (1 January 2007 to 28 February 2017) using the appropriate terminology as described in Appendix 1 of the Supplementary material. Conference proceedings of main international conferences (ASCO, ASTRO, ESMO, ESTRO, ECCO) were also searched. The reference lists of the articles reviewed as full texts were also searched manually. The literature search strategy was based on the PICO methodology [13], as discussed in the following sections.

In the era of precision oncology, the lack of prognostic biomarkers has hindered the evolution of standard-of-care management in HNSCC. Apart from HPV status, no molecular stratification is currently available for use in daily practice. In the last two decades, steady technological progress has highlighted the potential of imaging as a comprehensive tumour biomarker [47]. In the field of functional imaging, FDG PET is the most widespread, easily accessible modality that is able to provide surrogate metabolic information on tumour burden. The aim of our work was to define whether distinct FDG PET features can be intrinsically associated with prognostic relevance in the context of nonmetastatic HNSCC. We acknowledge several limitations which have to be taken into account when interpreting the data presented. First, most studies included in our systematic review were retrospective. Although a strict search methodology was followed, their potential heterogeneity in terms of patient selection, treatment administration and outcome measures may have affected the consistency of our analysis. Second, the technical variability in the performance of FDG PET scans is also a factor that cannot be ignored with a retrospective study design; only a prospective design can ensure that consensus acquisition recommendations [14] are rigorously adopted. Third, among the included studies the methods used to calculate the FDG PET metrics were not consistent. Heterogeneity in their definition has to be taken into account particularly for SUV_max and MTV, for which several threshold values were shown to be significant in discriminating patients with different outcomes.

Renewed interest in the role of FDG PET in the management of HNSCC was recently prompted by the publication of the PET-NECK trial [11]. The findings of this large prospective, multicentre phase 3 trial are practice-changing, since the study provided definitive evidence in favour of a response evaluation centred on the high negative predictive value (NPV) of a 12-week posttreatment FDG PET scan. However, the study had two main limitations that prevented the clarification of other relevant issues on the role of FDG PET in the management of HNSCC. First, none of the 564 patients enrolled in the trial underwent a baseline FDG PET scan; a qualitative comparison between pretreatment and posttreatment scans was therefore not performed. Second, FDG PET semiquantitative metrics could not be evaluated due to nonuniform calibration among the different scanners. From this perspective, the PET-NECK trial did not add any new data to the available low-level body of evidence on the prognostic role of specific FDG PET semiquantitative and qualitative features in HNSCC. Although many investigators have focused on this topic in the last 15 years [48], the literature is characterized by inconclusive and heterogeneous findings [49].

A crucial aspect that needs again to be underlined is the strict dependence of FDG PET information on the image acquisition modality, which in turn may be influenced by a series of factors, ranging from the technical parameters of the scanner to the timing of the scan with respect to treatment. As also demonstrated in our descriptive analysis (Table 5), there is significant variability in the correlation between semiquantitative metrics and outcome measures in HNSCC. We have already pointed out that in the posttreatment scenario a negative PET scan at 12 weeks after chemoradiation is a prognostic biomarker of long-term complete remission based on level 1 evidence. However, standardized interpretation of response to treatment is lacking. In this context, the Hopkins criteria are the only proposed scoring system for qualitative interpretation of FDG PET in HNSCC. Marcus et al. [29] showed that a five-point scale based on prespecified qualitative descriptors is accurate in discriminating complete from incomplete responses. The application of the Hopkins criteria resulted in a high NPV of 91.1% with an overall diagnostic accuracy of 86.9%. Notably, the results of the ECLYPS study [42] prospectively confirmed the reliability of the Hopkins criteria applied 12 weeks after the end of treatment, with an overall NPV of 92.1% and a very low number of equivocal reports. As accurately described by Garibaldi et al. [50] in a recent systematic review, the potential prognostic and predictive relevance of an interim FDG PET scan (scan acquired during treatment) is a controversial matter. At present, no firm conclusions can be drawn as to the ideal metabolic parameter to analyse early in treatment, the most informative threshold value, or the best time to re-scan the patient.

Taking all together, the use of FDG PET in patients with HNSCC provides prognostic information through standardized qualitative assessment at a minimum of 12 weeks after chemoradiation, but no added value during its delivery. It is therefore a rational approach to investigate before treatment whether baseline semiquantitative metrics are intrinsically able to characterize the outcome in patients with locally advanced disease. Conflicting evidence is available from the literature. Pak et al. [51] performed a systematic review and meta-analysis of 13 studies (1,180 patients) to assess the prognostic role of MTV and TLG before treatment. The authors found that high values of both volumetric parameters correlated significantly with a worse outcome. The pooled HRs for OS were 3.51 (95% CI 2.62–4.72, p < 0.00001) and 3.14 (95% CI 2.24 – 4.40, p < 0.00001) for MTV and TLG, respectively. However, the generalizability of these results is open to question. First, loose criteria were followed in the literature search strategy and inclusion of articles. Second, for both parameters no threshold values portending a worse outcome were defined, thus preventing further analysis of the data.

In a prospective study in 77 patients affected by stage II–IV HNSCC, Schinagl et al. [52] consistently applied five different segmentation methods for coregistered CT and FDG PET scans at baseline. Among the different metrics obtained, only the gross tumour volume (GTV) visually delineated on FDG PET images was significantly correlated with outcome in oral cavity and oropharyngeal tumours, while all isocontour-based volumes, SUV_mean and SUV_max, were not. A large single-centre [38] retrospective study on 287 patients receiving IMRT-based treatment showed different results. In a univariate analysis, increasing values of SUV_max (as a logarithmic variable) yielded a HR of 1.72 (95% CI 1.34–2.19) for a worse disease-free survival (DFS) and OS. Multivariate analysis showed an additive effect of increasing GTV (HR 1.74, 95% CI 1.33–2.27; increase in interquartile range from 25% to 75% corresponding to an increase in GTV from 27.4 cm³ to 95.8 cm³) and increasing SUV_max (HR 1.34, 95% CI 1.01–1.77; increase in interquartile range from 25% to 75% corresponding to an increase in SUV_max from 9.6 to 16.8) for a worse prognosis.

The link between FDG avidity and tumour volume has been further explored by different groups focusing on MTV. In this regard, the correlative, prospective imaging study of the randomized phase 3 RTOG 0522 trial [40] is noteworthy. Of the whole sample of 940 patients enrolled, 74 from 19 different centres provided both pretreatment and posttreatment FDG PET scans, as mandated upon inclusion. A prespecified acquisition imaging protocol was followed in all patients. Excellent centralized interobserver agreement (intraclass correlation coefficient ≥0.80) on semiquantitative metrics was reported. Based on voxels with a minimum of 40% SUV_max, baseline primary MTV above the median was the strongest prognosticator of worse LRC (HR 4.01, 95% CI 1.28–12.52, p = 0.2). Other retrospective studies [23, 27, 37] have underlined the prognostic value of baseline MTV, reporting different cut-off values as most significant for a worse outcome (combined primary and nodal MTV >40 ml, >20 ml and >18 ml correlating with worse DFS [23], LRC and OS [27], and disease-specific survival [37], respectively). The prognostic value of MTV analysed as a continuous variable has also been reported.

In a single-centre retrospective analysis in 83 patients, Tang et al. [53] found that an increase in primary baseline MTV of 17 ml (from the 25th to the 75th percentile) was associated with a doubling of the risk of disease progression (p = 0.0002) and of death (p = 0.0048). Of note, combined primary and nodal MTV (as a continuous variable) was also associated with a shorter PFS (HR 4.23, p < 0.0001; CI not reported) and OS (HR 3.21, p < 0.0029; CI not reported) in the subgroup of 64 patients with p16-positive oropharyngeal cancer. In a larger cohort of 122 patients with oropharyngeal cancer, Castelli et al. [45] assessed whether the use of different absolute and relative thresholds of SUV_max result in different discriminatory power of MTV. Using a 51% relative SUV_max threshold, combined primary and nodal MTV was the only significant factor in a multivariate analysis predicting OS (HR 1.43 per 10 ml, CI 1.23–1.65, p < 0.001) and DFS (HR 1.43 per 10 ml;,CI 1.23–1.65, p = 0.03). The optimal cut-off value for MTV 51% was 22.7 ml, which was able to discriminate 2-year DFS with rates of 63.3% versus 32.9% and LRC with rates of 68% versus 35.3%.

The absence of a consensus methodology on VOI delineation is clearly a limitation when comparing different datasets on the prognostic relevance of MTV, since no single optimal cut-off value is recognized. In line with previous experience, our data reinforce the prognostic role of pretreatment MTV as the most informative semiquantitative metabolic feature. In line with our search inclusion criteria, the patient population analysed was extremely homogeneous (about 95% of the whole sample size) in terms of disease stage, radiotherapy technique used and schedule of concomitant chemoradiotherapy. With all due limitations, our analysis provides further evidence on the predominant impact of pretreatment MTV on HNSCC outcome compared with all other available FDG PET metrics. Further consideration of its role also as a predictive biomarker may be generated by pattern-of-failure data correlating baseline FDG PET and radiation dose distribution in HNSCC. Due et al. [54] performed a retrospective analysis in 304 HNSCC patients with the aim of correlating the pattern of disease failure with FDG uptake on pretreatment PET scans. By performing a deformable registration of CT scans acquired at the time of recurrence with the planning PET/CT scan, the authors showed that 96% of relapses (95% CI 86–99%) occurred in the high-dose region. In addition, they found that recurrence density was higher in the central part of the target volume (p < 0.0001), with a significant correlation with increasing FDG avidity (p = 0.036). In a smaller cohort of 44 patients enrolled in a prospective phase 2 trial, Leclerc et al. [55] showed that all ten recurrences arose in areas receiving >95% of the dose determined on PET-based plans. A similar finding was reported by Mohamed et al. [56], who hypothesized that a 1-cm margin in addition to the 50% SUV_max isocontour on pretreatment FDG PET scans would cover the majority of type A recurrences (according to the authors’ definition, those that arise in the central high-dose area).

Once again, it has to be underlined that, among others, the main limitations of FDG in HNSCC are its suboptimal specificity and the large variability in segmentation methods. Potentially, it could be hypothesized that hypoxia PET [57] and diffusion-weighted magnetic resonance imaging [58] may be more refined imaging biomarkers in the field of HNSCC. However, conclusive results on their prognostic impact have long been awaited, mainly due to the lack of reproducibility and cost issues preventing their adoption on a large scale. In our opinion FDG PET will remain the most widespread functional imaging modality used in clinical practice for many years to come.