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Cox et al. J Cancer Metastasis Treat 2021;7:25 https://dx.doi.org/10.20517/2394-4722.2021.55 Page 7 of 11

Table 1. Overview of current and future concepts in radiotherapy for HNSCC
Concepts Currently Near future Distant future
RT dose/volume - Traditional binary dose - FDG-PET guided gradient dose - On individual basis, elective volumes will
prescription prescription be largely reduced or completely abandoned
- Large elective irradiation - Sentinel lymph node procedure - Selective irradiation of sentinel lymph
volumes node(s) only
FDG-PET for - Increasingly used, but not in - Algorithms for risk assessment of lymph - Biological target volumes based on more
radiotherapy planning a systematic manner nodes and segmentation of PET-signal specific PET-tracers
Interim PET response - Not widely implemented in - Dose adaptive RT (e.g., escalation/de- - Biological tumor profiling with various
evaluation clinical practice escalation) PET-tracers to guide patient tailored
- Anatomically adaptive RT treatment

HNSCC: Head and neck squamous cell carcinoma; RT: radiotherapy; FDG-PET: fluor-18-fluorodeoxyglucose positron emission tomography.

toxicity in patients with good response.

Prognostic PET-biomarkers
Timing is of crucial importance when determining the value of interim FDG-PET/CT for various reasons.
First, radiotherapy-induced mucositis occurring mostly in the second half of the treatment course could
complicate the interpretation of images. Secondly, evaluation should not be done too early because it takes
time to develop a response. And third, the earlier response prediction can be done, the more time remains
to modify the treatment strategy. There are good indications that week 2-3 of radiotherapy, corresponding
to a delivered dose of about 20 Gy, seems the most favourable time-point for interim PET-evaluation [44,45,47] .

In a meta-analysis, pre-treatment high metabolic tumor volume, defined as the sum of the volume of voxels
in a tumor with standardized uptake value (SUV) surpassing a certain threshold value, was significantly
associated with a worse loco-regional control and overall survival . Several studies reported that a lower
[46]
total lesion glycolysis (i.e., the product of SUVmean and metabolic tumor volume) at 3 weeks into treatment
was predictive for loco-regional control and overall survival in patients with HNSCC [45,48-50] . Metabolic
tumor volume and SUVmax reduction during treatment seem also prognostic for loco-regional
control [45,51,52] . Hentschel et al. found in a retrospective analysis that patients with a reduction of SUVmax
[47]
≥ 50% within the first 2 weeks of (C)RT, showed significantly higher 2-year overall survival rates (88% vs.
38%; P = 0.02) and 2-year loco-regional control rates (88% vs. 40%; P = 0.06) compared to patients with a
SUVmax reduction < 50%. However, evidence regarding this issue remains equivocal. At present, no firm
conclusions can be drawn about the optimal metabolic parameter to predict outcome early during
treatment using FDG-PET, nor the corresponding threshold values.

PET-guided adaptive radiotherapy
Early response evaluation with PET imaging could open a window of opportunity for adaptive treatment
strategies [Table 1] . First, there is the possibility to refine the target volume during the course of radiation
[53]
therapy based on changes in FDG-uptake, which would allow for a reduction of the treated volume and thus
facilitate healthy tissue sparing. Already in 2007, Geets et al. found that, using a gradient-based algorithm
[54]
on five FDG-PET scans performed before and during radiotherapy, PET-segmented target volumes could
be reduced by 15%-40% compared to baseline CT-planning. Other studies have demonstrated a reduction of
the mean parotid dose with CT-based re-planning during the course of radiation for a selected group of
patients, which resulted in a significantly lower risk of xerostomia [53,55] . The main difficulty of anatomically
adaptive radiotherapy is the fact that re-simulating, re-contouring, and re-planning of patients remains
highly time-consuming . Besides, there is no clear consensus about clinical or dosimetric criteria to select
[56]
patients who benefit most from re-planning. However, we envisage that this process will be largely
automated in the near future, based on technological advancement such as synthetic CT generation from