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Page 8 of 11 Cox et al. J Cancer Metastasis Treat 2021;7:25 https://dx.doi.org/10.20517/2394-4722.2021.55

daily cone-beam computed tomography and auto-contouring using artificial intelligence [57,58] . Though CT-
based automated re-planning could theoretically be performed on a daily basis, this is not realistic for FDG-
PET-guided re-planning. FDG-PET should be reserved for re-planning based on metabolic tumor response
[44]
once or twice during a course of radiotherapy .

Second, there is the strategy of radiotherapy dose (de-)escalation during treatment. Several studies
confirmed the feasibility of FDG-PET-guided “dose painting by numbers”, where voxel-wise dose escalation
is related to FDG-uptake to produce a non-uniform dose distribution [59-61] . Currently two randomized
controlled phase II trials are investigating whether radiotherapy dose escalation based on interim FDG-
PET/CT can improve loco-regional control compared to standard radiotherapy (NCT01341535 &
NCT01504815). However, in this era of concomitant chemotherapy, immunotherapy, and targeted therapy,
it is debatable if radiotherapy dose escalation is a reasonable approach to improve outcome, especially since
it may increase the risk of severe late toxicity such as mucosal ulcers . Therefore, we believe it is important
[62]
to keep the high dose volume (e.g., > 70 Gy) to a minimum. When using modern imaging, the target
definition is more accurate and GTV-CTV margins can be tighter [63-65] . Also, the traditional dose of 70 Gy
gross
may be unnecessarily high for microscopic local tumor spread. Applying an intermediate dose of
approximately 50-60 Gy to the periphery of the tumor may be adequate to eradicate small tumor extensions.
This opens an opportunity for dose escalation to smaller, but highly active metabolic tumor volumes, or
small tumor volumes that show residual FDG uptake towards the end of the radiation course, without
increasing the risk of late squealy. In the future of HNSCC treatment, it remains highly important to explore
the landscape of patient tailored radiotherapy-drug combinations and how PET-based early response
assessment, next to genetic and biological tumor profiling, can steer this process .
[66]

Opposite to radiotherapy dose intensification, interim PET treatment evaluation enables the opportunity for
dose de-escalation in patients with favourable prognosis and excellent intra-treatment tumor response in
order to decrease radiotherapy related morbidity. Clinical evidence regarding interim PET-guided dose de-
escalation in well-responding patients remains scarce, especially in HPV-negative HNSCC and patients
[67]
treated with primary radiotherapy . Recently, a non-randomized controlled trial has been initiated to
evaluate the safety of radiotherapy dose de-escalation in HPV-associated oropharyngeal cancer, based on
interim evaluation with FDG-PET/CT in week 2 of (C)RT (NCT04667585). Besides FDG, there are several
other PET-tracers that can be useful for intra-treatment tumor response evaluation and adaptive
radiotherapy, such as fluorothymidine (FLT), fluoro-ethyl-tyrosine (FET), fluoromisonidazole (FMISO) and
fluoroazomycin-arabinoside (FAZA) [21,44,67-69] . Similar to FDG, week 2-3 of radiotherapy seems to be the
optimal time-point for interim PET-evaluation with these tracers. Further discussion of these tracers is
outside the scope of this review.

CONCLUSION
The use of FDG-PET/CT in patients with HNSCC has major implications for diagnostic staging and
radiotherapy. High sensitivity of FDG-PET/CT for identification of smaller lymph node metastases not only
has consequences for radiotherapy target volume definition and dose prescription, but also has prognostic
implications. The use of FDG-PET/CT in radiotherapy planning opens a window of opportunity for
treatment de-intensification of the neck in order to decrease toxicity without compromising oncological
outcome. This concept is currently being investigated in the randomized controlled UPGRADE-RT trial.
Further prospective trials investigating adaptive radiotherapy based on interim PET-evaluation are needed,
especially regarding HPV-negative HNSCC and patients treated with primary radiotherapy.