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Page 6 of 11 Cox et al. J Cancer Metastasis Treat 2021;7:25 https://dx.doi.org/10.20517/2394-4722.2021.55

irradiated lymph nodes. Seven of 72 patients developed a nodal recurrence, 5 of which were in-field and 2
occurred in electively irradiated nodes with synchronous in-field recurrence. Patient-reported outcomes
assessment at 1 year showed superior or equivalent outcomes compared with baseline, except for saliva and
taste measures.

The above findings strongly suggest that the biologically equivalent dose of 36-40 Gy is sufficient to
eradicate occult nodal disease after state-of-the-art assessment of the neck. In fact, this dose appears to be
sufficient in both radiosensitive non-smoking, HPV-associated oropharyngeal cancer and higher-risk HPV-
negative HNSCC. The concept of FDG-PET-guided gradient dose prescription is solely based on the
estimation of tumor burden, and de-escalation of the elective dose is performed independent of tumor
radiosensitivity. This concept may apply to many other tumor types in which routine treatment includes
[29]
elective irradiation of nodal areas, such as cancers of the breast, cervix, prostate, rectum and bladder . The
effect of dose de-escalation on toxicity may vary according to the anatomical location of target volumes and
surrounding organs at risk. However, in all of the aforementioned dose de-escalation studies in HNSCC, a
majority of patients received concurrent chemotherapy, which may compensate for a (too) low elective dose
because of its radiosensitizing effect. Currently, the ongoing UPGRADE-RT trial (NCT02442375) is the first
multicenter randomized controlled trial investigating the safety and efficacy of FDG-PET-guided dose de-
escalation in HNSCC patients treated with primary radiotherapy, without the use of concomitant
[32]
chemotherapy . The primary endpoint of the UPGRADE-RT trial is dysphagia, measured on a 10-step
“normalcy of diet” scale from the performance status scale for patients with head and neck cancer. Three-
hundred patients will be randomized and accrual is expected to be complete by the end of 2021, and first
results to be reported in 2022.

Gradient dose concept
Implementing FDG-PET in radiation treatment planning, enables the opportunity to replace the current
two-dose-level practice for a “gradient dose” concept, in which dose is prescribed proportional to tumor
burden and the estimated risk of occult disease [Table 1] . In the intervention arm of the UPGRADE-RT
[29]
trial, only a partial implementation of the gradient dose concept is being evaluated . For dose prescription
[32]
to lymph nodes, an ordinal scale consisting of three dose levels is used, based on a risk assessment algorithm
combining nodal size and metabolic activity on FDG-PET/CT as a surrogate for nodal tumor burden. To
bring the gradient dose concept further, dose prescription to lymph nodes should ideally be done on a
continuous scale, attuned to tumor burden per individual node. The ultimate implementation of this
concept would imply selective irradiation of individual lymph nodes harbouring metastases, instead of
elective irradiation of complete anatomical nodal levels. There are several innovative diagnostic techniques
emerging that could support this implementation, such as ultra-small superparamagnetic iron-oxide
nanoparticle (USPIO)-enhanced MRI and sentinel lymph node detection using SPECT/CT . However, the
[41]
exact diagnostic value of these techniques in the detection of very small nodal tumor deposits is still under
investigation, impeding implementation of the gradient dose concept to its full extent at this point.

Interim treatment evaluation by PET
Despite treatment with concomitant (C)RT, loco-regional disease relapse occurs within the first 2 years in
[42]
30%-50% of patients with locally advanced HNSCC, mostly in initially involved sites . It would be of great
help if subgroups of patients that are poor responders to (C)RT can be identified before or early during the
treatment. Performing FDG-PET/CT during radiotherapy can be useful to assess metabolic tumor response
in addition to volume-based assessment by anatomical imaging. Several studies aimed to identify early
prognostic imaging biomarkers using interim FDG-PET, enabling on-treatment decisions to be made
regarding modification of treatment strategy (e.g., early dose de-escalation or switch to a different treatment
modality) [43-46] . The goals are to increase treatment effectivity in poor responders and reduce unnecessary