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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 5 of 11

Figure 2. Patient with T3N1M0 squamous cell carcinoma of the supraglottic larynx. CT-scan showing primary tumor (long arrow) and
small metastatic node (short arrow) (A). FDG-PET/CT scan showing high FDG-uptake in the primary tumor and moderate uptake in the
lymph node indicating low tumor load in this node (B). Conventional radiotherapy dosing; 70 Gy to primary tumor and metastatic node
and 50 Gy to elective lymph node regions (C). Gradient radiotherapy dosing; dose escalation (76 Gy) to gross tumor with high FDG-
uptake in primary location, 70 Gy to peripheral zone, intermediate dose (60 Gy) to low volume tumor deposit with intermediate FDG-
uptake (arrow), and low dose (36-40 Gy) to elective lymph node regions (D). Reprinted from Kaanders et al. [34] , with permission from
Elsevier. FDG-PET: Fluor-18-fluorodeoxyglucose positron emission tomography.

disease volume, while it is nowadays still treated with the unchanged elective dose of 50 Gy (EQD2)
originating from more than half a century ago. There is increasing evidence that lymph nodes that contain
only very low-volume deposits of metastatic squamous cell carcinoma can be eradicated with doses well
below 50 Gy [29,33,35,36] .

Deschuymer et al. performed a multicenter randomized controlled trial comparing an equivalent dose of
[35]
50 Gy with 40 Gy to the elective neck in 200 HNSCC patients treated with definitive (C)RT. After 5 years of
follow up, no difference in elective neck failures between the dose levels were reported (2 elective-only
recurrences in each arm) and no effect on overall survival was observed. The lower elective dose of 40 Gy
resulted in a significant reduction of xerostomia and a trend toward less dysphagia at 6 months [35,37,38] .
However, in the 40 Gy arm, additional dose constraints were set to the swallowing apparatus, which
potentially biases the toxicity outcomes of the trial. Furthermore, the dysphagia outcome scale of the
RTOG-EORTC late toxicity scoring was used, which is quite a crude scale (e.g., ability to eat solid vs. semi-
solid vs. only liquid foods), and may therefore be unable to detect subtle differences.

A single-arm phase 2 study using 36 Gy electively in 54 patients with locally advanced HNSCC showed no
elective volume recurrences after a median follow-up of 36 months in surviving patients . Notably, 54% of
[39]
these patients had HPV-positive oropharyngeal cancer, which is considered to be more radiosensitive and
all patients received concurrent chemotherapy. At the Memorial Sloan Kettering Cancer Center, current
clinical practice is to de-escalate the dose of the elective neck to 30 Gy (EQD2), albeit only in HPV-positive
oropharyngeal cancer receiving concomitant platinum based chemotherapy .
[40]
Recently the single-arm INFIELD trial investigated the possibility to improve acute and late morbidity of
patients with oropharyngeal and laryngeal cancer, both by tailoring the elective irradiation only to regions
[36]
with a legitimate risk of recurrence (> 5%) and by lowering the elective dose to 40 Gy . Following an
“involved node” approach, nodal levels III and IV were only electively irradiated if the immediate proximal
level contained pathologic lymph nodes. Irradiation of level IB and V was only performed in case of
suspicious lymph nodes in these levels. Ninety percent of the patients received concurrent chemotherapy.
At a median follow-up of 24.7 months for surviving patients, there were no solitary recurrences in electively