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Page 4 of 11 Cox et al. J Cancer Metastasis Treat 2021;7:25 https://dx.doi.org/10.20517/2394-4722.2021.55

Figure 1. Target volume transformation. Nodal target volume transformation is defined as “upgrading” lymph node metastasis from the
elective CTV to GTV based on their increased detectability resulting from improved diagnostic imaging techniques. Target volume
transformation may result in overtreatment of both volumes. First, the boost-dose is now prescribed to small lymph node metastases
that would have traditionally been treated with the elective dose. Second, the traditional elective dose is prescribed to the elective CTV
while the occult tumor volume within the elective CTV is decreased as a result of improved diagnostic imaging (A). By refining
traditional binary dose prescription to a gradient dose prescription that is proportional to (occult) tumor volume, the current
overtreatment can be addressed in order to decrease treatment-related morbidity without compromising efficacy (B). Reprinted from
van den Bosch et al. [29] , with permission from Elsevier. CTV: Clinical target volume; GTV: gross tumor volume.

Intermediate dose level
First, small nodal metastases that previously remained undetected and used to be part of the CTV elective-nodal
will currently be irradiated with a high boost dose of 70 Gy (EQD2) because they are now included in the
GTV, which may be unnecessarily high for the relatively low tumor burden in these lymph nodes. Studies
investigating recurrence in the electively irradiated neck have identified selection criteria for lymph nodes
that can be treated with intermediate dose. An analysis of 1166 electively irradiated lymph nodes in 264
HNSCC patients identified nodal size (summed long- and short-axis diameter ≥ 17 mm) as an important
[30]
risk factor for nodal failure after elective irradiation with 45 Gy (EQD2) . However, a relevant proportion
of nodes with a summed diameter ≥ 17 mm turns out to be false positive, which confirms the need for
additional parameters to facilitate adequate risk assessment of lymph nodes . Because FDG-uptake reflects
[30]
the metabolic activity of tumor deposits it can be used as a surrogate measure of tumor load. FDG-PET/CT
has the potential to discriminate between nodes with low, moderate, or high tumor burden using
standardized nodal FDG-uptake thresholds [9,31] .

By combining nodal size and FDG-uptake as a parameter for tumor load, a nodal risk assessment algorithm
for standardized evaluation of lymph nodes could be defined [30-32] . For selected metastases with moderate
tumor burden, an intermediate dose level of 60 Gy (EQD2) may be sufficient, as no recurrences in electively
irradiated lymph nodes were observed above this dose in the previously mentioned retrospective analysis
[Figure 2] . Radiobiological evaluations also show a high tumor control probability of occult metastatic
[30]
nodes < 10 mm at the 60 Gy dose level [29,33] .

Elective dose and volume de-escalation
Another consequence of this target volume transformation is that the CTV elective-nodal will contain lower