Dosimetric impact of the positioning variation of tumor treating field electrodes in the PriCoTTF‐phase I/II trial

Abstract Purpose The aim of the present study based on the PriCoTTF‐phase I/II trial is the quantification of skin‐normal tissue complication probabilities of patients with newly diagnosed glioblastoma multiforme treated with Tumor Treating Field (TTField) electrodes, concurrent radiotherapy, and temozolomide. Furthermore, the skin‐sparing effect by the clinically applied strategy of repetitive transducer array fixation around their center position shall be examined. Material and Methods Low‐dose cone‐beam computed tomography (CBCT) scans of all fractions of the first seven patients of the PriCoTTF‐phase I/II trial, used for image guidance, were applied for the dosimetric analysis, for precise TTField transducer array positioning and contour delineation. Within this trial, array positioning was varied from fixation‐to‐fixation period with a standard deviation of 1.1 cm in the direction of the largest variation of positioning and 0.7 cm in the perpendicular direction. Physical TTField electrode composition was examined and a respective Hounsfield Unit attributed to the TTField electrodes. Dose distributions in the planning CT with TTField electrodes in place, as derived from prefraction CBCTs, were calculated and accumulated with the algorithm Acuros XB. Dose‐volume histograms were obtained for the first and second 2 mm scalp layer with and without migrating electrodes and compared with those with fixed electrodes in an average position. Skin toxicity was quantified according to Lyman's model. Minimum doses in hot‐spots of 0.05 cm2 and 25 cm2 (ΔD0.05cm 2, ΔD25cm 2) size in the superficial skin layers were analyzed. Results Normal tissue complication probabilities (NTCPs) for skin necrosis ranged from 0.005% to 1.474% (median 0.111%) for the different patients without electrodes. NTCP logarithms were significantly dependent on patient (P < 0.0001) and scenario (P < 0.0001) as classification variables. Fixed positioning of TTField arrays increased skin‐NTCP by a factor of 5.50 (95%, CI: 3.66–8.27). The variation of array positioning increased skin‐NTCP by a factor of only 3.54 (95%, CI: 2.36–5.32) (P < 0.0001, comparison to irradiation without electrodes; P = 0.036, comparison to irradiation with fixed electrodes). NTCP showed a significant rank correlation with D25cm2 over all patients and scenarios (rs = 0.76; P < 0.0001). Conclusion Skin‐NTCP calculation uncovers significant interpatient heterogeneity and may be used to stratify patients into high‐ and low‐risk groups of skin toxicity. Array position variation may mitigate about one‐third of the increase in surface dose and skin‐NTCP by the TTField electrodes.

Conclusion: Skin-NTCP calculation uncovers significant interpatient heterogeneity and may be used to stratify patients into high-and low-risk groups of skin toxicity.
Array position variation may mitigate about one-third of the increase in surface dose and skin-NTCP by the TTField electrodes.
dosimetry, glioblastoma, non-coplanar IMRT, tumor treating fields 1 | INTRODUCTION Concurrent tumor-treating field (TTField)-and radiotherapy treatment is under dynamic discussion, particularly since preclinical studies suggested that its combination may comprise an enhanced clinical efficacy. [1][2][3] This is attributed to the ability to serve as a radiosensitizer. 1 Conversely, an adverse effect of concurrent TTFieldand radiotherapy treatment reported is TTFields-related skin toxicity. 4 Previous studies showed that concurrent TTField-and radiotherapy treatment may cause both, an increased buildup effect and an increased back scatter effect on exit dose, leading to increased skin toxicity. 5 This merits watchfulness for the clinical use of concurrent TTField-and radiotherapy treatment. 5 Some authors suggest that caution should be exercised when considering therapeutic radiation with TTField arrays in place, as their results highlight potentially prohibitive skin toxicity. 5 Phantom studies implied that wearing transducer arrays during radiotherapy should not lead to a clinically significant underdosage of the target volume due to the attenuation of the treatment beams. 6,7 Yet, increased skin doses were noticed. 6,7 Without radiotherapy, Stupp et al. report only a mild to moderate skin toxicity from transducer arrays. 8 As a new concept, simultaneous radiotherapy with TTFields is conducted within the multicenter PriCoTTF-phase I/II trial (European database on medical devices (Eudamed) CIV 18-08-025247). The clinical I/II trial examines the efficacy of TTField electrodes with concurrent radiotherapy and temozolomide in patients with newly diagnosed glioblastoma multiforme (GBM). Skin reaction of grade III-IV is the primary endpoint of the PriCoTTF-phase I/II trial. The secondary endpoint of the trial is the dosimetric skin exposure. A previous study from our group showed that in the first seven patients included in the PriCoTTF-phase I/II trial dose deviations in the CTV due to transducer arrays were not clinically significant confirming feasibility of combined adjuvant radiochemotherapy and concurrent TTFields from a dosimetric point of view. 9 The dose buildup in the skin resulted in a dose increase of below 8.5% outside the "hottest"

| METHODS
The present dosimetric analysis is based on the first seven patients of the PriCoTTF-phase I/II trial. Prior to concurrent TTField radiotherapy patient cases were discussed in an interdisciplinary, neurooncological tumor board. Inclusion criteria were a newly diagnosed, histopathologically confirmed glioblastoma, age ≤70 years and Karnofsky performance status (KPS) ≥ 60% or age ≥70 years and KPS ≥ 50%. Written informed consent was obtained from all patients previous to concurrent TTField radiotherapy. Four transducer arrays, each consisting of nine TTField electrodes on an adhesive tape, were fixed on the skin of the head in an anterior, posterior, left lateral, and right lateral position. The arrays were changed every 3-4 days. Prior to fixation of new arrays, the skin was allowed to recover for 4-6 hrs without electrodes. At the days of array change, arrays were relocated after the daily radiation fraction and therefore patients were irradiated without the arrays. In    Figure S1). Therefore, we surrendered the recalculation of the dose distributions for the superficial layers with the Monte Carlo Simulation algorithm and focused on the clinical Acuros XB dose calculation. The dose calculation grid was set to 1.5 mm resolution.

2.B | Dose accumulation
The accumulated dose distribution with the observed varying elec-

| RESULTS
The minimum doses to the highest exposed 0.05 cm 2 and 25 cm 2 of skin are shown in Table 1 for the seven patients and scenarios 1-5.
Analysis of variance showed a significant patient and scenario dependent effect on the D25 cm 2 (P < 0.0001, ANOVA F-test). Sce-  Table 4 shows together with the data in Table 3    The basal cell layer of the epidermis is the target for radiation-induced skin toxicity and is located in a depth of 0.07 mm. This depth should be considered for skin dose measurements. 23 Radiation doses in such superficial target volumes may be measured by film dosimetry. 24 However, these are impractical in the clinical routine underneath the TTField arrays with changing array positions from fixation period to fixation period. Skin dose depends on field size, beam energy, beam modifying devices, obliquity of the fields, curvature of the patient surface and other factors. 25 Here, we used the superficial layer of 2 mm thickness from 0 to 2 mm below body surface, that is, at an average depth of 1 mm, to estimate skin toxicity. structure was by about 15%-20% higher than in the outer 0.5 mm.
T A B L E 4 Calculated gEUD (in Gy) of the skin layer in 2-4 mm depth for the five different scenarios in the first seven patients A-G of the PriCoTTF-phase I/II trial.

SUPPORTING IN FORMATION
Additional supporting information may be found online in the Supporting Information section at the end of the article. with TTField electrodes which are moved around their center (2 mm green, 4 mm red; eAcuros and eMC).