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

Abstract

PurposeThe 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 MethodsLow‐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 (D0.05cm2, D25cm2) size in the superficial skin layers were analyzed.ResultsNormal 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).ConclusionSkin‐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.

Impact of transducer arrays on deep-site dosimetry in radiotherapy with concurrent TTFields for glioblastoma (extreme analysis)

“…Then, they calculated the dose of radiotherapy plans with and without TTFields arrays of actual cases based on MV-CT and found that there were no clinically signi cant differences in target coverage and OAR sparing between the two groups. There were also some subsequent calculation-based studies [12][13][14][15] reaching a conclusion similar to that of Straube.…”

“…The metal artifacts caused by TTFields electrodes on kV-CT make it di cult to calculate the dose in the presence of electrodes in kV-CT. Straube et al focused on the calculation-based deep-site dosimetry in glioblastoma radiotherapy with concurrent TTFields [11][12][13][14][15] , which were either based on MV-CT or arti cially assigned electrode HU in kV-CT (3817 or 3832, etc.). However, there is a lack of uniform standard and solid basis for the assignment of electrode HU in these calculation-based researches.…”

The Routine Application of Tumor-Treating Fields in the Treatment of Glioblastoma WHO° IV

“…Recently, the prediction algorithm for skin irritation probability was presented. According to it, the variation of array positioning reduced the risk of skin irritation by about one-third ( 33 ). Moreover, practical suggestions for dermatological symptomatic treatment have been distributed ( 34 ).…”

Anti-cancer mechanisms of action of therapeutic alternating electric fields (tumor treating fields [TTFields])

“…To date, TTFields has been approved by the FDA for the treatment of rGBM as monotherapy, nGBM in combination with adjuvant chemotherapy, and malignant pleural mesothelioma in combination with chemotherapy ( Stupp et al., 2012 , 2015 , 2017 ; Ceresoli et al., 2019 ). Additionally, TTFields is safe, and the most common side effect that was observed in vivo and in various clinical trials was mild to moderate dermatitis underlying the electrode transducer arrays, which can be managed with slight repositioning of the arrays or topical corticosteroids ( Salzberg et al., 2008 ; Stupp et al., 2012 , 2015 , 2017 ; Pless et al., 2013 ; Mrugala et al., 2014 ; Kesari et al., 2017 ; Zhu et al., 2017 ; Taphoorn et al., 2018 ; Vergote et al., 2018 ; Ceresoli et al., 2019 ; Lu et al., 2019 ; Rivera et al., 2019 ; Bokstein et al., 2020 ; Lacouture et al, 2020 ; Shi et al., 2020 ; Song et al., 2020 ; Wu et al., 2020 , 2021 ; Kim et al., 2020a ; Nour et al., 2021 ). Due to the survival benefits and minimal side effects of TTFields observed in clinical trials thus far ( Supplementary Table S4 ), additional pre-clinical investigations and clinical trials are currently underway with an aim to understand the efficacy of this novel therapeutic modality in various cancer types including nGBM and NSCLC brain metastases in pediatric and adult patients ( Johnson et al., 2017 ; Lau et al., 2017 ), hepatocellular carcinoma, pancreatic cancer, ovarian cancer, malignant pleural mesothelioma, and gastric adenocarcinoma ( https://www.novocure.com ).…”