Combined radiotherapy and concurrent tumor treating fields (TTFields) for glioblastoma: Dosimetric consequences on non-coplanar IMRT as initial results from a phase I trial

Guberina, Nika; Pöttgen, Christoph; Kebir, Sied; Lazaridis, Lazaros; Scharmberg, C.; Lübcke, Wolfgang; Niessen, Michael; Guberina, Maja; Scheffler, Björn; Jendrossek, Verena; Jabbarli, Ramazan; Pierscianek, Daniela; Sure, Ulrich; Schmidt, Teresa; Oster, Christoph; Hau, Peter; Grosu, A.L.; Stuschke, Martin; Glas, Martin; Nour, Y.; Lüdemann, Lutz

doi:10.1186/s13014-020-01521-7

Cited by 15 publications

(27 citation statements)

References 33 publications

(51 reference statements)

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“…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” 1 cm 2 with TTFields which moved around their center position 9 .…”

Section: Introductionmentioning

confidence: 73%

“…1 cm, at each change of the transducer arrays in the plane of the skin. This variation of TTField array position from fixation period to fixation period resulted in 95% confidence ellipses with a mean half‐length of the major axis of about 2.7 cm and of the minor axis of about 1.8 cm 9 …”

Section: Methodsmentioning

confidence: 99%

“…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" 1 cm 2 with TTFields which moved around their center position. 9 The present dosimetric analysis of the dose distributions in the outer skin layer, calculated by a clinical Acuros XB algorithm (Acuros XB, Emami et al 12 is analyzed to detect interpatient differences.…”

Section: Introductionmentioning

confidence: 99%

“…9 The dose buildup in the skin resulted in a dose increase of below 8.5% outside the "hottest" 1 cm 2 with TTFields which moved around their center position. 9 The present dosimetric analysis of the dose distributions in the outer skin layer, calculated by a clinical Acuros XB algorithm (Acuros XB, Emami et al 12 is analyzed to detect interpatient differences. Furthermore, the effect of TTField electrodes and the mitigation effect of variation of array positions around their center on skin normal tissue toxicities shall be examined.…”

Section: Introductionmentioning

confidence: 99%

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

Nour

Pöttgen

Kebir

et al. 2021

J Applied Clin Med Phys

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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.

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Section: Introductionmentioning

confidence: 73%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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

Nour

Pöttgen

Kebir

et al. 2021

J Applied Clin Med Phys

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“…In addition to traditional chemotherapy and radiation, there are also a number of innovative treatments that have come into recent use for GBM, including carmustine wafers (Gliadel®) [9,10] , an intracranially implanted local chemotherapy, as well as low-intensity alternating electrical tumor treating fields (Optune® therapy) with anti-proliferative properties [11][12][13][14] . These treatment options have been shown to confer significant benefit to some patients and have the advantage of being well-tolerated with few side effects as they are localized (Gliadel®) or non-invasive (Optune®) therapies [9][10][11][12][13][14] . Tumor treating fields (TTFields) in particular show true potential for incorporation into standard-of-care based on a recent clinical trial of TTFields plus TMZ, which produced a median overall survival of 20.9 months compared to TMZ alone [14,15] .…”

Section: Introductionmentioning

confidence: 99%

Mechanisms of temozolomide resistance in glioblastoma - a comprehensive review

Singh¹,

Miner²,

Hennis³

et al. 2020

CDR

171

194

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Glioblastoma (GBM) is the most common primary malignant brain tumor in adults and has an exceedingly low median overall survival of only 15 months. Current standard-of-care for GBM consists of gross total surgical resection followed by radiation with concurrent and adjuvant chemotherapy. Temozolomide (TMZ) is the firstchoice chemotherapeutic agent in GBM; however, the development of resistance to TMZ often becomes the limiting factor in effective treatment. While O6-methylguanine-DNA methyltransferase repair activity and uniquely resistant populations of glioma stem cells are the most well-known contributors to TMZ resistance, many other molecular mechanisms have come to light in recent years. Key emerging mechanisms include the involvement of other DNA repair systems, aberrant signaling pathways, autophagy, epigenetic modifications, microRNAs, and extracellular vesicle production. This review aims to provide a comprehensive overview of the clinically relevant molecular mechanisms and their extensive interconnections to better inform efforts to combat TMZ resistance.

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