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

BMC Cancer volume 25, Article number: 600 (2025) Cite this article

Abstract

Objective

To study the impact of transducer arrays on the deep-seated dosimetry of radiotherapy with concurrent tumor treating fields (TTFields) for glioblastoma.

Methods

Firstly, the covering style of transducer arrays to CIRS-038 phantom was designed to simulate the “extreme situation”: four arrays were attached to the phantom as a style similar with that in clinical scene and, meanwhile, to assure that layer of interest of CIRS-038 was surrounded by twelve electrodes (three in each array). Then, eight patients undergone glioblastoma radiotherapy were selected, and the planed dose of each patient was delivered to the phantom with dosimetry film inside without and with transducer arrays. For the phantom with arrays, CBCT was used to check the dedicated covering style before dose delivery. Finally, Gamma-based consistency analysis was performed for two dose distributions for each plan (without/with arrays).

Results

The covering style of the TTFields array met the requirements in 8 cases before dose delivery. Gamma indexes under the four criteria (2%/2 mm, 2%/3 mm, 3%/2 mm and 3%/3 mm) were (93.16 ± 5.16)%, (96.08 ± 3.49)%, (96.77 ± 2.54)% and (97.96 ± 1.61)%, respectively.

Conclusion

Even in extreme situation (twelve electrodes covering the same cross-section), the perturbation of the TTFields arrays to the deep-seated dose distribution of the radiotherapy for glioblastoma is weak and acceptable.

Peer Review reports

Glioblastoma (GBM) is the most common and aggressive primary brain tumor, characterized by high incidence and poor prognosis [1]. The current standard of care for GBM involves maximal safe resection followed by chemoradiotherapy and, however, the survival period of patients remains limited, with a median survival of only about 15 months [2]. Significant efforts have been made to improve survival outcomes, including exploring more radiation modalities [3], utilizing multimodal imaging [4], and integrating immunotherapy and targeted therapies [5, 6]. While some progress has been achieved, it remains insufficient to meet the urgent clinical needs.

Tumor treating fields (TTFields) has confirmed advantages in improving overall survival (OS) and progression-free survival (PFS) in glioblastoma without significant deterioration in health-related quality of life (HRQoL) [7,8,9]. The primary mechanism of TTFields, characterized by the antimitotic effect, along with several indirect mechanisms such as increased cell membrane permeability, highlights the potential when combined with other therapeutic modalities. Current treatment strategies frequently integrate TTFields with chemotherapy, particularly temozolomide. However, emerging evidence suggests potential synergistic effects when TTFields are combined with targeted therapies, radiotherapy, and immunotherapy [10]. Recently, therapeutic synergies between TTfields and radiotherapy have been found, which has led to several preclinical and clinical studies about radiotherapy with concurrent TTFields for glioblastoma [11,12,13,14,15].

Technically, the device used to establish the treating field is a transducer array consisting of 9 button-type ceramic electrodes arranged in 3 × 3. The grouped four arrays are attached to the skull of patient to establish the required intracranial electric field with frequency between 100 kHz and 300 kHz and strength between 1 V/cm and 3 V/cm [16]. Therefore, scalp adverse reactions represent the predominant side effects linked to TTFields therapy. As such, in clinical settings, it is imperative to periodically remove the electrodes to administer scalp care to patients. Nevertheless, on one hand, the process of donning and doffing electrodes carries risks such as the deterioration of conductive gel, potential damage to circuitry, and compromised sterility. Consequently, TTFields arrays are engineered for single use and are replaced with new ones post-removal, thereby escalating treatment expenses. On the other hand, each instance of removal and replacement constitutes a laborious and time-intensive endeavor, fraught with the possibility of positioning inaccuracies. These elements demand additional patient time and further medical resources. Thus, discarding arrays prior to each radiotherapy fraction and substituting them with new ones post-treatment not only incurs substantial treatment costs but also imposes a significant medical workload, potentially undermining treatment compliance and the ultimate survival prognosis [17]. Furthermore, as research on the synergistic effects of radiotherapy and TTFields continues to advance, it is conceivable that future clinical practice may involve maintaining TTFields operation during radiation dose delivery, although conclusive clinical evidence to support this approach is currently lacking. Thus, it is necessary to consider the situation of patients receiving radiotherapy dose while wearing the TTFields arrays both in terms of clinical benefit and cost-effectiveness. Therefore, it is important to study the dosimetric effect of the TTFields arrays on glioblastoma radiotherapy, especially the deep-seated dosimetry reflecting the target coverage.

The metal artifacts caused by TTFields electrodes on kV-CT make it difficult to calculate the dose in the presence of electrodes in kV-CT. Straube et al. focused on the calculation-based deep-seated dosimetry in glioblastoma radiotherapy with concurrent TTFields [18,19,20,21,22], which were either based on MV-CT or artificially 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. In addition, the use of different dose calculation algorithms will also introduce uncertainty to the results [23]. These challenges affect the reliability of dose calculations involving electrodes and may lead to a loss of confidence in the radiotherapy centers to apply this treatment modality. Therefore, measurement-based dosimetry studies are needed to validate the results of calculation-based studies and further verify the dosimetry effects of TTFields arrays on radiotherapy for glioblastoma. In this study, the effect of the TTFields arrays on deep-seated dose distribution of glioblastoma radiotherapy with concurrent TTFields was investigated based on measurements using an extreme analysis method.

Method

Patient cohort

Eight patients who received glioblastoma radiotherapy with concurrent TTFields were selected. This study was approved by the Ethics Committee of Jiangsu Cancer Hospital, Jiangsu Province, China (Ethic number: 2022-028) and was conducted in accordance with the Declaration of Helsinki. All patients provided verbal informed consent prior to inclusion in the study for the research use and publishing of their clinical data. The planning CT-scan (Siemens Healthineers, Erlangen, Germany) were performed with 2 mm slice thickness in the absence of the transducer arrays in order to avoid beam hardening artifacts. The radiotherapy plans were designed by experienced radiotherapy dosimetrists using Eclipse v15.6 treatment planning system (TPS) (Varian Medical Systems, Palo Alto, CA, USA). Photon of 6 MV were used for all radiotherapy plans. All radiotherapy plans used volumetric modulated arc radiotherapy (VMAT) technology with a single arc field covering an angle of 360°. Optimization algorithm was photon optimization (PO) algorithm, and the dose calculation algorithm was Anisotropic Analytical Algorithm (AAA) with grid of 2.5 mm. All target coverage, organ at risk (OAR) sparing and other dose distribution indexes meet clinical requirements. All radiotherapy plans were delivered on the TrueBeam platform (Varian Medical Systems, Palo Alto, CA, USA). The basic information of the involved patients, the prescribed dose and the MU of plan are shown in Table 1.

The TTFields treatment plans were generated in the NovoTALTM software (Novocure GmbH, Lucerne, Switzerland). The placements of the grouped arrays were optimized according to the shape and size of the patient’s skull and planned target volume (PTV), as well as the positional relationship between them. In general, the four arrays were approximately located in the frontal lobe, posterior occipital, and left and right temporal lobes, respectively. The least time of wearing arrays per day was 18 h, and arrays need be replaced by new ones with fine-tuned positions every three days to reduce scalp adverse reactions [8, 24]. All patients wore the TTFields arrays starting from the first day of radiotherapy, and radiation doses were delivered through these arrays.

Table 1 General information of eight cases of radiotherapy with concurrent TTFields for glioblastoma
Full size table

Extreme simulation

The CIRS-038 anthropomorphic head & neck phantom (SunNuclear, Florida, USA) was used to simulate patients receiving radiotherapy with concurrent TTFields. The CIRS-038 has an external profile and internal anatomy structure in CT similar to that of the human skull, and has a designated location to place dosimetry film [25]. Firstly, CT (Siemens Healthineers, Erlangen, Germany) scan was performed to CIRS-038 with the layer thickness of 1 mm, and the scanned CT images were imported into TPS. Then, each CT image of the eight cases was registered to the phantom and PTV, OAR and other structures were copied to the phantom. In final, new single-arc VMAT plans were generated using the same optimization objectives with the reference plans based on the phantom CT and real structures.

The coverage style of the TTFields arrays on the phantom follows two principles: (1) as close as possible to the clinical coverage style; (2) a total of 12 electrodes (from four TTFields arrays) were wrapped around the skull in the same observation transverse layer (either of the two specified transverse layers in CIRS-038 where the dosimetry film can be placed). The second principle was designed aiming to simulate the most extreme situations in electrode wrapping. Figure 1 shows the CIRS-038 phantom wearing the TTFields arrays complying with the above principles.

Fig. 1
figure 1

CIRS-038 wearing the TTFields arrays complying with the extreme principles (a: frontal view; b: Side view; Red arrow: TTFields array; Orange arrow: phantom)

Full size image

Dose delivery and data analysis

For each selected cases, film placement (in transverse section) and arrays coverage on the phantom were firstly completed. The EBT3 radiation dosimetry film was chosen in this study. Subsequently, the setup of the phantom was completed on the TrueBeam platform. Then, cone beam CT (CBCT) was performed to guide and verify the phantom positioning with a rigid image registration. Since the distribution of electrodes was designed to densely cover only a few designated layers (including the observation layer), and therefore the CT slices of these layers were affected by metal artifacts, making them unsuitable for image guidance and positioning verification. However, other slices, located at a certain distance from electrodes, were not affected by artifacts and used for the guidance and verification of the phantom positioning. Next was the verification of the dedicate coverage style. After verification, the selected radiotherapy plan was loaded and the dose was delivered to the CIRS-038 wearing the TTFields arrays as well as the film inside. After arrays removing, film replacing and positioning re-verification, the same radiotherapy plan was again performed, delivering the dose to the CIRS-038 without arrays coverage.

After the dose delivery of all radiotherapy plans were completed, the obtained dosimetry films were placed in darkness for 24 h. The films with dose patterns was scanned using the Epson V700 scanner. Then, the conversion of optical density distribution to dose distribution based on dose scale curve was completed in DoseLab software (Varian Medical Systems, Palo Alto, CA, USA) [26]. For each of the eight cases, local-Gamma-based consistency analysis with a 10% dose threshold was performed for the two dose distributions without and with coverage [27].

Results

Verification of extreme

Each glioblastoma radiotherapy plan required a CBCT-based verification for the phantom positioning and the arrays coverage style prior to dose delivery. Figure 2 (a-1) and (b-1) respectively display the CT and CBCT images in overlay mode of the artifact-free layers (used for image guidance and positioning verification) of case #2 and case #4. Based on the bony markers, it can be seen that the two overlap well, indicating that the phantom positioning was accurate. Figure 2 also shows the CT images (a-2 and b-2) and the corresponding CBCT images (after registration) (a-3 and b-3) at the observing layers (where films were located) in the CIRS-038 of case #2 and #4. Two marks (red arrow indicates in a-2 and green arrow indicates in b-2) can be seen in the CT image, which were used to identify the observation layers with EBT3 films. In the corresponding CBCT image, there were a total of 12 electrodes surrounding the skull and leading to the banded artifacts [28]. Before dose delivery of the radiotherapy plans of eight cases, the accuracy of the phantom positioning and the coverage style of the TTFields arrays were confirmed.

Fig. 2
figure 2

CT and CBCT images in overlay mode of the artifact-free layers used for image guidance and positioning verification of case #2 (a-1) and case #4 (b-1); CT image of the observation layer (a-2) of case #2 and the corresponding CBCT image (a-3); Red arrow: marker indicating the upper film-inserted place inside the phantom; The CT image of the observation layer (b-2) of case #4 and the corresponding CBCT image (b-3); Green arrow: marker indicating the lower film-inserted place inside the phantom; Red line: PTV or CTV outline

Full size image

Dose distributions

Figure 3 shows the planned dose distribution (3a) of the region of interest at the observation layer of case #6 and the measured dose distributions obtained by films without and with array coverage (3b and 3c). There was a slight difference between the two measured dose distributions in the region around the position of (x = 4 cm, y = 7 cm). However, the Gamma-based consistency analysis between the two showed that the Gamma index was 94.5% under the criteria of 2%/2 mm and 98.3% under the criteria of 3%/3 mm, demonstrating high consistency. Gamma indexes between the deep-seated dose distributions without and with arrays coverage for all eight cases are shown in Table 2. Under the four types of criteria (2%/ 2 mm, 2%/ 3 mm, 3%/ 2 mm and 3%/3 mm), Gamma indexes were (93.16 + 5.16)%, (96.08 + 3.49)%, (96.77 + 2.54)% and (97.96 + 1.61)%, respectively.

Fig. 3
figure 3

Planned dose distribution (a) of the region of interest (deep-seated) at the observation layer of case #6 and the measured dose distributions obtained by films without and with array coverage (3b and 3c)

Full size image
Table 2 Gamma index reflecting consistency between the deep-seated dose distributions without and with arrays coverage
Full size table

Discussion

The dosimetric effects of TTFields arrays on glioblastoma radiotherapy, especially the deep-seated dosimetry related to target coverage, need to be studied in considerations of both clinical benefits and economic & convenience. The metal artifacts caused by TTFields array on kV-CT will lead to three problems: Firstly, it is difficult to give accurate electrode position and size for kV-CT. Secondly, the HU value of the electrode is ambiguous, as well as the electron density. Moreover, the banded artifacts intrude into the surrounding tissues and overlap the original values. Straube et al. found that MV-CT can solve the electrode artifact problem to a certain extent, and the percent depth dose feature calculated based on MV-CT is closer to the measured value than that of kV-CT [18]. 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 significant differences in target coverage and OAR sparing between the two groups. There were also some subsequent calculation-based studies [19,20,21,22] reaching a conclusion similar to that of Straube.

In the measurement-based research, limited by the feasible means, the deep-seated dose distribution is relatively hard to be directly given. Li et al. used Delta4 to measure the deep-seated dose distribution under the TTFields array coverage [19]. However, the geometry of the phantom and coverage style of arrays used is much different from the clinical situation. For the first time, the coverage style of arrays mimics that with the human cranial geometry and is designed so that 12 button-shaped electrodes covered the skull in the same transverse layer. In this case, if electrodes have adverse effects on the deep-seated dose distribution, the distortion of the distribution in the layer wrapped by the 12 electrodes should be the most severe. Therefore, the perturbation of the TTFields electrodes to the deep-seated dose distribution can be understood by observing the consistency between the dose distributions of the electrodes-wrapped layer and the corresponding electrodes-free layer.

Gamma-based analysis demonstrated that the agreement between the two distributions was close to or greater than 95% under the 3%/3 mm criteria. Gamma index was less than 90% in no case under the 3%/2 mm criteria, only one case under the 2%/3 mm criteria and two cases under the 2%/2 mm criteria, respectively. Conventionally segmented mode is generally adopted for glioblastoma radiotherapy. Thus, taking the 3%/3 mm criteria as the standard to evaluate the consistency of the two dose distributions is generally accepted in clinical practice [29,30,31]. In other words, even when the number of wrapped electrodes reaches twelve, the distortion of the deep-seated dose distribution is still small. This is consistent with other calculation-based results, further boosting the confidence in technical view of radiotherapy units to carry out this technique.

The analytical method adopted in this study belongs to the “extreme case” analysis method. The presence of metal electrodes can lead to the distortion of the dose distribution in the radiotherapy patients, but the degree of influence depends on the type of metal, size and many other factors [32]. The “extreme analysis” assumes that one certain layer of the patient’s brain is surrounded by 12 (reach to maximum) TTFields electrodes, at which point the electrodes are at their maximum resistance to radiation. In clinical settings, however, there is usually extremely low probability to have twelve electrodes surrounding the same layer. A retrospective examination of coverage style of the TTFields arrays in 75 cases underdone glioblastoma radiotherapy with concurrent TTFields has been carried out in our center, and no “extreme case” has been found yet. Therefore, in clinical practice, the consistency between the arrays-wearing dose distribution and the arrays-free one at any layer of the patient should be better than that in the “extreme case”. On the other hand, periodic adjustment of the arrays positions (to reduce scalp adverse reactions) and the inter-fractional random fluctuations of the head position during the overall radiotherapy course may also reduce the degree to which the dose distribution at the same layer is affected by the electrode arrays. Based on the results of this study, it can be fully inferred that TTFields array has little effect on the deep-seated dose of glioblastoma radiotherapy. Future dosimetry research may focus on the evaluation, inhibition and protection of skin dose enhancement in the presence of TTFields arrays [13, 24, 33]. Moreover, how accurate the patient position can be determined using CBCT with electrodes mounted registered to simulation CT without electrodes may be another critical issue to be investigated, which may have an “indirect” impact on the dosimetry [34].

There are limitations to this study. On one hand, the phantom used has a limited number of places where the film can be inserted. Therefore, only the dose distribution of the specified layer under the extreme condition of the phantom can be observed for a given glioblastoma radiotherapy plan, and situations of other layers cannot be evaluated. On the other hand, measurement-based studies using dosimetry film can only give the information of deep-seated dose distribution, but not the quantitative indicators reflecting target coverage and OAR sparing. In the future, the application of 3D gels radiation dosimeters may be a potential solution [35, 36]. Moreover, while the 8-patient cohort provides a valuable starting point, expanding the sample size to 15–20 patients in future studies would strengthen the findings, particularly for hypo-fractionated regimens with doses per fraction of 2.5–3 Gy.

Conclusion

Even in the extreme case of TTFields electrodes wrapping (12 electrodes covering the same layer), the deep-seated dose distribution in glioblastoma radiotherapy with concurrent TTFields is very weakly disturbed. Therefore, from the perspective of deep-seated dosimetry, the presence of TTFields arrays do not diminish the enforceability of glioblastoma radiotherapy plans and the precision of dose delivery. Future dosimetry research may focus on the evaluation, inhibition and protection of skin dose enhancement in the presence of TTFields arrays.

Data availability

No datasets were generated or analysed during the current study.

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Acknowledgements

The authors wish to thank the colleagues and peers who kindly agreed to share their data and provide help: Jingjing Wu, Yuanyuan Wang and Shiyao Wang.

Funding

National Key Research & Development Program of China (2022YFC2404605); Spark Basic Research Program of Jiangsu Cancer Hospital (ZJ202309).

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Author notes

  1. Jiajun Zheng and Zhi Wang contributed equally to this work.

Authors and Affiliations

  1. Department of Radiation Oncology, Jiangsu Cancer Hospital, the Affiliated Cancer Hospital of Nanjing Medical University, Jiangsu Institute of Cancer Research, Nanjing, 210009, China

    Jiajun Zheng, Huanfeng Zhu, Wenjie Guo, Jianfeng Wu, Li Sun, Dan Zong & Xia He

  2. School of Biomedical Engineering and Informatics, Nanjing Medical University, Nanjing, 210024, China

    Jiajun Zheng

  3. Department of Radiation Oncology, the First Affiliated Hospital of Anhui Medical University, Hefei, 230031, China

    Zhi Wang

  4. Department of Environmental Genomics, Jiangsu Key Laboratory of Cancer Biomarkers, Prevention and Treatment, Collaborative Innovation Center for Cancer Personalized Medicine, Nanjing Medical University, Nanjing, 210024, China

    Xia He

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Contributions

Jiajun Zheng was involved in the conception and design of the study. Zhi Wang, Huanfeng Zhu, Wenjie Guo, Jianfeng Wu, Li Sun, and Dan Zong were involved in the analysis and interpretation of the data, the drafting and critical revision of the manuscript. Jiajun Zheng and Xia He were involved in the final approval of the version submitted for publication.

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Correspondence to Jiajun Zheng or Xia He.

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Ethics approval and consent to participate

This study was approved by the Ethics Committee of Jiangsu Cancer Hospital, Jiangsu Province, China (Ethic number: 2022-028) and was conducted in accordance with the Declaration of Helsinki. All patients provided verbal informed consent prior to inclusion in the study for the research use and publishing of their clinical data.

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Zheng, J., Wang, Z., Zhu, H. et al. Impact of transducer arrays on deep-seated dosimetry in radiotherapy with concurrent TTFields for glioblastoma (extreme analysis). BMC Cancer 25, 600 (2025). https://doiorg.publicaciones.saludcastillayleon.es/10.1186/s12885-025-14003-4

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  • DOI: https://doiorg.publicaciones.saludcastillayleon.es/10.1186/s12885-025-14003-4

Keywords

BMC Cancer

ISSN: 1471-2407

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