Tumor Treating Fields (TTFields) therapy is the standard-of-care for patients with newly-diagnosed and recurrent glioblastomas (Stupp et al., 2017; Stupp et al., 2012). Its anti-cancer efficacy is derived from alternating electric fields tuned to a frequency of 200 kHz, which disrupt tumor cells in mitosis, cause double strand DNA breaks, and impose other types of cellular stress response resulting in secondary autophagy, immunogenic cell death or both (Gera et al., 2015; Karanam et al., 2017; Shteingauz et al., 2018; Voloshin et al., 2020). TTFields are delivered continuously to the patient’s head via two pairs of orthogonally positioned transducer arrays (Swanson et al., 2016). Daily compliance at ≥75% or continuous use for ≥18 h is an important determinant of treatment efficacy (Toms et al., 2019). Furthermore, TTFields are approved for the treatment of mesothelioma and 4 arrays are placed on the patient’s chest wall (Ceresoli et al., 2019). Randomized clinical trials also showed improved efficacy in patients with advanced staged non-small cell lung cancer when combined with immune checkpoint inhibitor (Leal et al., 2023), and those with 1–10 brain metastases when integrated with radiosurgery (Mehta et al., 2024). Therefore, TTFields will likely be incorporated as an adjuvant treatment for other malignancies in the future.

A major complication associated with continuous use of TTFields is localized breakdown of scalp or skin (Lacouture et al., 2020; Lacouture et al., 2014). These dermatologic complications, which include erythema, pruritis, and secondary infection (Lacouture et al., 2020), are thought to be a result of allergic reactions to hydrogel, which is situated between the electrodes and scalp or skin to facilitate electric field penetration, rather than from TTFields themselves emanating from the electrodes. High ambient temperature and hyperhidrosis are also modifying factors that may alter the severity of these complications (Lacouture et al., 2020). However, we postulated that the dermatologic complications are unrelated to hydrogel allergy but associated with the intensity of TTFields, and therefore we explored the possibility of optimizing the delivery of TTFields by minimizing field intensity on the scalp while maximizing it within the tumor. First, we analyzed 12 patient models (7 head models from glioblastoma patients, 3 thorax models from non-small cell carcinoma patients, and 2 pelvis models from ovarian cancer patients) and investigated the TTFields’ coverage effects on scalp/skin, skull and target(s) under different hydrogel electric conductivities. We found that there is a general difference in the optimum conductivity between head and body (thorax and pelvis) models; but variability also exists among individual patients within each anatomic treatment site. Second, to mitigate scalp irritation, we performed simulation studies by varying hydrogel and whole scalp conductivities, with the latter mimicking the effect of applying topical agents on the scalp. Changes in TTFields coverage in the scalp, skull, and target volumes were systematically explored using 17 patient models (12 glioblastoma, 3 non-small cell carcinoma, and 2 ovarian cancer patients). Finally, alterations in TTFields penetration were also investigated by varying the electric conductivity only in the region of the skin layer directly beneath the hydrogels, and we noted improved TTFields penetration into the brain when gadolinium and other non-reactive, highly conductive mixtures were injected into the scalp layer.

Magnetic resonance imaging (MRI) data from 12 glioblastoma patients, who underwent TTFields therapy, as well as positron emission tomography-computed tomography (PET-CT) imaging data from 3 lung carcinoma and 2 ovarian carcinoma patients, were used to segment intracranial, intrathoracic, and intrapelvic anatomic structures under an institutional review board approved protocol at the Dana Farber Cancer Institute. T1 post-gadolinium MR sequences were used as previously described to delineate gross tumor volumes in the brain tumor models (Lok et al., 2017). PET data were used to define the FDG-positive gross tumor volume (GTV) in the lung and pelvic models, where a uniform 3 mm expansion around the GTV was conducted to create the clinical target volume (CTV), as previously described (Lok et al., 2023; Lok et al., 2021). A 3-dimensional finite element mesh was then generated for each model in ScanIP (Synopsys, Mountain View, CA) and then imported into COMSOL Multiphysics 5.5 (COMSOL, Burlington, MA) for finite element analysis. Sensitivity analysis as a function of hydrogel electric conductivity was achieved by varying the electric conductivity parameter in log unit intervals between 0.001 and 1000 S/m for each model. The nominal value for hydrogel electric conductivity was 0.1 S/m as previously used across multiple modeling studies (Lok et al., 2017; Timmons et al., 2017; Wenger et al., 2015). Additionally, the nominal value used in this study for the scalp and skin conductivity was 0.00105 S/m. Head models were developed with hydrogel electric conductivity up to 10 S/m due to a lower propensity of electric field saturation, compared to thorax and pelvis models that had conductivity values beyond 10 S/m and up to 1000 S/m due to their greater axial diameters for electric field penetration. The electric conductivity of the whole scalp in the head was modeled from 0.001 to 10 S/m, while the electric conductivity of the skin on the body was modeled from 0.001 to 100 S/m. Furthermore, conductive fluids in the regions within the scalp or skin directly underneath each hydrogel layer were modeled in log unit increments from 0.001 to 100 S/m.

Appropriate material properties and boundary conditions were specified as previously described, and magnetic fields were assumed to be negligible at the frequency range for the operation of TTFields (Lok et al., 2017; Lok et al., 2021). The AC/DC module from COMSOL Multiphysics was used to solve for the electric field distribution in each model. To quantify the distributions as a function of hydrogel, skin, scalp, and conductive fluids, plan quality metrics (PQMs) derived from each model’s respective volume histograms, were used to make comparisons within Excel 2019 (Microsoft, Redmond, WA). PQMs included 95% coverage metrics such as E_95%, SAR_95%, and CD_95%, which are electric fields strength, specific absorption rate (or the rate at which energy is absorbed), and current density received by 95% volume of a particular tissue, respectively. Median coverage for electric field, SAR and current density were also utilized to quantitatively compare between models, denoted by E_50%, SAR_50%, and CD_50%, respectively. The 5% metrics such as E_5%, SAR_5%, CD_5% were used to quantify hotspots, specifically the intensity of each metric within 5% of tissue.

We found that the hydrogel-scalp or hydrogel-skin interface is critical for the penetration of TTFields into the intracranial space or other body cavities, respectively. Kirson et al. found that higher TTFields intensity correlated with increased percent of tumor cell kill in experimental cell culture models (Kirson et al., 2007). To optimize delivery of TTFields for the treatment of cancer, the penetrating dose at the tumor volume(s) in the brain or torso should be maximized while the hotspots on the scalp or skin surface minimized. The conductivity of the hydrogel as well as the skin or scalp itself is speculated to alter TTFields coverage at both GTV and/or CTV as well as the hotspot on the scalp or skin. This may occur under the conditions of high ambient temperature and increased humidity. Indeed, as we increased the conductivity of hydrogel or volume of scalp directly below each hydrogel layer, TTFields intensity at the GTV or CTV reached a maximum beyond which no further increase occurred, suggesting that the scalp or other skin surface may function as a variable conductor to mitigate these effects. Interestingly, increasing the conductivity of the entire scalp or skin resulted in a peak electric-field intensity characteristics within the GTV, with a corresponding decrease in field intensity at the scalp or skin. Therefore, optimal delivery is possible by altering the conductivity of the entire scalp or skin.

The observed saturation characteristics is likely due to a relationship between electric conductivity and the response of charge carriers under the influence of time-dependent alternating electric fields. This relationship is determined by the concentration and allowable motion of charges that determine a material’s electric conductivity according to field intensity and the quantity of electric charges within an enclosed space according to Gauss’ Law. As the conductivity of the hydrogel approaches large values, its electrical response behaves similar to that of metals, where the charge carrier density can then be calculated according to the Drude model (Dressel and Scheffler, 2006). Charge carrier density is typically constant for a particular material in specific states of matter and, therefore, can only conduct a certain amount of electric charge. As we increase the electric conductivity of hydrogel, the charge carrier density increases. However, since the electric conductivity of the anatomical structures throughout the rest of the head models remains constant in this study, the intrinsic charge carrier densities are also unchanged. Therefore, increasing the conductivity of hydrogel results in saturation of electric field, SAR and CD intensities within the head models. A similar explanation is also applicable to the body models.

The saturation point for electric fields coverage as a function of hydrogel conductivity is twice as high for thorax and pelvis models compared to the head models (Wenger et al., 2015). This may be due to the higher output from the NovoTTF-100L device for the thorax and pelvis (https://www.accessdata.fda.gov/cdrh_docs/pdf18/H180002C.pdf) compared to the NovoTTF-100A or NovoTTF-200A for the head. Specifically, the maximum intensity for NovoTTF-100L is 1,414 mA while the maximum for NovoTTF-100A or NovoTTF-200A is 900 mA, or a ratio of 1.6. In addition, each NovoTTF-100L array includes up to 20 ceramic electrodes arranged in a 4 × 4 rectangular configuration with 2 additional electrodes at either side of the long axis (https://www.accessdata.fda.gov/cdrh_docs/pdf18/H180002D.pdf), compared to the 9 electrodes in a rectangular 3 × 3 configuration for NovoTTF-100A or NovoTTF-200A (https://www.accessdata.fda.gov/cdrh_docs/pdf10/P100034c.pdf). Furthermore, the girth of body cavities is larger than the head and thus requiring higher injected current for deeper penetration. Therefore, the combination of higher electric output, greater number of electrodes, and increased required current injection could contribute to the higher saturation point for hydrogel conductivity in the thoracic and pelvic models.

One of the limitations of our study is that we did not discern between the basal and the dermal skin layers, both of which have unique physical and physiological properties that may account for differences in electric field interactions. Skin dosimetry within radiation oncology has been a continued challenge from the perspective of determining toxicity and their associated effects such as erythema, desquamation, and necrosis (Lee et al., 2022; Hoppe et al., 2008). In fact, the International Commission on Radiological Protection (ICRP) recommends evaluating the skin dose at both the basal and dermal layers separately at different depths (ICRP, 1977; ICRP, 1982; ICRP, 1992). Although ionizing radiotherapy and TTFields interact with biological tissue differently, treatments from both modalities have been reported to generate varying amounts of erythema in different patients (Lok et al., 2015; Lukas et al., 2017; Butcher and Williamson, 2021). These differences and varying effects would warrant further studies dedicated to identifying the specific interaction of TTFields at different layers of the skin. From a biologic perspective, scalp and skin could respond by hypervascularization to counteract increasing doses of applied TTFields. Hyper-vascularized scalp or skin could shunt the electric fields away from the depth of skin beneath the electrodes, causing the fields to scatter tangentially away from the point of contact rather than penetrating perpendicularly into the scalp or skin. In our prior report, scalp erythema was noted in a lateral or tangential fashion rather than localized just underneath the electrodes (Lok et al., 2015). It is probable to employ a simple approach that may be readily available, which is by applying local topicals to increase moisturization, especially using products with higher concentrations of glycerin, within the stratum corneum of the skin (Verdier-Sévrain and Bonté, 2007; Crowther et al., 2008; Loden, 2012). That is, by increasing moisturization within the epidermis, wetter skin has demonstrated increased electric conductivity and thus allow increased penetration of TTFields while minimizing charge retention within the epidermis (Wickett and Damjanovic, 2017; Li et al., 2001; Zhang et al., 2005).

There are differences in the PQMs for electric field, SAR and CD among individual head, thorax, and pelvis models. This type of individual variability indicates that TTFields coverage at the GTV or CTV are modulated by other parameters, including the geometry or location of the tumor, presence or absence of a necrotic core, association with cerebral edema, and proximity to a source of fluid such as the ventricles or bladder. First, tumors possessing asymmetry and angulated geometry have higher electric field values compared to those with symmetry and less angulation (Lok et al., 2017). This is most likely from charges accumulating at the sharp corners resulting in a higher electric force in certain regions of the tumor and therefore achieving a greater anti-tumor effect. Second, the presence of a necrotic core concentrates the electric fields to this intra-tumoral fluid-filled space and thus enabling the GTV to accumulate a greater amount of TTFields (Lok et al., 2017). Lastly, when the tumor is adjacent to ventricles or bladder, higher charges within these fluid-filled cavities may concentrate TTFields to the respective GTV or CTV (Lok et al., 2017; Lok et al., 2021). Consequently, tumor-associated or organ-specific characteristics modulate the distribution of TTFields within the intracranial, intrathoracic and intrapelvic sites.

There are potential variables that may alter TTFields distribution in the real-world patient population. Scalp thickness may be different among patients and scalp health, such as dandruff, velocity of hair growth, and diseases such as psoriasis and dermatitis, may alter penetration of TTFields from the surface. Tissue anisotropy may be another factor. However, the skull is a more significant attenuator of TTFields than the scalp. We believe that our approach in individualized modeling coupled with sensitivity analysis helps to mitigate these variables. Furthermore, there is a tradeoff between accuracy in individualized patient models and efficiency in modeling larger samples using an idealized brain or body segment (Ballo et al., 2019). We believe that personalized treatment or personalized TTFields planning is the best strategy to identify individual patient variabilities, and this will lead to a more accurate result. Our series that included 12 glioblastoma, 3 lung carcinoma and 2 ovarian carcinoma patients is still one of the largest in patient-specific models for the analysis of TTFields.

TTFields delivery for the treatment of cancer can be modulated by the conductivity of the hydrogel and skin/scalp at the transducer-scalp or transducer-skin interface. Optimizing this aspect of TTFields delivery may increase tumor control while minimizing toxicity at the surface. Electrically conductive topical applications to the epidermis may reduce scalp or skin irritations while simultaneously maximizing delivery of TTFields to the tumor.