In Vivo Safety of Tumor Treating Fields (TTFields) Applied to the Torso

Abstract

Background: Tumor Treating Fields (TTFields) therapy is a non-invasive, loco-regional, anti-mitotic treatment modality that targets rapidly dividing cancerous cells, utilizing low intensity, alternating electric fields at cancer-cell-type specific frequencies. TTFields therapy is approved for the treatment of newly diagnosed and recurrent glioblastoma (GBM) in the US, Europe, Israel, Japan, and China. The favorable safety profile of TTFields in patients with GBM is partially attributed to the low rate of mitotic events in normal, quiescent brain cells. However, specific safety evaluations are warranted at locations with known high rates of cellular proliferation, such as the torso, which is a primary site of several of the most aggressive malignant tumors.

Methods: The safety of delivering TTFields to the torso of healthy rats at 150 or 200 kHz, which were previously identified as optimal frequencies for treating multiple torso cancers, was investigated. Throughout 2 weeks of TTFields application, animals underwent daily clinical examinations, and at treatment cessation blood samples and internal organs were examined. Computer simulations were performed to verify that the targeted internal organs of the torso were receiving TTFields at therapeutic intensities (≥ 1 V/cm root mean square, RMS).

Results: No treatment-related mortality was observed. Furthermore, no significant differences were observed between the TTFields-treated and control animals for all examined safety parameters: activity level, food and water intake, stools, motor neurological status, respiration, weight, complete blood count, blood biochemistry, and pathological findings of internal organs. TTFields intensities of 1 to 2.5 V/cm RMS were confirmed for internal organs within the target region.

Conclusions: This research demonstrates the safety of therapeutic level TTFields at frequencies of 150 and 200 kHz when applied as monotherapy to the torso of healthy rats.

Keywords: Tumor Treating Fields (TTFields); cancer treatment; electric field simulations; safety; torso.

Figure 1

Localization of TTFields and sham arrays on the torso of rats. Illustrations of the positioning of the 2 array pairs, one shown in yellow and the other in green, on the depilated rat torso: (A) top view, depicting the anteroposterior positioning of the 2 ceramic discs of each dorsal array (ventral arrays may be seen transparently in the background); and (B) front view, demonstrating the orthogonality of the 2 array pairs.

Figure 2

Animal weight at the beginning and end of 2 weeks of sham or TTFields application. Average weights ± standard deviations at study start and end are shown for control animals versus animals treated with TTFields at frequencies of 150 kHz (A) or 200 kHz (B). TTFields vs control non-significant; Student’s t-test.

Figure 3

Animal complete blood count (CBC) at the end of 2 weeks of sham or 200 kHz TTFields application. Average ± standard deviations at study end are shown for control animals versus animals treated with TTFields. TTFields vs control non-significant; Student’s t-test. (WBC, white blood cells; RBC, red blood cells; HGB, hemoglobin; MCV, mean corpuscular volume; MCH, mean corpuscular hemoglobin; MCHC, MCH concentration).

Figure 4

Animal blood biochemistry at the end of 2 weeks of sham or 200 kHz TTFields treatment. Average ± standard deviations at study end are shown for control animals versus animals treated with TTFields. TTFields vs control non-significant; Student’s t-test. (LDH, lactate dehydrogenase; GGT, gamma-glutamyl transferase; ALP, alkaline phosphatase; ALT, alanine aminotransferase; AST, aspartate aminotransferase; CPK, creatinine phosphokinase).

Figure 5

Histopathology analysis of internal organs from animals at the end of 2 weeks of sham or 200 kHz TTFields treatment. Images from one representative animal from each group are shown (H&E staining, ×20 magnification).

Figure 6

Simulations of EF intensities in the rat torso during 200 kHz TTFields application. Arrays were positioned on the rat model in accordance with their position in the safety study (only 1 side of the animal with 2 arrays is visible) (A). EF intensity distribution was simulated for 200 kHz TTFields at the current determined relevant from the in vivo study of 280 mA, and is shown from a side view for each of the 2 array pairs and as a merged average image of both (B).