This study investigated the effects of skull modulation on the enhancement of intracranial TTFields intensity, including adjusting different configurations of SR surgery or performing cranioplasty surgery with replaced materials. Skull thinning, drilling, and skull replacement with high-conductivity materials could all increase API.
The distribution of TTFields was predominantly determined by the local conductivities of brain tissues, which was also the prerequisite hypothesis of this research36. The dense skull offered the toughest impediment to the penetration of the external electric fields. Interestingly, other brain tissues except for the skull presented negative relationships with TTFields. This phenomenon might be due to “the charge shielding effects” that induced converse electric fields against the external TTFields. Therefore, the elevation of conductivity within these tissues could cause a decrease in the intracranial dosage of electric fields. As Lang S et al reported that peritumoral edema could hinder the TTFields penetration, and 6mm of edema blocked 52% of intracranial electric field intensity37. Hence manipulating the conductivity of the brain and skull could be a potential facilitation to TTFields, for instance, alleviating the brain edema through Bevacizumab and steroids, or alternating the configurations and materials of the skull.
In comparison between the two commonly implanted materials, titanium and PEEK, the former offered more intracranial augmentation to TTFields, and the intensity was elevated as the increase of the replaced area, but the growth rate of API declined as the skull defects further expanded. And we considered that the excessive implantation not only accompanied higher risks of infection, and might not provide clinical benefits as expected. Parameters of the CSF and connective tissue were also incorporated as reference models, because the resected lesions would soon be filled with fluid, and a stepwise re-organization by connective tissues. The conductivity of titanium is far larger than that of CSF, and the titanium implant offered much stronger augmentation to TTFields in the MTL model. However, their differences in the intensity of intracranial electric fields were only about 3% in the RH model. The distinction might lie in the complex configurations of gyri and sulci, which could generate more shielding charges against the external electric fields. Therefore, theoretically, titanium might not be as effective as what was observed in the RH model, but it requires further evidences in real patients.
Korshoej AR reported in 2016 that SR surgery could enhance electric fields in the tumor regions38. Based on the MRI data of two patients with superficial or deep brain tumors, they stated that craniectomy could elevate the dosage of TTFields in both models, especially for the superficial tumor, and the size and shape of the burr holes affected the peritumoral electric intensity 38. The primary results further supported their following clinical trials39. In the phase I clinical trial OptimalTTF-1, 15 GBM patients with the first recurrence were enrolled. They all received a second brain tumor debulk surgery and other physician’s choices of therapy39. The tumors were all near the surface of the brain and 4 patients did not receive TTFields due to personal reasons. Three drilling patterns were applied with significantly prolonged median progression free survival (mPFS) and mOS (mPFS, 4.6 months; 6-month PFS rate, 36%; mOS, 15.5 months) 29. To clarify the exact augmentation of SR surgery to TTFields, one phase II clinical trial (NCT04223999) is ongoing.
Admittedly, the authenticity was compromised by the simplified MTL model and RH model. In particular, the RH model was constructed based on the imaging data of a healthy subject, and we simplified the model to eliminate as many individualized features as possible, then a virtual tumor was manually placed to shape a relatively standardized realistic head model 40, 41. This was mainly for avoiding the confounding factors that affected TTFields dosimetry other than electric field strength, such as head shape and tumor morphology 42. Nevertheless, due to the complex anatomy of the head, variations in neuro-fiber topology, and the isotropic conductivity distribution, orthogonal electric fields with 2 pairs of transducer arrays might introduce considerable correlations which were indexed as fractional anisotropy (FA) 40, 42. Even at the optimal electrode position with maximum TTFields intensity, FA could still bias the pattern of the electric fields 36. Thus, we applied only 1 pair of 3\(\times\)3 transducer arrays in the left-right field direction parallel to the tumor. Diffusion tensor imaging (DTI) was not available for the subject, and detailed simulation concerning FA could not be acquired. Moreover, only one RH model might not be representative for all patients. These limitations all indicated an urgent need for prospective simulation studies on real patients.
Another limitation was the lack of thermal simulation on the head model. Despite broad clinical applications in cranioplasty, titanium is notorious for its skin burnt under heat or direct sunlight exposure. The alternating electric fields might also increase the heat produced by titanium. Also, the skull drilling is an invasive procedure, which warrants precise scheme and design, but we only simulated some of the occasions where the burr holes were set corresponding to the electrodes. Further exploration on the configurations of skull drilling and the safety of cranioplasty with other replaced materials are still required for further clinical applications.
Besides, considering the edge effect of the transducer array, our research did not involve the influence of the relative position of electrodes and the tumor on the peritumoral field intensity. In our simulation, we set the tumor fixed deeply and directly below the center of the electrode array, in which case we believed that the edge effect of electrodes had subtle impact on the peritumoral electrical fields 40.
Our research was aimed at the clinical optimization of TTFields. Except for the method of altering skull conductivity as mentioned above, reducing the heat produced by electrodes are also essential (see Fig. 6), which is the key problem hindering its usage. Researches have focused on simulating the heat transfer pattern of TTFields28, but to our knowledge, none reported feasible solutions. Further studies might overcome this issue from the perspective of materials. Besides, although the new version of TTFields has facilitated patients’ life, many still complained about carrying the battery43. From the perspective of thermal effects and life quality, implantable electrodes embedded in the skull or brain parenchyma, and the implantable batteries, which are similar to the design of cardiac pacemakers or deep brain stimulation with batteries placed in the chest, could both increase the compliance of patients. As for the clinical practices, the current application of TTFields urgently requires appropriate criteria for evaluation. The clinical trials of TTFields mainly used scales like Mini-Mental Status Exam (MMSE), EORTC quality-of-life questionnaire core-30 (QLQ-C30), and BN20 to assess life quality and functions, and used Macdonald, or RANO criteria to assess the radiological progression of GBM patients treated with TTFields44, 45. But there were reports of delayed response to TTFields as well45. It is still required to verify in an extended population whether the established evaluation scales could represent the responses to TTFields, whether there is also pseudoprogression during the treatment, and whether there are other predictive factors, such as blood or imaging biomarkers and local minimum dose density (LMiDD)25. Finally, as more studies attempting to reveal the anti-tumor mechanisms of TTFields, combinatory treatment regimens are also under consistent investigation46. The upcoming studies could be focused on answering these questions.
The design of current TTFields that are applied in the clinic warrants further optimization, including better temperature control of the electrodes, performing SR surgery to enhance TTFields, and managing peritumoral edema to minimize its blocking effects. The devices also warrant further optimizing so that they can be lighter to carry, have implantable generators and electrodes, and be more durable in usage. Predictive factors from serum biomarkers and imaging markers are also required, and more combinatory regimens to augment TTFields should be further explored.