Laser-Induced Thermal Therapy in the Management of Low-Grade Gliomas: A Narrative Review

Introduction

Gliomas are a common type of tumour in the central nervous system (CNS), originating from glial cells [1]. These tumours diffusely infiltrate the surround- ing brain tissue. Gliomas are classified into grades I to IV, based on molecular and histopathological markers, among other factors [2]. According to the WHO classification system, low-grade gliomas (LGGs) are benign tumours that fall within the first two grades. Although typically slow-growing, LGGs can transform into malignant grades over decades [3]. Survival rates for LGGs are relatively high com- pared with other gliomas [1]. The exact cause of gli- omas is unknown, but risk factors include environ- mental and genetic factors, particularly therapeutic radiation [4]. Despite being generally non-threatening and slow- growing, LGGs have a strong tendency to infiltrate surrounding tissues, raising concerns [5]. The dis- ease course varies greatly, leading to differing clini- cal approaches, with some clinicians favouring sur- veillance and others proactive surgical resection [6]. Understanding the nature of LGGs is crucial to opti- mize their management and improve outcomes [6]. The natural history of LGGs is influenced by various factors, including clinical presentation, radiological imaging, genetic characteristics, and treatment tim- ing [5]. These factors contribute to the complexity of LGGs and necessitate individualized treatment plans [5]. The natural history of LGGs can be divided into three phases: an initial silent phase, a symptomatic phase, and a progressive phase [5]. The increased use of MRI has led to more incidental discoveries of LGGs [5]. While early discovery is promising, man- aging incidentally discovered LGGs remains chal- lenging [5]. A clinical trial by Potts et al. compared the natural surgical history and management of inci-

dental and symptomatic gliomas, finding that pa- tients with incidental LGGs had smaller tumours, a higher likelihood of complete surgical resection, and improved overall survival, though progression rates were similar in both groups [7]. Common symptoms of symptomatic LGGs include seizures, headaches, and vision problems [8]. Treatment for LGGs typically involves surgery, ra- diation therapy, and chemotherapy, each with its own challenges, such as impacts on brain function and side effects. The National Comprehensive Can- cer Network’s guidelines recommend surgery as the primary approach, aiming for gross total resection if feasible, otherwise subtotal resection [9]. Pathologi- cal assessment of the resected tumour helps deter- mine the glioma type and presence of specific bi- omarkers, guiding further management [9]. Patients are classified based on their risk of tumour regrowth, with low-risk patients typically undergoing surveil- lance and high-risk patients receiving adjuvant radi- otherapy and chemotherapy [9]. Follow-up is bian- nual to monitor for recurrence and manage treat- ment-emergent adverse events (TEAEs) [9]. Achieving maximally safe resection while maintain- ing neurological function is challenging due to ana- tomical variations between patients [10]. Radiother- apy toxicity can cause cognitive, visual, and audi- tory dysfunction, as well as complications such as radiation necrosis, secondary neoplasms, and hypo- pituitarism [8]. Chemotherapy, while beneficial for some, can cause side effects such as nausea, alope- cia, myelosuppression, liver toxicity, and neurotoxi- city, limiting patients’ quality of life [8]. The inva- sive nature of the tumour and restricted therapeutic strategies result in high relapse rates and generally poor outcomes [11].

Molecular and genetic data, such as IDH mutation and 1p/19q co-deletion, are important biomarkers that affect tumour behaviour and treatment out- comes. Molecular characteristics can aid in the diag- nosis and prognosis of LGGs [8]. IDH mutations are common in gliomas and can sub-classify LGGs [8]. Tumors with IDH mutations and 1p/19q co-dele- tions are more likely to be oligodendrogliomas,

while those with IDH and TP53 mutations but with- out 1p/19q co-deletion are more likely astrocytomas [8]. IDH-mutated tumours generally have favoura- ble prognoses and are more chemosensitive [8]. Tu- mours with 1p/19q deletions have improved median survival times [8]. Molecular neuropathology in LGGs continues to be a focus of research, with on- going exploration of targeted therapies [8,10]. However, despite these advances, there are signifi- cant unmet needs in the management of LGGs. Ex- isting therapies often fall short of achieving long- term control and can have substantial side effects [7- 9]. This highlights the need for innovative treat- ments that can provide better outcomes with fewer complications. Laser-induced thermal therapy (LITT) is one such emerging modality. LITT is a minimally invasive technique that uses laser energy to ablate tumour tissue precisely, with the added benefit of disrupting the blood-brain barrier to en- hance drug delivery [5,8]. The therapeutic implications of molecular bi- omarkers, such as IDH mutations and 1p/19q dele- tions, are crucial in the context of LITT. These bi- omarkers not only aid in diagnosis and prognosis but also influence the response to therapies, including LITT [10,9]. Understanding these molecular charac- teristics can help tailor LITT protocols to improve efficacy and patient outcomes.

Methodology

This narrative review aims to provide an in-depth analysis of laser-induced thermal therapy (LITT) in the management of low-grade gliomas (LGGs). The review process involved an extensive search of ma- jor academic databases, including PubMed, Sci- enceDirect, and Scopus, to identify relevant studies published between January 2000 and December 2024. Inclusion criteria encompassed clinical trials, observational studies, and systematic reviews focus- ing on LITT, its effectiveness, and its role in glioma treatment. Only studies published in peer-reviewed journals and written in English were included. Key search terms included "laser-induced thermal thera- py," "low-grade gliomas," "treatment," "laser abla- tion," and "blood-brain barrier." After the initial

search, studies were selected based on their rele- vance to the research question, with a focus on those that discussed LITT’s clinical application, techno- logical advancements, and potential to enhance treatment outcomes for LGGs. The selected articles were analysed for their findings on the efficacy of LITT in comparison with tradi- tional treatment modalities, its safety profile, and any complications or limitations associated with the procedure. Data from these studies were synthesized to highlight the advantages and challenges of using LITT in LGG management. Laser-induced thermal therapy (LITT) is a mini- mally invasive surgical technique that uses laser-in- duced heat to ablate pathological tissue. It was first introduced in the early 2000s and has since gained traction as a treatment option for low-grade gliomas (LGGs), particularly in cases where conventional therapies such as surgery, radiation, or chemother- apy are not viable or have proven ineffective. LITT is performed under MRI guidance, allowing for pre- cise targeting of the tumour while minimizing dam- age to surrounding brain tissue. Several studies have highlighted the effectiveness of LITT in treating both primary and recurrent gliomas, with promising results in improving survival rates and reducing tumour size. For instance, a systematic review and meta-analysis by Ivan et al. (2016) re- ported an overall survival (OS) of 14.2 months for patients with glioblastoma and WHO grade III astro- cytoma treated with LITT, with a complication rate of 3.4% [12]. However, for low-grade gliomas spe- cifically, studies have shown more favourable out- comes. A study by Strauss et al. (2024) reported a progressive reduction in tumour volume and a me- dian survival time of 36 months for patients with LGGs treated with LITT [4]. Additionally, LITT has been shown to offer advantages over traditional open craniotomy, particularly in patients with inop- erable or deeply seated tumours. LITT’s ability to disrupt the blood-brain barrier (BBB) temporarily increases the permeability of therapeutic agents, such as chemotherapy drugs, allowing for more ef-

fective drug delivery to the tumour site [13]. This ef- fect has been particularly beneficial in treating glio- mas resistant to conventional treatments. Quality of life and functional outcomes post-LITT have also been positive. A pilot study by Peña Pino et al. (2024) found that patients reported less pain and narcotic use post-LITT compared with craniot- omy, with 89% of patients preferring LITT over cra- niotomy [1]. Another study by Srinivasan et al. (2022) showed that LITT patients had shorter ICU and hospital stays and similar functional outcomes at 180 days post-treatment than those who under- went resection [2]. Despite its advantages, LITT is not without risks. Complications such as motor deficits, aphasia, in- tracerebral haemorrhage, and cerebral oedema have been reported in a small subset of patients. These complications are often related to the proximity of the tumour to critical brain structures, such as the corticospinal tracts and language centres, highlight- ing the importance of careful pre-operative planning and real-time imaging during the procedure [14-20]. In a review of the literature, five articles reported complication rates ranging from 3% to 10%, while two articles highlighted the effectiveness of LITT, with survival outcomes ranging from 24 to 36 months for LGGs.

Discussion

Laser-induced thermal therapy (LITT) has emerged as a promising technique for managing low-grade gliomas (LGGs), particularly for tumours that are in- operable, recurrent, or located in regions that are dif- ficult to access through traditional surgery. Several studies highlight the advantages of LITT over tradi- tional surgical approaches, primarily due to its min- imally invasive nature and precision in targeting tu- mour tissue while sparing surrounding healthy brain structures. LITT has demonstrated promising results in treating both primary and recurrent gliomas. Studies have shown that LITT is effective in reduc- ing tumour volume, leading to improved survival outcomes. A systematic review and meta-analysis by Ivan et al. (2016) reported an overall survival (OS)

of 14.2 months for patients treated with LITT, in- cluding those with glioblastomas and WHO Grade III astrocytomas, with a complication rate of only 3.4% [12]. Similar survival outcomes were noted by Muir et al. (2022) for patients with newly diagnosed gliomas treated with LITT [21]. Additionally, LITT has been particularly useful in patients with recurrent gliomas, which have typi- cally exhausted other treatment options such as sur- gery, chemotherapy, or radiation therapy. LITT has been shown to be an effective alternative in these cases, offering the possibility of repeated treatments without the limitations imposed by traditional surgi- cal interventions. Mohammadi et al. (2019) reported comparable survival rates for patients treated with LITT as upfront therapy for newly diagnosed glio- blastomas (nGBM) compared to a matched cohort of biopsy-only patients [22]. Furthermore, the use of LITT allows for a less invasive procedure with shorter recovery times, enabling patients to return sooner to their normal activities. One of the significant advantages of LITT is its abil- ity to disrupt the blood-brain barrier (BBB), which often limits the effectiveness of conventional chem- otherapy in treating gliomas. Recent studies have shown that LITT can temporarily disrupt the BBB, allowing for enhanced drug delivery. For example, Leuthardt et al. (2016) demonstrated that LITT caused a temporary disruption of the peritumoral blood-brain barrier in glioblastoma patients, im- proving the permeability of chemotherapy agents [23]. This effect is particularly important for glio- mas, as the BBB poses a significant challenge to the effective delivery of many therapeutic agents. In a study by Salehi et al. (2020), LITT was shown to in- crease the permeability of the BBB for up to 30 days following the procedure, which could facilitate bet- ter drug delivery for treating gliomas [24]. LITT’s ability to enhance drug delivery is an important fac- tor in improving patient outcomes, particularly for tumours resistant to conventional therapies. While LITT is generally considered a safe and effective procedure, it is not without its risks. The most com-

mon complications associated with LITT include neurological deficits, intracerebral haemorrhage, and cerebral oedema. Neurological deficits, particu- larly motor deficits and aphasia, have been reported in studies involving LITT. The incidence of motor deficits ranges from 11.6% to 29.0%, while aphasia occurs in approximately 6.0% to 17.6% of patients [14-20]. These deficits are often transient, but in some cases they can be permanent. The risk of motor deficits is particularly high when tumours are lo- cated near the corticospinal tracts (CSTs). Sharma et al. (2016) used diffusion tensor imaging (DTI) to map and delineate the CSTs in 80 patients, finding that the risk of motor deficits was significantly higher when there was overlap between the thermal injury zone and the CST [25]. Intracerebral haemorrhage (ICH) is another poten- tial complication, with an incidence ranging from 2.9% to 14.2% [26, 27-29]. These haemorrhages typically occur during the insertion of the laser fibre or stereotactic biopsy. Pruitt et al. (2017) identified that ICH could occur due to inadequate dural punc- ture or vascular injury during the procedure [30]. To minimize the risk of ICH, it is essential to use pre- cise pre-operative imaging techniques, such as MRI and CT angiography, to guide the laser probe and avoid blood vessels. Cerebral oedema is a well-rec- ognized complication following LITT, particularly when large tumours are treated. To mitigate this risk, corticosteroids like dexamethasone are often admin- istered before and after the procedure [31]. In cases where oedema becomes severe and refractory, fur- ther interventions, such as hemicraniectomy, may be required. Jethwa et al. (2019) emphasized the im- portance of managing oedema carefully, especially in cases involving large tumours that require sub- stantial ablation volumes [28]. While LITT offers numerous advantages, certain limitations need to be addressed. One major limita- tion is its effectiveness in treating larger, more irreg- ularly shaped tumours. Larger tumours require the use of multiple catheters, and the risk of complica- tions such as oedema and ICH increases. Spherical

tumours, by contrast, are easier to treat due to the more predictable distribution of laser energy [32]. Tumours adjacent to cerebrospinal fluid (CSF) spaces or blood vessels pose additional challenges due to thermal energy distortion [33]. Moreover, LITT’s role in the management of newly diagnosed glioblastomas is still under investigation. While LITT has shown promise for recurrent gliomas, the existing evidence does not yet support its wide- spread use as a first-line treatment for newly diag- nosed gliomas. A study by Shah et al. (2019) re- ported that LITT-treated patients had lower progres- sion-free survival (PFS) and OS compared with those undergoing surgical resection, particularly for deeply seated lesions [34]. This suggests that while LITT is a valuable tool, it is not a replacement for traditional surgical resection in many cases. Future studies should focus on optimizing LITT pro- tocols, refining imaging techniques, and developing more sophisticated laser probes to improve targeting accuracy. Additionally, combining LITT with other therapies, such as immunotherapy, chemotherapy, or gene therapy, could offer new avenues for improving treatment outcomes. For example, LITT's ability to disrupt the BBB may enhance the efficacy of immu- notherapies by facilitating the delivery of immune cells or agents to the tumour site [34]. Long-term studies will be essential to assess the durability of LITT’s effects, especially in terms of recurrence- free survival and overall survival. Cost-effectiveness and accessibility are also im- portant considerations for the broader adoption of LITT. A cost-effectiveness analysis by Voigt and Barnett (2016) found that LITT improves survival at a cost that is considered good value compared with traditional surgical options [35]. The minimally in- vasive nature of the procedure often results in shorter hospital stays and quicker recovery times, which can reduce overall healthcare costs [36]. However, the availability of LITT is currently lim- ited to specialized centres with the necessary equip- ment and expertise, which may restrict access for some patients. Ongoing clinical trials and technolog- ical advancements continue to shape the future of

LITT. For instance, real-time thermal mapping and advanced imaging techniques are being developed to enhance the precision and safety of the procedure [37]. Additionally, research into the use of nanotech- nologies to improve heat conduction and expand treatment coverage is under way [37]. These innova- tions hold promise for making LITT a more effective and widely accessible treatment option for patients with LGGs and other brain tumours.

Conclusion

Laser-induced thermal therapy (LITT) has proven to be a promising and effective treatment option for low-grade gliomas (LGGs), particularly for tumours that are difficult to access through conventional sur- gical methods or those that have recurred after pre- vious therapies. The minimally invasive nature of LITT, combined with its ability to precisely target tissue while sparing healthy brain structures, offers significant advantages over traditional surgical ap- proaches. As LITT technology continues to evolve, further re- search is needed to optimize its protocols and refine its applications. Combining LITT with other treat- ment modalities, such as chemotherapy or immuno- therapy, could open new avenues for improving out- comes in glioma treatment. Additionally, long-term clinical trials will be crucial in determining the long- term efficacy and safety of LITT in the treatment of LGGs. In conclusion, while LITT is not a replacement for traditional resection in all cases, it offers a valuable adjunct in the treatment of low-grade gliomas, par- ticularly for patients with tumours inoperable by conventional means or those with recurrent disease. With ongoing advancements in technology and tech- nique, LITT has the potential to significantly im- prove the prognosis and quality of life for patients with low-grade gliomas.