Controversy Over Focal Therapy for HGGs
It is well established that HGG tumor cells often metastasize great distances from the enhancing portion of the tumor and sometimes even to the contralateral hemisphere.[52,77] Despite retrospective studies supporting the use of stereotactic radiosurgery for HGGs, randomized prospective studies found no survival benefit for radiosurgery when added to conventional radiation. This observation could be used to argue against a significant effect on outcome for a focal therapy such as LITT. However, modern radiosurgery does not produce an effect on tissue for several weeks to months; LITT should more appropriately be compared with open resection, which is acutely cytoreductive and has been shown to have an impact on HGGs.[1,5,11,12] The LITT procedure can produce an acute gross-total ablation that immediately coagulates the entire enhancing portion of the tissue or induce short-term necrosis and apoptosis.[47,59,60,62] This has been observed radiographically as immediate central necrosis of the tumor. Furthermore, beyond the analogy of resection, preliminary animal studies in LITT have indeed shown that laser ablation acutely leads to breakdown of the BBB.[3,4,6,7,73] The breakdown in the BBB in regions where metastatic cells may reside may potentiate adjuvant therapy and immune reactions postulated to occur after LITT. These properties of LITT have the potential to exert positive effects to a wider area than the ablated region. Furthermore, with advanced intraoperative imaging capabilities, LITT has the potential to achieve gross-total ablation without the morbidity of open surgery. These findings argue that LITT offers acute ablation of the tumor and should not necessarily be compared with historical results in radiosurgery trials.
Use of LITT for Select Patients With HGG: Incorporating a Laser Therapy Into a Standard Practice Algorithm
After GTR and temozolomide plus radiation combination therapy, standard management algorithms for newly diagnosed HGGs may vary slightly from institution to institution depending on clinical trials. Treatment strategies for recurrent HGGs are probably even more disparate from hospital to hospital. Clinical trials vary from immunotherapies to targeted molecular therapies, and many require a significant amount of tumor sample for vaccine generation or correlative studies. However, for some patients open surgery is not an option due to deep location of the tumor or comorbid conditions. Review of the literature revealed that approximately 20% of HGGs with LITT treated thus far have been in deep locations, especially the thalamus and basal ganglia. For this group of patients, LITT offered a minimally invasive option with reduced operative times, less blood loss, and shorter hospital stays.[27,67] Generally, LITT may serve as a cytoreductive option for some of these patients over biopsy alone or no surgery at all.
Because the data on LITT for HGGs consist of Level IV evidence, additional clinical experience is essential to evaluate the efficacy of LITT in both newly diagnosed and recurrent HGGs. To achieve additional experience and data, it would be beneficial to incorporate LITT into the treatment algorithms of patients with HGG (Fig. 4). If a patient with newly diagnosed HGG is a viable surgical candidate and is interested in traditional resection, we propose that they continue with standard of care traditional craniotomy for gross-total and maximally safe resection and tissue collection, followed by standard chemoradiation in or outside of a clinical trial (Fig. 4A, left column). However, if a patient presents with newly diagnosed HGG and is not a candidate for open resection (e.g., due to difficult to access tumor in the thalamus) or declines traditional surgery, 2 surgical options can be offered: 1) standard of care biopsy alone (Fig. 4A, center column); or 2) needle biopsy and treatment with stereotactic LITT (Fig. 4A, right column). An open biopsy may be performed with craniotomy for the collection of adequate tumor volume needed for some immunotherapy and clinical trials: that is a clear advantage of this option (Fig. 4A, center column). For patients undergoing stereotactic needle biopsy (Fig. 4A, right column), the biopsy procedure could be immediately followed by gross-total LITT of the tumor. All treatments would be followed by chemoradiation.
Management algorithm for patients with HGG that includes LITT for the treatment of (A) newly diagnosed and (B) recurrent HGGs.
The typical pathways available for recurrent tumors are more limited due to of the lack of effective conventional therapies. Level II–III evidence supports repeat resection follow by salvage chemotherapy and clinical trial participation (Fig. 4B, left column). However, patients who are not candidates or who decline traditional resection can either immediately begin salvage chemotherapy within or outside of clinical trials (Fig. 4B, center column), or they may be offered salvage LITT followed by salvage chemotherapy (Fig. 4B, right column). Creating a streamlined and clinically reasonable management algorithm to enroll candidates for LITT will generate the data necessary to evaluate treatment efficacy with case-control cohorts.
Emerging Application—Laser Therapy as a Potential Adjunct to Chemotherapy
Enhanced Delivery of Chemotherapy. To circumvent the BBB in local drug delivery to the brain, recent approaches have focused on bypassing it. One method is the use of Gliadel wafers, a polymer implant impregnated with BCNU, which are placed intraoperatively in the resection cavity to circumvent the BBB. This approach resulted in a statistically significant but modest improvement in survival in both newly diagnosed and recurrent GBM.[10,78,79] The modest survival benefit of Gliadel could be due to the short duration of drug delivery, because most BCNU is released within 5 days. However, the fact that 5 days of direct BCNU delivery can improve survival of patients with GBM to a degree approaching that achieved by 8 months of systemic chemotherapy is remarkable in itself, supporting the hypothesis that the BBB is a critical barrier to the cytotoxic chemotherapy effect. Unfortunately, Gliadel is not widely used due to its complication profile. Another approach to bypassing the BBB is the convection-enhanced delivery system, in which a catheter is surgically inserted into the tumor to deliver chemotherapy. This invasive procedure requires prolonged hospitalization and meticulous maintenance of the external catheter to prevent serious complications, and as a result remains investigational and is rarely used.
Disruption of Peritumoral BBB. The use of MRI-guided LITT to induce sustained disruption of the peritumoral BBB raises the intriguing possibility that laser ablation might not simply represent a tool for cytoreduction, but might also be a vehicle for enhancing drug delivery. During LITT, the maximal temperature in the core can reach greater than 70°C, resulting in coagulation necrosis. The temperature in the peritumoral region is lower but remains high enough (> 40°C) to disrupt the BBB. This has been histologically demonstrated by local extravasation of dyes, antibodies, and chemotherapy.[47,59,60,62] Disruption of the BBB is radiographically evidenced by new peritumoral contrast enhancement extending several centimeters from the tumor edge (versus the original tumor enhancement that is lost due to the heat ablation). These observations suggest that an interesting byproduct of laser ablation is the disruption of the peritumoral BBB. These radiographic changes often persist for several weeks, providing a rare window of opportunity during which drug delivery can potentially be enhanced to eliminate infiltrative tumor cells in the tumor periphery, where most recurrences occur.
Although the procedure remains under investigation, current data show that LITT causes BBB disruption.[22,47,54,59,60,62] Indeed, the role of hyperthermia in increasing BBB permeability has been previously described in several animal models of brain hyperthermia. In a rodent model of human glioma, the global heating of a mouse's head to 42°C for 30 minutes in a warm water bath significantly increased the maximal brain concentration of a thermosensitive liposome encapsulated with the chemotherapeutic drug Adriamycin. To affect locoregional hyperthermia in the brain, retrograde infusion of a hyperthermic saline solution at 43°C into the rat left external carotid artery reversibly increased BBB permeability to Evans blue albumin in the left cerebral hemisphere. In the most analogous method to LITT in humans, LITT in rodents resulted in locoregional disruption of the BBB as evidenced by increased locoregional passage of the Evans blue dye, serum proteins (e.g., fibrinogen and IgM), and the cytotoxic drug paclitaxel. Based on these data, it is reasonable to hypothesize that hyperthermia-induced disruption of the peritumoral BBB by LITT represents a potential tool to enhance delivery of chemotherapy to this region and effectively target residual disease, in addition to primary cytoreduction. Indeed, clinical trials are underway to test this in patients with recurrent HGGs (https://clinicaltrials.gov/show/NCT01851733).
Neurosurg Focus. 2014;37(6):e1 © 2014 American Association of Neurological Surgeons