**7. Use of LITT in brain metastasis and radiation necrosis**

Brain metastasis is a common and challenging clinical scenario affecting up to 40% of patients with systemic malignancies [100–102]. Lung carcinoma (16–19%) is the leading systemic cause of brain metastasis followed by renal (6–9%), melanoma (7–7.4%), breast (5%) and colorectal

cancers (1.2–1.8%) [103, 104]. Prognosis in patients with brain metastasis is often dismal, due to limited therapeutic options. Majority of chemotherapeutic agents and targeted immuno‐ therapies do not cross the blood brain barrier, hence limited applicability of these agents in management of patients with brain metastasis. Stereotactic radiosurgery (SRS) has emerged as a primary therapeutic modality in patients with single or multiple brain metastases with an improvement in overall survival and quality of life [13, 14, 105, 106]. However, there is a subset of patients (up to 23%) who fail SRS with progression of metastatic disease and subsequent mortality [13, 15]. Brain metastasis from radio-resistant systemic tumors such as renal cell carcinoma, sarcoma, melanoma and triple negative breast carcinoma carries a worse progno‐ sis, despite better control rates with SRS as compared to conventional radiotherapy [107]. Stereotactic radiosurgery is also associated with adverse radiation effects (AREs) with a 1-year cumulative incidence of 13–14%, which increases with size and volume of the tumor [108–111]. Of these adverse radiation effects, radiation necrosis (RN) is the most challenging in terms of diagnosis and management with a reported incidence ranging between 1.4% and 25% [16–18, 112]. Imaging modalities such as MR perfusion, MR spectroscopy, 6-[(18)F]-fluoro-L-3,4 dihydroxyphenylalanine (F-DOPA)/FDG PET, l-methyl-(11)C-methionine ((11)C-MET) and SPECT scan have been shown to be useful in differentiating radiation necrosis from recur‐ rent metastasis or tumor [113–116]. The sensitivity, specificity, accuracy of perfusion MRI and F-DOPA PET have been reported to be 86.7, 68.2, 75.6 and 90, 92.3, 91.3%, respectively [114]. SPECT scan has been shown to have the highest specificity of 97.8% (sensitivity 87.6%) for differentiating tumor progression and radiation necrosis and may be preferred over other imaging modalities [116]. Medical therapeutic options for RN include corticosteroids, Bevacizumab, hyperbaric oxygen therapy, anticoagulation (heparin or warfarin) or vitamin E [117–125]. Surgical resection of RN can be considered in symptomatic patients with mass effect in accessible areas [125]. Therefore, there is always a scope for newer treatment strat‐ egies in the management of patients with brain metastasis to improve the clinical outcomes. LITT is a minimally invasive technique that offers an alternative therapeutic option in patients with either SRS-failed or radio-resistant brain metastasis. LITT also offers an opportunity to have a histological diagnosis before laser ablation in cases of suspicion between recurrence of metastasis and radiation-related changes. The minimally invasive nature of this technology permits its utility in patients with multiple medical comorbidities with poor Karnofsky performance status (KPS) and tumors in difficult-to-access locations.

First use of laser therapy for brain metastasis was reported in 1986, with successful-laser assisted ablation of a midbrain metastasis from primary lung adenocarcinoma [126]. In 1990, Sugiyama et al. [90] reported the utility of laser in patients with deep-seated tumors includ‐ ing metastasis. Later, Schulze et al. [36] studied the histological effects of laser thermothera‐ py in seven patients with brain metastasis and eight patients with glial tumors. In this study, authors reported that laser therapy created a unique pattern of architectural changes at the histological level with central zone of necrosis surrounded by edematous tissue. This sur‐ rounding edematous tissue tends to undergo cystic changes following regenerative and resorptive changes [36]. In addition to thermal coagulation, laser-induced tumor damage is caused by disruption of cellular membranes and organelles. Authors advocated this techni‐ que in older patients with significant medical comorbidities and brain tumors. First pilot clinical trial investigating the safety and feasibility of LITT in patients with resistant focal metastatic brain tumors was reported in 2008 [2]. Four patients with six metastatic brain tumors (temporal lobe, *n* = 2; parietal lobe, *n* = 2; frontal lobe, *n* = 1; and occipital lobe, *n* = 1) were enrolled in this trial. Follow-up MRI scans were performed at 7, 15, 30 and 90 days after the procedure to monitorthe zone of thermal necrosis. LITT was well tolerated and all patients were discharged within 14 h after the procedure in this study [2]. There was an acute in‐ crease in the tumor volume immediately after the procedure followed by a gradual reduc‐ tion in the volume during the follow-up imaging. No adverse events, complications or tumor recurrence within the ablated zones were noted during the follow up [2]. Results of this trial were published in 2011, which showed no tumor recurrence in ablated zones in all 7 patients (15 metastatic tumors) at a follow up of 30 months [19]. Mean age of patients enrolled in this study was 54 years, with breast or pulmonary adenocarcinoma and average number of metastasis per patient was 3.3. Total coverage of the tumor under TDT lines was achieved in nine patients and partial coverage in six patients. Single applicator for laser delivery was used in majority of patients (*n* = 13) and two applicators in anothertwo due to complex tumor shape. Majority of tumors were less than 2 cm in size (*n* = 10) and another five were 2–3 cm in size. Mean duration of the procedure and hospital stay was 135 mins and 26 h, respectively, and all patients were discharged within 24 h of procedure [19]. Complications such as blood suffu‐ sion, probe misplacement, transient aphasia and cerebellar syndrome were reported follow‐ ing LITT therapy. Of note, there was a mean increase of 26% (range 0–124%) in tumor volume at a mean interval of 4.7 days (range 0–15 days) afterthe procedure, which returned to baseline volume within 20 days (range 0–75 days). Following LITT, contrast-enhancing rim of the metastasis disappeared in a mean interval of 12.2 months. Mean overall survival and progres‐ sion-free survival following LITT were 17.4±3.5 months and 3.8±1.0 months, respectively [19].

cancers (1.2–1.8%) [103, 104]. Prognosis in patients with brain metastasis is often dismal, due to limited therapeutic options. Majority of chemotherapeutic agents and targeted immuno‐ therapies do not cross the blood brain barrier, hence limited applicability of these agents in management of patients with brain metastasis. Stereotactic radiosurgery (SRS) has emerged as a primary therapeutic modality in patients with single or multiple brain metastases with an improvement in overall survival and quality of life [13, 14, 105, 106]. However, there is a subset of patients (up to 23%) who fail SRS with progression of metastatic disease and subsequent mortality [13, 15]. Brain metastasis from radio-resistant systemic tumors such as renal cell carcinoma, sarcoma, melanoma and triple negative breast carcinoma carries a worse progno‐ sis, despite better control rates with SRS as compared to conventional radiotherapy [107]. Stereotactic radiosurgery is also associated with adverse radiation effects (AREs) with a 1-year cumulative incidence of 13–14%, which increases with size and volume of the tumor [108–111]. Of these adverse radiation effects, radiation necrosis (RN) is the most challenging in terms of diagnosis and management with a reported incidence ranging between 1.4% and 25% [16–18, 112]. Imaging modalities such as MR perfusion, MR spectroscopy, 6-[(18)F]-fluoro-L-3,4 dihydroxyphenylalanine (F-DOPA)/FDG PET, l-methyl-(11)C-methionine ((11)C-MET) and SPECT scan have been shown to be useful in differentiating radiation necrosis from recur‐ rent metastasis or tumor [113–116]. The sensitivity, specificity, accuracy of perfusion MRI and F-DOPA PET have been reported to be 86.7, 68.2, 75.6 and 90, 92.3, 91.3%, respectively [114]. SPECT scan has been shown to have the highest specificity of 97.8% (sensitivity 87.6%) for differentiating tumor progression and radiation necrosis and may be preferred over other imaging modalities [116]. Medical therapeutic options for RN include corticosteroids, Bevacizumab, hyperbaric oxygen therapy, anticoagulation (heparin or warfarin) or vitamin E [117–125]. Surgical resection of RN can be considered in symptomatic patients with mass effect in accessible areas [125]. Therefore, there is always a scope for newer treatment strat‐ egies in the management of patients with brain metastasis to improve the clinical outcomes. LITT is a minimally invasive technique that offers an alternative therapeutic option in patients with either SRS-failed or radio-resistant brain metastasis. LITT also offers an opportunity to have a histological diagnosis before laser ablation in cases of suspicion between recurrence of metastasis and radiation-related changes. The minimally invasive nature of this technology permits its utility in patients with multiple medical comorbidities with poor Karnofsky

294 Neurooncology - Newer Developments

performance status (KPS) and tumors in difficult-to-access locations.

First use of laser therapy for brain metastasis was reported in 1986, with successful-laser assisted ablation of a midbrain metastasis from primary lung adenocarcinoma [126]. In 1990, Sugiyama et al. [90] reported the utility of laser in patients with deep-seated tumors includ‐ ing metastasis. Later, Schulze et al. [36] studied the histological effects of laser thermothera‐ py in seven patients with brain metastasis and eight patients with glial tumors. In this study, authors reported that laser therapy created a unique pattern of architectural changes at the histological level with central zone of necrosis surrounded by edematous tissue. This sur‐ rounding edematous tissue tends to undergo cystic changes following regenerative and resorptive changes [36]. In addition to thermal coagulation, laser-induced tumor damage is caused by disruption of cellular membranes and organelles. Authors advocated this techni‐ que in older patients with significant medical comorbidities and brain tumors. First pilot

Another study reported progression-free and overall median survival of 5.8 months each following LITT in five patients with metastasis (non-small cell lung carcinoma, *n* = 2; colon adenocarcinoma, *n* = 1, melanoma, *n* = 1, fallopian tube carcinoma, *n* = 1) [20]. Frontal lobe was involved in two patients, fronto-parietal in one, insula in one and parietal in one patient. Four patients had one trajectory and another two patients had double trajectories for laser thera‐ py. Of note, mean hospital and ICU stay following LITT were 4.4 days and 1 day, respective‐ ly, in patients with metastasis [20]. This duration of hospital stay following LITT was significantly higher as compared to previous study by Carpentier et al. [19, 20]. Complica‐ tions such as transient aphasia (insula) and hemiparesis (frontal) were noted following LITT, which improved gradually with steroids. Patient with melanoma metastasis showed stable tumor size with edema and decrease in size of lesion at 1 and 3 months, respectively, follow‐ ing LITT on follow-up MRI [20]. Two patients had systemic progression; other two had CNS progression and none of the patients required additional treatment in this study.

Torres-Reveron et al. [3] reported the utility of LITT in six patients with progressive brain metastatic tumors (non-small cell lung cancer, *n* = 2; melanoma, *n* = 2; small cell lung cancer, *n* = 1; ovarian cancer, *n* = 1) following SRS. Tumor recurrence was diagnosed using PET and SPECT imaging in two patients, each using these imaging modalities; however interestingly, stereotactic biopsy prior to ablation therapy was negative in all the patients [3]. There was an

increase in length (63%) and width (64%) of the tumor on post-operative MRI at 2 weeks after LITT compared to preoperative size similar to previous studies [19, 20, 24]. However, in concordance with previous studies, tumor size returned to baseline within 4.5 to 6 months following the procedure in all the patients [3]. Interestingly, initial increase in size of lesion was not associated with increase in concurrent FLAIR signal changes on post-operative MRI at 2 weeks after the procedure. These radiological changes were also associated with improve‐ ment in clinical symptoms and thus the ability to wean off the patient from steroids. Satisfactory tumor control was achieved in four out of six patients; one patient had progres‐ sion of systemic disease and died within 1 month of procedure. Another patient had progres‐ sive increase in tumor size 3 months afterthe procedure following initialresponse, and surgical resection of the tumor showed tumor progression. No significant complications were reported in this study. Similarly, another study investigated the efficacy of LITT in recurrent lesions following stereotactic radiosurgery for brain metastasis [21]. Of note, biopsy and histological diagnosis was not routinely performed in this study and authors advocated LITT irrespec‐ tive of clinical diagnosis (tumor recurrence vs. radiation necrosis). Seventeen LITT proce‐ dures were performed in 16 patients and 14 patients (15 procedures) were available for follow up in this study. Non-small cell lung carcinoma (*n* = 12) was the most common systemic malignancy metastasizing to the brain, followed by breast and colon adenocarcinoma. Average time interval between SRS and LITT was 64.3 weeks [21]. Greater than 25% increase in tumor volume as compared to the immediate post-operative scan (after 24 h) was defined as local treatment failure or recurrence. Mean tumor size that was treated using LITT was 3.66 cm3 and 3.3 lesions were treated per treatment [21]. Mean procedure time, mean duration of ablation and in-patient hospital stay were 136.0, 7.43 and 1.2 days, respectively, in this study. Interestingly, postoperative MRI (within 24 h) revealed an average increase of 278% in tumor volume size following LITT in 12/14 patients and the other two patients showed 74 and 91% decrease in preoperative tumor volume. Subsequently, greater than 10% reduction in tumor volume was observed in seven patients at a median interval of 24 weeks, achieving a local control rate of 75.8% (13 of 15 lesions). Two patients experienced recurrence at 4 and 18 weeks following LITT within the treated zone and underwent surgical resection of the recurrent tumor. The median progression-free survival and overall survival at 39 weeks follow up were 37 weeks and 57%, respectively. Mortality was related to extra cranial disease in five patients and intracranial disease distant from the treated site in one patient. Two complica‐ tions including non-operative hemorrhage (*n* = 1) and new onset hemiparesis (*n* = 1) was noted following LITT; former patient expired secondary to extra cranial progression and the other patient improved with steroids [21].

A recent study reported delayed failure in two patients who underwent LITT following tumor progression and refractory cerebral edema after SRS [23, 49]. LITT was performed 7 months (breast adenocarcinoma) and 14 weeks (lung adenocarcinoma) after stereotactic radiosur‐ gery. Patient with lung adenocarcinoma metastasis to the external capsule had significant perilesional edema following radiosurgery and also experienced severe side effects secon‐ dary to steroid therapy (refractory hyperglycemia, weight gain and bilateral proximal muscle weakness), therefore LITT was considered 14 weeks after SRS [23]. This patient had signifi‐ cant clinical improvement and steroid was weaned off in 2 weeks following ablation therapy.

However, first patient with parietal metastasis and second patient with external capsule metastasis demonstrated tumor recurrence at 6 and 11 months, respectively, which was histologically confirmed following surgical resection [49]. A recent review based on pooled 25 patients with brain metastasis who were treated with LITT reported a median overall survival (OS) of 12.6 months (range 9.0–19.8 months) and progression-free survival (PFS) to vary between 3.8–8.5 months [127]. Severe complication rate was reported to be 8% and included events such as perioperative hemorrhage (non-surgical) and blood suffusion. Intracranial progression of disease (excluding local progression, 8%) and extra cranial progression as the etiology of mortality was reported in 36 and 55% of patients respectively following LITT for brain metastasis. Median survival time (9.0–19.8 months) and severe complication rate of 8% following LITT are similar to 1.4–16.1 months and 6–19%, respective‐ ly, following surgical management of brain metastasis [128]. Given these comparable out‐ comes, LITT is an effective therapeutic option for patients with resistant brain metastasis in difficult-to-access areas. There is a paucity of literature on the utility of LITT in patients with radiation necrosis (RN). It is often difficult to distinguish patients with radiation necrosis and those with tumor recurrence following stereotactic radiosurgery. Therefore, the majority of reported cases could represent a mixture of these clinical conditions, even following stereo‐ tactic biopsy. In an anecdotal report, LITT was used for diagnosed RN following stereotactic biopsy (may represent a mixed lesion), as patient was refractory and not able to tolerate standard medical management (steroids and bevacizumab) for suspected RN [24]. Patient developed several steroid-related complications along with several medical comorbidities. In light of these facts and the presence of a lesion in a difficult-to-access area (left centrum semiovale), LITT was considered in this patient with RN following SRS for brain metastasis (non-small cell lung carcinoma). As demonstrated in earlier reports, there was a significant improvement in clinical symptoms following LITT and patient was weaned off the steroid in 2 weeks after the procedure. However, there was a mild increase in size of lesion with no significant FLAIR signal changes at 7 weeks postoperative MRI, which was consistent with the literature.

increase in length (63%) and width (64%) of the tumor on post-operative MRI at 2 weeks after LITT compared to preoperative size similar to previous studies [19, 20, 24]. However, in concordance with previous studies, tumor size returned to baseline within 4.5 to 6 months following the procedure in all the patients [3]. Interestingly, initial increase in size of lesion was not associated with increase in concurrent FLAIR signal changes on post-operative MRI at 2 weeks after the procedure. These radiological changes were also associated with improve‐ ment in clinical symptoms and thus the ability to wean off the patient from steroids. Satisfactory tumor control was achieved in four out of six patients; one patient had progres‐ sion of systemic disease and died within 1 month of procedure. Another patient had progres‐ sive increase in tumor size 3 months afterthe procedure following initialresponse, and surgical resection of the tumor showed tumor progression. No significant complications were reported in this study. Similarly, another study investigated the efficacy of LITT in recurrent lesions following stereotactic radiosurgery for brain metastasis [21]. Of note, biopsy and histological diagnosis was not routinely performed in this study and authors advocated LITT irrespec‐ tive of clinical diagnosis (tumor recurrence vs. radiation necrosis). Seventeen LITT proce‐ dures were performed in 16 patients and 14 patients (15 procedures) were available for follow up in this study. Non-small cell lung carcinoma (*n* = 12) was the most common systemic malignancy metastasizing to the brain, followed by breast and colon adenocarcinoma. Average time interval between SRS and LITT was 64.3 weeks [21]. Greater than 25% increase in tumor volume as compared to the immediate post-operative scan (after 24 h) was defined as local treatment failure or recurrence. Mean tumor size that was treated using LITT was 3.66 cm3 and 3.3 lesions were treated per treatment [21]. Mean procedure time, mean duration of ablation and in-patient hospital stay were 136.0, 7.43 and 1.2 days, respectively, in this study. Interestingly, postoperative MRI (within 24 h) revealed an average increase of 278% in tumor volume size following LITT in 12/14 patients and the other two patients showed 74 and 91% decrease in preoperative tumor volume. Subsequently, greater than 10% reduction in tumor volume was observed in seven patients at a median interval of 24 weeks, achieving a local control rate of 75.8% (13 of 15 lesions). Two patients experienced recurrence at 4 and 18 weeks following LITT within the treated zone and underwent surgical resection of the recurrent tumor. The median progression-free survival and overall survival at 39 weeks follow up were 37 weeks and 57%, respectively. Mortality was related to extra cranial disease in five patients and intracranial disease distant from the treated site in one patient. Two complica‐ tions including non-operative hemorrhage (*n* = 1) and new onset hemiparesis (*n* = 1) was noted following LITT; former patient expired secondary to extra cranial progression and the other

A recent study reported delayed failure in two patients who underwent LITT following tumor progression and refractory cerebral edema after SRS [23, 49]. LITT was performed 7 months (breast adenocarcinoma) and 14 weeks (lung adenocarcinoma) after stereotactic radiosur‐ gery. Patient with lung adenocarcinoma metastasis to the external capsule had significant perilesional edema following radiosurgery and also experienced severe side effects secon‐ dary to steroid therapy (refractory hyperglycemia, weight gain and bilateral proximal muscle weakness), therefore LITT was considered 14 weeks after SRS [23]. This patient had signifi‐ cant clinical improvement and steroid was weaned off in 2 weeks following ablation therapy.

patient improved with steroids [21].

296 Neurooncology - Newer Developments

Patel et al. [98] reported the utility of LITT in patients with a variety of intracranial patholo‐ gies including patients with recurrent metastasis or radiation necrosis (*n* = 37) [98]. Total operative time and ablation time were 2.8±0.6 h and 8.7±8.1 mins, respectively. Postopera‐ tive complications such as neurological worsening (*n* = 7), hemorrhage (*n* = 1), edema (*n* = 1), infection (*n* = 1) and thermal injury to pituitary leading to secondary complications (*n* = 1) were reported [98]. Overall survival and progression-free survival or recurrence was not reported in this study [98].

LITT has shown initial promising results in patients with recurrent brain metastasis and RN (to some extent) following SRS. However, long-term prospective randomized controlled studies are warranted and required to validate the efficacy of LITT forthese clinical indications.
