Magnetic Resonance-Guided Laser-Induced Thermal Therapy for the Treatment of Progressive Enhancing Inflammatory Reactions Following Stereotactic Radiosurgery, or PEIRs, for Metastatic Brain Disease

Magnetic Resonance-Guided Laser-Induced Thermal Therapy for the Treatment of Progressive... Abstract BACKGROUND In patients who have previously undergone maximum radiation for metastatic brain tumors, a progressive enhancing inflammatory reaction (PEIR) that represents either tumor recurrence or radiation necrosis, or a combination of both, can occur. Magnetic resonance-guided laser-induced thermal therapy (LITT) offers a minimally invasive treatment option for this problem. OBJECTIVE To report our single-center experience using LITT to treat PEIRs after radiosurgery for brain metastases. METHODS Patients with progressive, enhancing reactions at the site of prior radiosurgery for metastatic brain tumors and who had a Karnofsky performance status of ≥70 were eligible for LITT. The primary endpoint was local control. Secondary end points included dexamethasone use and procedure-related complications. RESULTS Between 2010 and 2017, 59 patients who underwent 74 LITT procedures for 74 PEIRs met inclusion criteria. The mean pre-LITT PEIR size measured 3.4 ± 0.4 cm3. At a median follow-up of 44.6 wk post-LITT, the local control rate was 83.1%. Most patients were weaned off steroids post-LITT. Patients experiencing a post-LITT complication were more likely to remain on steroids indefinitely. The rate of new permanent neurological deficit was 3.4%. CONCLUSION LITT is an effective treatment for local control of PEIRs after radiosurgery for metastatic brain disease. When possible, we recommend offering LITT once PEIRs are identified and prior to the initiation of high-dose steroids for symptom relief. Brain metastases, Laser ablation, Laser-induced thermal therapy, MRgLITT, Radiosurgery failure ABBREVIATIONS ABBREVIATIONS LITT laser-induced thermal therapy MRgLITT magnetic resonance-guided laser-induced thermal therapy MRI magnetic resonance imaging PEIR progressive enhancing inflammatory reaction RN radiation necrosis SRS stereotactic radiosurgery WBRT whole-brain radiation therapy Brain metastasis is the most common tumor of the brain, with around 200 000 new diagnoses per year. Treatment of newly diagnosed brain metastases has shifted to stereotactic radiosurgery (SRS) with or without whole-brain radiation therapy (WBRT). Recurrence is not uncommon with reported rates of 5.4% to 19.7%.1-8 Radiation necrosis (RN) is a potential complication following SRS, occurring in 6.7-25.8% of patients.1,6,9,10 Distinguishing between tumor recurrence and RN can be challenging. Radiographic modalities such as magnetic resonance spectroscopy, perfusion-weighted magnetic resonance imaging (MRI) and PET offer diagnostic tools to help identify recurrence vs RN; however, results are often inconclusive.11,12 Similarly, biopsy of the lesion can also provide equivocal results, revealing both tumor cells and RN. One of the clinical dilemmas that remains is the belief that if the progressive enhancement represents RN that it will ultimately stabilize without the need for treatment. However, RN can become irreversibly progressive, and predicting which patients will demonstrate progression is not possible. Because it is often difficult to distinguish between pure RN and recurrent metastasis, we have termed this finding progressive enhancing inflammatory reactions, or PEIRs. This is purely a radiographic diagnosis based and termed progressive on the basis of increasing enhancement over 2 consecutive MR scans spaced 6 to 8 wk apart. Patients who are not candidates for surgery and cannot tolerate medical management of infield progression at the site of prior SRS are therefore left without viable options for further treatment. We have previously reported the utility of magnetic resonance-guided laser-induced thermal therapy (MRgLITT) in treating recurrent, enhancing lesions following SRS for metastatic brain disease.13 Other groups have similarly reported data on the use of LITT for infield recurrence and RN.14-22 Due to the difficulty in differentiating between infield recurrence and RN following SRS, and considering LITT has demonstrated reasonable control across both pathologies, we argue against the need for extensive diagnostic workup in order to identify the exact histology of PEIRs following SRS. In our patient population, we consider PEIRs as a single entity without differentiating between RN and tumor progression. In this study, we present our experience with LITT in patients with metastatic brain disease who present with PEIRs at the sites of prior SRS who did not undergo a biopsy as part of their diagnostic workup. This study is a continuation of a previously published smaller series.13 METHODS Patient Selection The study was conducted with the approval of our institutional review board and represents a retrospective cohort study that used data from a prospectively accumulated database. Between November 2010 and May 2017, patients who presented to our institution for intracranial PEIRs were evaluated by a multidisciplinary board consisting of neurosurgeons, neuroradiologists, neurooncologists, and neuropathologists. Informed consent was obtained. Specifically, the following criteria were used to identify recurrence or continued progression: radiologist interpretation of the lesion, new enhancement that progressed over 2 consecutive scans by at least 25% in 2 out of 3 dimensions, or PEIRs that required an intervention for symptom control. Patients were deemed poor candidates for additional radiation therapy because of a history of maximal irradiation. All patients had prior SRS to the target PEIR. Patients were required to have a Karnofsky performance status of ≥70, have extracranial disease under reasonable control as evidenced by 2 consecutive stable PET scans, and have a life expectancy of at least 3 mo. Both asymptomatic and symptomatic patients were eligible for LITT if clear evidence of radiological progression as described above existed. Patients with multiple brain metastases were included based on the following criteria: 3 or fewer dominant PEIRs that would be the target of laser ablation, no radiographic progression of disease elsewhere in the brain, and a target PEIR that was <4 cm in linear dimension, in addition to the criteria listed above. Patients who were concurrently receiving other forms of treatment for RN, such as pentoxifylline, vitamin E, and/or bevacizumab, were excluded. Operative Technique and Procedure The laser thermal ablation technique performed at our institution has been previously described.23 Briefly, laser applicators (Visualase®, Medtronic Inc, Dublin, Ireland) were placed stereotactically with the use of a frameless technique in the operating room. Patients were then transported to MRI where real-time thermal ablation was performed on a 1.5-T MR scanner. Laser ablation was performed until maximal ablation coverage of the PEIR was achieved. Biopsies before or after the procedure were not performed. MRI Scans Preoperative PEIRs were measured using OsiriX software (Pixmeo SARL, Bernex, Switzerland) from an MRI obtained the day prior to or the day of LITT. All patients underwent clinical and radiological follow-up with serial MRIs at 24 h after the procedure, a second MRI at 4 to 8 wk later, and thereafter, serial MRIs of the brain at an interval of 4 to 12 wk until death or local recurrence of the treated PEIR. Only those patients with at least 8 wk of follow-up and were compliant with the above-mentioned schedule were considered suitable for data collection and study analysis. End Points The primary end point was local control of the ablated PEIR. Local control was defined as the lack of progression following LITT (ie, LITT failure). Specifically, the following criteria were used to identify recurrence or continued progression: new enhancement that progressed over 2 consecutive scans by at least 25% in 2 out of 3 dimensions, or PEIRs that required an intervention for symptom control. Secondary end points included procedure-related complications and dexamethasone use following the procedure. Statistical Design Prism 7 software was used to complete the statistical data analyses. Continuous data are reported as means with standard error of the means. Categorical data are reported as frequencies and percentage. Statistical significance was defined as P < .05. Continuous data were analyzed using nonparametric Wilcoxon rank-sum tests. Comparisons between complications, pre-LITT, and post-LITT steroid use were analyzed using chi-squared and Fisher's exact tests, and odds ratios (OR) are reported with the 95% confidence interval (CI). RESULTS Patient Characteristics Between November 2010 and May 2017, a total of 59 patients with 74 PEIRs underwent 74 LITT procedures. Fourteen patients with a total of 15 PEIRs were excluded from the study. The 13 patients lost to follow-up were from outside our hospital system, and we were unable to obtain complete details of their postoperative course. One patient underwent withdrawal of care and hospice 1 mo following surgery. These 14 patients (15 PEIRs) were thus excluded from data analysis. This yielded 45 patients, ages 35 to 90 yr of age, with 59 PEIRs who underwent 59 LITT procedures for inclusion in data analysis (Figure 1). Median time between SRS and LITT was 71.9 wk (range 10-290 wk). Patient demographics and procedure details are summarized in Table 1. FIGURE 1. View largeDownload slide Patient inclusion flow diagram. FIGURE 1. View largeDownload slide Patient inclusion flow diagram. TABLE 1. Patient Demographics and Laser Ablation Characteristics   n  Age (yr)  SRS to LITT Interval (wk)  Pre-LITT Lesion Size (cm3)  Depth to Target (mm)  No. of Ablations  Ablation Time (s)  All Lesions  59  63.1 ± 1.4  73.5 ± 8.3  3.4 ± 0.4  78.0 ± 2.2  2.9 ± 0.1  304.0 ± 23.2  1° Histology     NSCLC  31  66.2 ± 2.0  71.2 ± 9.9  2.8 ± 0.4  77.8 ± 2.6  2.9 ± 0.2  310.7 ± 30.1   Breast  17  59.3 ± 2.3  99.8 ± 20.5  3.6 ± 0.8  77.9 ± 5.7  2.9 ± 0.3  306 ± 50.0   Colon  2  67.0 ± 3.0  37.0 ± 8.0  5.6 ± 1.6  81.1 ± 8.9  3.0 ± 0  229.5 ± 52.5   RCC  2  63.0 ± 0  19 ± 0  2.4 ± 1.3  76.5 ± 16.5  2.0 ± 1.0  298 ± 73.0   Melanoma  3  67.7 ± 5.2  48.3 ± 29.35  4.5 ± 2.6  74.0 ± 9.5  3.0 ± 0.6  251.3 ± 117.5   Testicular  2  40.5 ± 5.5  72 ± 0.0  6.0 ± 2.0  84.3 ± 5.7  4 ± 1.0  450 ± 214   Cervical  1  53  46.1  4.6  66  2  150   SCLC  1  67  35.4  3.1  95  3  285  LITT Failure     No  49  63.0 ± 1.6  76.9 ± 9.6  3.2 ± 0.4  76.6 ± 2.4  2.9 ± 0.2  301.9 ± 23.3   Yes  10  63.4 ± 3.8  53.2 ± 12.6  4.0 ± 0.9  84.9 ± 5.7  2.8 ± 0.4  319.8 ± 80.0    n  Age (yr)  SRS to LITT Interval (wk)  Pre-LITT Lesion Size (cm3)  Depth to Target (mm)  No. of Ablations  Ablation Time (s)  All Lesions  59  63.1 ± 1.4  73.5 ± 8.3  3.4 ± 0.4  78.0 ± 2.2  2.9 ± 0.1  304.0 ± 23.2  1° Histology     NSCLC  31  66.2 ± 2.0  71.2 ± 9.9  2.8 ± 0.4  77.8 ± 2.6  2.9 ± 0.2  310.7 ± 30.1   Breast  17  59.3 ± 2.3  99.8 ± 20.5  3.6 ± 0.8  77.9 ± 5.7  2.9 ± 0.3  306 ± 50.0   Colon  2  67.0 ± 3.0  37.0 ± 8.0  5.6 ± 1.6  81.1 ± 8.9  3.0 ± 0  229.5 ± 52.5   RCC  2  63.0 ± 0  19 ± 0  2.4 ± 1.3  76.5 ± 16.5  2.0 ± 1.0  298 ± 73.0   Melanoma  3  67.7 ± 5.2  48.3 ± 29.35  4.5 ± 2.6  74.0 ± 9.5  3.0 ± 0.6  251.3 ± 117.5   Testicular  2  40.5 ± 5.5  72 ± 0.0  6.0 ± 2.0  84.3 ± 5.7  4 ± 1.0  450 ± 214   Cervical  1  53  46.1  4.6  66  2  150   SCLC  1  67  35.4  3.1  95  3  285  LITT Failure     No  49  63.0 ± 1.6  76.9 ± 9.6  3.2 ± 0.4  76.6 ± 2.4  2.9 ± 0.2  301.9 ± 23.3   Yes  10  63.4 ± 3.8  53.2 ± 12.6  4.0 ± 0.9  84.9 ± 5.7  2.8 ± 0.4  319.8 ± 80.0  LITT: laser-induced thermal therapy; NSCLC: non–small-cell lung cancer; RCC: renal cell carcinoma; SCLC: small-cell lung cancer; SRS: stereotactic radiosurgery; wk: weeks; yr: years. Means reported with standard error of the means. View Large TABLE 1. Patient Demographics and Laser Ablation Characteristics   n  Age (yr)  SRS to LITT Interval (wk)  Pre-LITT Lesion Size (cm3)  Depth to Target (mm)  No. of Ablations  Ablation Time (s)  All Lesions  59  63.1 ± 1.4  73.5 ± 8.3  3.4 ± 0.4  78.0 ± 2.2  2.9 ± 0.1  304.0 ± 23.2  1° Histology     NSCLC  31  66.2 ± 2.0  71.2 ± 9.9  2.8 ± 0.4  77.8 ± 2.6  2.9 ± 0.2  310.7 ± 30.1   Breast  17  59.3 ± 2.3  99.8 ± 20.5  3.6 ± 0.8  77.9 ± 5.7  2.9 ± 0.3  306 ± 50.0   Colon  2  67.0 ± 3.0  37.0 ± 8.0  5.6 ± 1.6  81.1 ± 8.9  3.0 ± 0  229.5 ± 52.5   RCC  2  63.0 ± 0  19 ± 0  2.4 ± 1.3  76.5 ± 16.5  2.0 ± 1.0  298 ± 73.0   Melanoma  3  67.7 ± 5.2  48.3 ± 29.35  4.5 ± 2.6  74.0 ± 9.5  3.0 ± 0.6  251.3 ± 117.5   Testicular  2  40.5 ± 5.5  72 ± 0.0  6.0 ± 2.0  84.3 ± 5.7  4 ± 1.0  450 ± 214   Cervical  1  53  46.1  4.6  66  2  150   SCLC  1  67  35.4  3.1  95  3  285  LITT Failure     No  49  63.0 ± 1.6  76.9 ± 9.6  3.2 ± 0.4  76.6 ± 2.4  2.9 ± 0.2  301.9 ± 23.3   Yes  10  63.4 ± 3.8  53.2 ± 12.6  4.0 ± 0.9  84.9 ± 5.7  2.8 ± 0.4  319.8 ± 80.0    n  Age (yr)  SRS to LITT Interval (wk)  Pre-LITT Lesion Size (cm3)  Depth to Target (mm)  No. of Ablations  Ablation Time (s)  All Lesions  59  63.1 ± 1.4  73.5 ± 8.3  3.4 ± 0.4  78.0 ± 2.2  2.9 ± 0.1  304.0 ± 23.2  1° Histology     NSCLC  31  66.2 ± 2.0  71.2 ± 9.9  2.8 ± 0.4  77.8 ± 2.6  2.9 ± 0.2  310.7 ± 30.1   Breast  17  59.3 ± 2.3  99.8 ± 20.5  3.6 ± 0.8  77.9 ± 5.7  2.9 ± 0.3  306 ± 50.0   Colon  2  67.0 ± 3.0  37.0 ± 8.0  5.6 ± 1.6  81.1 ± 8.9  3.0 ± 0  229.5 ± 52.5   RCC  2  63.0 ± 0  19 ± 0  2.4 ± 1.3  76.5 ± 16.5  2.0 ± 1.0  298 ± 73.0   Melanoma  3  67.7 ± 5.2  48.3 ± 29.35  4.5 ± 2.6  74.0 ± 9.5  3.0 ± 0.6  251.3 ± 117.5   Testicular  2  40.5 ± 5.5  72 ± 0.0  6.0 ± 2.0  84.3 ± 5.7  4 ± 1.0  450 ± 214   Cervical  1  53  46.1  4.6  66  2  150   SCLC  1  67  35.4  3.1  95  3  285  LITT Failure     No  49  63.0 ± 1.6  76.9 ± 9.6  3.2 ± 0.4  76.6 ± 2.4  2.9 ± 0.2  301.9 ± 23.3   Yes  10  63.4 ± 3.8  53.2 ± 12.6  4.0 ± 0.9  84.9 ± 5.7  2.8 ± 0.4  319.8 ± 80.0  LITT: laser-induced thermal therapy; NSCLC: non–small-cell lung cancer; RCC: renal cell carcinoma; SCLC: small-cell lung cancer; SRS: stereotactic radiosurgery; wk: weeks; yr: years. Means reported with standard error of the means. View Large Magnetic resonance-guided laser-induced thermal therapy Fifty-nine LITT procedures were performed for 59 PEIRs (Figure 1). The mean pre-procedure volume measured 3.4 ± 0.4 cm3 (range 0.24-10.8 cm3, median 2.9 cm3). One PEIR was treated with 2 catheters; otherwise, all other PEIRs were treated with a single catheter. On average, the number of ablations per treatment was 2.9 (range 1-6, median 3), depth to target was 78.0 mm (range 7.5-124.3 mm, median 75 mm), ablation dose was 11.3 watts (range 8.3-15 watts, median 11.3 watts), and total ablation time was 304.9 s (range 39-965 s, median 270 s; Table 1). Radiological Local Control Median follow-up was 44.6 wk (range 8-251.1 wk). MRI surveillance of the 59 treated PEIRs identified 10 with recurrence, resulting in a local control rate of 83.1% (Figure 2). LITT failure occurred at a median 18.8 wk post-LITT (range 4.6-111.1 wk). Six PEIRs recurred or demonstrated continued progression within 6 mo of the LITT procedure, 3 recurred between 6 and 8 mo, while the last case was found to have delayed recurrence at 2.1 yr. Five failures were treated with craniotomy for surgical resection, followed by SRS in 1 patient, 3 failures were treated with a repeat LITT procedure, and 2 patients elected not to pursue further intervention. Patient age, tumor size, and ablation characteristics were similar between patients who failed LITT and those who did not show recurrence or continued progression (Table 1). FIGURE 2. View largeDownload slide Local control flow diagram. FIGURE 2. View largeDownload slide Local control flow diagram. Periprocedural Monitoring and Complications All laser catheters were adequately placed as confirmed by MRI and no case required repositioning of the catheter. There was a total of 53 hospital admissions for the 59 LITT procedures. The median length of stay after the procedure was 1 d. Thirteen patients experienced 16 complications, yielding a complication rate of 25.0% (Table 2). The most common postoperative complication was new or increased motor weakness, which was encountered in 9 patients. No patients suffered stroke, infection, or hemorrhage requiring open intervention. There were no procedure-related mortalities. Of the 13 patients with new or worsened neurological deficits following LITT, 7 (53.8%) had complete resolution at last follow-up, 4 (30.1%) had partial resolution at last follow-up, and 2 (15.4%) had persistence of the new deficit at last follow-up, resulting in a rate of permanent new neurological deficit following 59 LITT procedures of 3.4%. Patients who suffered procedure-related complications had a significantly longer mean post-LITT hospital length of stay compared to patients who did not suffer complications (3.0 ± 0.6 d vs 1.7 ± 0.2 d, respectively; P < .5). Patients who experienced complications were more likely to be on dexamethasone prior to the procedure and to be continued on dexamethasone indefinitely post-LITT than patients who did not experience complications (OR 4.0 95% CI 1.0-13.6, P = .04 and OR 5.6 95% CI 1.2-20.9, P = .03, respectively). TABLE 2. Periprocedural Complications Lesion  Lesion Location  Pre-LITT Lesion Size (cm3)  New Neurological Deficit Following LITT  Degree of Resolution at Last Follow-up  Pre-LITT Steroid Dose  Post-LITT Steroid Course  6  Right middle cerebellar peduncle  2.68  Right facial nerve palsy (House-Brackmann IV)  Persistent  None  2-wk taper to off  7  Left frontal lobe  1.51  Expressive aphasia  Complete  6 mg every 6 h  4 mg twice a day until death  13  Right frontal lobe  2.17  Increased left arm weakness, increased seizure frequency  Complete  2 mg twice a day  6-mo taper to off  16  Right frontal lobe  4.4  Left hemiparesis  Partial  4 mg twice a week  4 mg twice a week until death  18  Right frontal lobe  3.88  Left hemiparesis  Partial  None  4-wk taper to off  22  Right parietal lobe  6.28  Left arm weakness  Partial  None  2-wk taper to off  29  Left occipital lobe  4.9  Right eye visual hallucinations  Complete  None  1-wk taper to off  31  Left pons  3.51  Left hemiparesis, slurred speech  Partial  None  6 mg every 6 hours at last follow-up  32  Left frontal lobe  7.88  Expressive aphasia  Complete  4 mg twice a day  6-wk taper to off  34  Right cerebellum  3.21  Right arm weakness  Persistent  1 mg twice a day  1 mg twice a day at last follow-up  39  Left frontal lobe  7.45  Expressive aphasia, right hemiparesis  Complete  4 mg twice a day  8-wk taper to off  47  L parietal lobe  0.51  Right arm weakness  Complete  4 mg twice a day  1 wk taper to off  53  L parietal lobe  3.54  Right arm weakness  Complete  None  1 wk taper to off  Lesion  Lesion Location  Pre-LITT Lesion Size (cm3)  New Neurological Deficit Following LITT  Degree of Resolution at Last Follow-up  Pre-LITT Steroid Dose  Post-LITT Steroid Course  6  Right middle cerebellar peduncle  2.68  Right facial nerve palsy (House-Brackmann IV)  Persistent  None  2-wk taper to off  7  Left frontal lobe  1.51  Expressive aphasia  Complete  6 mg every 6 h  4 mg twice a day until death  13  Right frontal lobe  2.17  Increased left arm weakness, increased seizure frequency  Complete  2 mg twice a day  6-mo taper to off  16  Right frontal lobe  4.4  Left hemiparesis  Partial  4 mg twice a week  4 mg twice a week until death  18  Right frontal lobe  3.88  Left hemiparesis  Partial  None  4-wk taper to off  22  Right parietal lobe  6.28  Left arm weakness  Partial  None  2-wk taper to off  29  Left occipital lobe  4.9  Right eye visual hallucinations  Complete  None  1-wk taper to off  31  Left pons  3.51  Left hemiparesis, slurred speech  Partial  None  6 mg every 6 hours at last follow-up  32  Left frontal lobe  7.88  Expressive aphasia  Complete  4 mg twice a day  6-wk taper to off  34  Right cerebellum  3.21  Right arm weakness  Persistent  1 mg twice a day  1 mg twice a day at last follow-up  39  Left frontal lobe  7.45  Expressive aphasia, right hemiparesis  Complete  4 mg twice a day  8-wk taper to off  47  L parietal lobe  0.51  Right arm weakness  Complete  4 mg twice a day  1 wk taper to off  53  L parietal lobe  3.54  Right arm weakness  Complete  None  1 wk taper to off  LITT: laser-induced thermal therapy. View Large TABLE 2. Periprocedural Complications Lesion  Lesion Location  Pre-LITT Lesion Size (cm3)  New Neurological Deficit Following LITT  Degree of Resolution at Last Follow-up  Pre-LITT Steroid Dose  Post-LITT Steroid Course  6  Right middle cerebellar peduncle  2.68  Right facial nerve palsy (House-Brackmann IV)  Persistent  None  2-wk taper to off  7  Left frontal lobe  1.51  Expressive aphasia  Complete  6 mg every 6 h  4 mg twice a day until death  13  Right frontal lobe  2.17  Increased left arm weakness, increased seizure frequency  Complete  2 mg twice a day  6-mo taper to off  16  Right frontal lobe  4.4  Left hemiparesis  Partial  4 mg twice a week  4 mg twice a week until death  18  Right frontal lobe  3.88  Left hemiparesis  Partial  None  4-wk taper to off  22  Right parietal lobe  6.28  Left arm weakness  Partial  None  2-wk taper to off  29  Left occipital lobe  4.9  Right eye visual hallucinations  Complete  None  1-wk taper to off  31  Left pons  3.51  Left hemiparesis, slurred speech  Partial  None  6 mg every 6 hours at last follow-up  32  Left frontal lobe  7.88  Expressive aphasia  Complete  4 mg twice a day  6-wk taper to off  34  Right cerebellum  3.21  Right arm weakness  Persistent  1 mg twice a day  1 mg twice a day at last follow-up  39  Left frontal lobe  7.45  Expressive aphasia, right hemiparesis  Complete  4 mg twice a day  8-wk taper to off  47  L parietal lobe  0.51  Right arm weakness  Complete  4 mg twice a day  1 wk taper to off  53  L parietal lobe  3.54  Right arm weakness  Complete  None  1 wk taper to off  Lesion  Lesion Location  Pre-LITT Lesion Size (cm3)  New Neurological Deficit Following LITT  Degree of Resolution at Last Follow-up  Pre-LITT Steroid Dose  Post-LITT Steroid Course  6  Right middle cerebellar peduncle  2.68  Right facial nerve palsy (House-Brackmann IV)  Persistent  None  2-wk taper to off  7  Left frontal lobe  1.51  Expressive aphasia  Complete  6 mg every 6 h  4 mg twice a day until death  13  Right frontal lobe  2.17  Increased left arm weakness, increased seizure frequency  Complete  2 mg twice a day  6-mo taper to off  16  Right frontal lobe  4.4  Left hemiparesis  Partial  4 mg twice a week  4 mg twice a week until death  18  Right frontal lobe  3.88  Left hemiparesis  Partial  None  4-wk taper to off  22  Right parietal lobe  6.28  Left arm weakness  Partial  None  2-wk taper to off  29  Left occipital lobe  4.9  Right eye visual hallucinations  Complete  None  1-wk taper to off  31  Left pons  3.51  Left hemiparesis, slurred speech  Partial  None  6 mg every 6 hours at last follow-up  32  Left frontal lobe  7.88  Expressive aphasia  Complete  4 mg twice a day  6-wk taper to off  34  Right cerebellum  3.21  Right arm weakness  Persistent  1 mg twice a day  1 mg twice a day at last follow-up  39  Left frontal lobe  7.45  Expressive aphasia, right hemiparesis  Complete  4 mg twice a day  8-wk taper to off  47  L parietal lobe  0.51  Right arm weakness  Complete  4 mg twice a day  1 wk taper to off  53  L parietal lobe  3.54  Right arm weakness  Complete  None  1 wk taper to off  LITT: laser-induced thermal therapy. View Large There was no correlation between tumor size and resulting complications. Steroid Use Of the 53 patient admissions, 16 patients were taking dexamethasone prior to surgery. Postoperatively, all except for 3 patients were started on dexamethasone tapers. The majority of patients were prescribed a 1- to 2-wk taper. In summary, 4 (25%) of 16 patients on pre-LITT dexamethasone were continued on steroids at death or last follow-up compared to 5 (13.5%) of 37 patients not on pre-LITT dexamethasone continued on steroids at death or last follow-up (Table 3). This difference trended toward but did not reach statistical significance. Additionally, 25% of patients on steroids preoperatively remained on steroids indefinitely. TABLE 3. Effects of Procedure-Related Complications and Steroid Use   n  Age (yr)  Pre-LITT Lesion Size (cm3)  Post-LITT LOS (d)  Patients on Pre-LITT Steroids  Patients on Post-LITT Steroids  Patients With Complications  All patients  53  63.1 ± 0.1  3.4 ± 0.4  2.0 ± 0.2  29.6  16.6%  25.0%  Complication     No  40  61.2 ± 1.6  3.3 ± 0.4  1.7 ± 0.2a  22.50%a  10.0%b  –   Yes  13  67.4 ± 3.0  3.7 ± 0.5  3.0 ± 0.6a  53.6%a  38.5%b  –  Pre-LITT Steroids     No  37  62.8 ± 1.8  3.5 ± 0.4  1.7 ± 0.3  –  13.5%  18.8%   Yes  16  63.8 ± 2.5  3.1 ± 0.6  2.7 ± 0.6  –  25.0%  37.5%  Post-LITT Steroids     No  44  63.1 ± 1.6  3.1 ± 0.4  2.0 ± 0.3  27.2%  –  20.45%   Yes  9  63.2 ± 3.6  4.3 ± 0.9  1.9 ± 0.3  44.4%  –  44.4%    n  Age (yr)  Pre-LITT Lesion Size (cm3)  Post-LITT LOS (d)  Patients on Pre-LITT Steroids  Patients on Post-LITT Steroids  Patients With Complications  All patients  53  63.1 ± 0.1  3.4 ± 0.4  2.0 ± 0.2  29.6  16.6%  25.0%  Complication     No  40  61.2 ± 1.6  3.3 ± 0.4  1.7 ± 0.2a  22.50%a  10.0%b  –   Yes  13  67.4 ± 3.0  3.7 ± 0.5  3.0 ± 0.6a  53.6%a  38.5%b  –  Pre-LITT Steroids     No  37  62.8 ± 1.8  3.5 ± 0.4  1.7 ± 0.3  –  13.5%  18.8%   Yes  16  63.8 ± 2.5  3.1 ± 0.6  2.7 ± 0.6  –  25.0%  37.5%  Post-LITT Steroids     No  44  63.1 ± 1.6  3.1 ± 0.4  2.0 ± 0.3  27.2%  –  20.45%   Yes  9  63.2 ± 3.6  4.3 ± 0.9  1.9 ± 0.3  44.4%  –  44.4%  LITT: laser-induced thermal therapy; LOS: length of stay; wk: weeks; yr: years; n: hospital admissions for LITT procedure. aDifference reached statistical significance, OR 4.0 95% CI 1.0-13.6, P = .04. bDifference reached statistical significance, OR 5.6, 95% CI 1.2-20.9, P = .03. Means reported with standard error of the means. View Large TABLE 3. Effects of Procedure-Related Complications and Steroid Use   n  Age (yr)  Pre-LITT Lesion Size (cm3)  Post-LITT LOS (d)  Patients on Pre-LITT Steroids  Patients on Post-LITT Steroids  Patients With Complications  All patients  53  63.1 ± 0.1  3.4 ± 0.4  2.0 ± 0.2  29.6  16.6%  25.0%  Complication     No  40  61.2 ± 1.6  3.3 ± 0.4  1.7 ± 0.2a  22.50%a  10.0%b  –   Yes  13  67.4 ± 3.0  3.7 ± 0.5  3.0 ± 0.6a  53.6%a  38.5%b  –  Pre-LITT Steroids     No  37  62.8 ± 1.8  3.5 ± 0.4  1.7 ± 0.3  –  13.5%  18.8%   Yes  16  63.8 ± 2.5  3.1 ± 0.6  2.7 ± 0.6  –  25.0%  37.5%  Post-LITT Steroids     No  44  63.1 ± 1.6  3.1 ± 0.4  2.0 ± 0.3  27.2%  –  20.45%   Yes  9  63.2 ± 3.6  4.3 ± 0.9  1.9 ± 0.3  44.4%  –  44.4%    n  Age (yr)  Pre-LITT Lesion Size (cm3)  Post-LITT LOS (d)  Patients on Pre-LITT Steroids  Patients on Post-LITT Steroids  Patients With Complications  All patients  53  63.1 ± 0.1  3.4 ± 0.4  2.0 ± 0.2  29.6  16.6%  25.0%  Complication     No  40  61.2 ± 1.6  3.3 ± 0.4  1.7 ± 0.2a  22.50%a  10.0%b  –   Yes  13  67.4 ± 3.0  3.7 ± 0.5  3.0 ± 0.6a  53.6%a  38.5%b  –  Pre-LITT Steroids     No  37  62.8 ± 1.8  3.5 ± 0.4  1.7 ± 0.3  –  13.5%  18.8%   Yes  16  63.8 ± 2.5  3.1 ± 0.6  2.7 ± 0.6  –  25.0%  37.5%  Post-LITT Steroids     No  44  63.1 ± 1.6  3.1 ± 0.4  2.0 ± 0.3  27.2%  –  20.45%   Yes  9  63.2 ± 3.6  4.3 ± 0.9  1.9 ± 0.3  44.4%  –  44.4%  LITT: laser-induced thermal therapy; LOS: length of stay; wk: weeks; yr: years; n: hospital admissions for LITT procedure. aDifference reached statistical significance, OR 4.0 95% CI 1.0-13.6, P = .04. bDifference reached statistical significance, OR 5.6, 95% CI 1.2-20.9, P = .03. Means reported with standard error of the means. View Large DISCUSSION LITT continues to gain popularity as a salvage treatment option for PEIRs after radiation for brain metastasis. In this study, we report our institution's experience with this technology in a cohort of patients with metastatic brain disease who were radiographically diagnosed with tumor recurrence and/or RN inside the radiation field of treatment and who were treated without a biopsy. We placed these patients into a single diagnostic entity that we termed PEIRs, to help reflect that the treatment strategy can be effective even without separating them into 2 distinct categories. At a median follow-up of 44.6 wk, we achieved a local control rate of 83.1%. This study represents the largest series to date of patients undergoing LITT for recurrence after treatment for brain metastasis. Several other studies have reported on LITT for progressive enhancement following SRS for metastatic brain disease, ranging from 1 to 7 patients with median follow-up ranging from 7 to 52 wk, achieving local control rates of 14% to 100%.13,14,16-19,21,22 One of the benefits of using LITT in this population may be the ability to eliminate the need to differentiate between a recurrent metastatic tumor and RN. Some groups, as is our practice, do not perform biopsy prior to LITT.15,17 In our practice, results of the biopsy would not change the treatment plan, and are only performed if the information will help guide systemic therapy. Other groups do perform a biopsy prior to LITT, though they proceeded with LITT immediately following the biopsy, suggesting that they, too, do not alter their treatment plans based upon the biopsy results.17,18,21 We undoubtedly spend immense resources and time attempting to understand the underlying physiology with the idea that one process is always progressive (recurrent tumor), while the other (RN) is usually not. Both processes, however, can demonstrate progression and lead to significant symptoms and neurological deficits. We have shown that the use of this technology, even in the absence of tissue confirmation via biopsy, yields a reasonable local control rate in patients who have failed primary treatment of brain metastases. This leads us to believe that while LITT can control a recurrent tumor, it can also halt the progression of RN. Two relatively large series reporting on complications associated with LITT identified complication rates of 26.5% and 22.4%.24,25 Our complication rate falls within this range. The risks of LITT can be broadly placed into 2 categories: (1) related to laser insertion and (2) related to thermal ablation.24 In this study, we did not encounter any symptomatic complications related to laser insertion. Risks related to thermal ablation include damage to nearby healthy brain tissue, incomplete ablation, and ablation-induced hemorrhage and cerebral edema. A volumetric analysis of 16 lesions treated with LITT demonstrated on postoperative MRI within 1-h of LITT that ablated lesions enlarged in size on average 281% due to tissue damage and resultant edema.26 Similarly, we previously reported a mean 278% increase in lesion size on MRI 24 h following LITT with reduction back to pretreatment size over the months following the procedure.13 We hypothesize that ablated PEIRs adjacent to eloquent cortex can cause new neurological symptoms due to postablation edema, with resolution of symptoms as they decrease in size during the follow-up period. The majority of our patients with new post-LITT neurological symptoms had complete or partial resolution during follow-up. Literature review of 243 patients reported a permanent deficit rate following LITT of 5.8%25 slightly higher than our rate of permanent neurological deficit of 3.4%. LITT represents one treatment option for recurrent brain metastases or RN following SRS; however, other options exist, including repeat SRS if one is convinced that the underlying physiology represents pure tumor recurrence. One such study examining repeat SRS to recurrent lesions identified a local control rate of 79%, matching the local control rate achieved in our patient population. Importantly, they found 24% of cases developed symptomatic RN and that the volume receiving a cumulative dose of 40 Gy over the 2 SRS treatments was predictive of RN development.8 Repeat SRS to previously irradiated recurrent lesions offers a treatment option for patients who are not surgical candidates or for lesions that are not surgically accessible. However, confirmation of recurrent tumor (vs RN) is required, which can be challenging, and repeat SRS comes with the risk of developing RN, which the abovementioned studies demonstrate is not an insignificant risk, and potentially at a much higher rate than the peri-procedural risk from MRgLITT. Our patients were deemed not eligible for additional SRS by our multidisciplinary board due to having received previous SRS and concerns for neurotoxicity. Another option for recurrent PEIRs following SRS is surgical resection. Three studies examined surgical resection for recurrence of metastases previously treated with SRS with or without WBRT. These studies reported local control rates of 69%, 74%, and 79% and procedure-related complication rates of 9%, 20%, and 22%.27-29 Our local control rate (83.1%) exceeds the best reported of the 3 studies, though our complication rate (25%) is slightly higher. The complication rate of surgical resection in these studies may be lower due to the ability to safely access the lesions with normal surgical corridors. On the other hand, MRgLITT offers a treatment option in these “unresectable locations.” We are performing LITT for more complicated targets, both morphometrically and in regard to location relative to eloquent cortex, which may also contribute to a higher complication rate, and so a comparison to the risk profile from open surgery may not be appropriate. We feel a key to the success of LITT is early intervention once follow-up imaging demonstrates new, progressive enhancement at the sites of previously treated metastases. Based on our study findings and clinical experience, we believe LITT should be offered prior to the PEIRs becoming symptomatic and requiring high-dose dexamethasone. We found that patients entering the procedure on dexamethasone were more likely to be continued on steroids indefinitely in the postoperative period compared to patients who entered the procedure not already on dexamethasone. Additionally, patients already on dexamethasone prior to the procedure were more likely to experience a post-LITT complication. The additive effects of patients’ baseline cerebral edema requiring steroid treatment and new post-ablation edema likely account for the increased complication rate. However, LITT did show a significant effect on the ability to wean patients off steroids following the procedure in that 29.6% of all patients entered the procedure on dexamethasone compared to 16.6% who were continued on dexamethasone indefinitely in the post-LITT period. Limitations This study has a few limitations. Fifteen (20.3%) of the 74 treated lesions were lost to or had inadequate follow-up at the time of data analysis which may contribute to selection bias. Additionally, while we have reported local control with a moderate follow-up period, we do not have data on quality of life measures. As LITT continues to emerge as a minimally invasive treatment option for intracranial lesions, it will be important to know its effect on quality of life. Future studies should include such data. Although this present study represents the largest series examining LITT for PEIRs after radiosurgery for brain metastases, with the longest follow-up to date, larger studies with longer follow-up are needed. CONCLUSION This is the largest single institution series to report on the utility of MRgLITT for the treatment of PEIRs after radiosurgery for brain metastasis. MRgLITT potentially offers an effective salvage therapy without the need to histologically differentiate between tumor recurrence and RN. We recommend offering MRgLITT early once progression is determined. Complications are more likely encountered following treatment of patients already requiring high-dose dexamethasone, particularly within eloquent regions. Further follow-up in a larger patient population is needed to better define the long-term outcomes following LITT. Disclosures Dr Danish receives an honorarium from Medtronic. The other authors have no personal, financial, or institutional interest in any of the drugs, materials, or devices described in this article. REFERENCES 1. Minniti G, Clarke E, Lanzetta G et al.   Stereotactic radiosurgery for brain metastases: analysis of outcome and risk of brain radionecrosis. Radiat Oncol . 2011; 6( 1): 48. Google Scholar CrossRef Search ADS PubMed  2. Baschnagel AM, Meyer KD, Chen PY et al.   Tumor volume as a predictor of survival and local control in patients with brain metastases treated with Gamma Knife surgery. J Neurosurg . 2013; 119( 5): 1139– 1144. Google Scholar CrossRef Search ADS PubMed  3. Likhacheva A, Pinnix CC, Parikh NR et al.   Predictors of survival in contemporary practice after initial radiosurgery for brain metastases. Int J Radiat Oncol Biol Phys . 2013; 85( 3): 656– 661. Google Scholar CrossRef Search ADS PubMed  4. Yamamoto M, Serizawa T, Shuto T et al.   Stereotactic radiosurgery for patients with multiple brain metastases (JLGK0901): a multi-institutional prospective observational study. Lancet Oncol . 2014; 15( 4): 387– 395. Google Scholar CrossRef Search ADS PubMed  5. Cho KR, Lee MH, Kong DS et al.   Outcome of gamma knife radiosurgery for metastatic brain tumors derived from non-small cell lung cancer. J Neurooncol . 2015; 125( 2): 331– 338. Google Scholar CrossRef Search ADS PubMed  6. Sneed PK, Mendez J, Vemer-van den Hoek JG et al.   Adverse radiation effect after stereotactic radiosurgery for brain metastases: Incidence, time course, and risk factors. J Neurosurg . 2015; 123( 2): 373– 386. Google Scholar CrossRef Search ADS PubMed  7. Koiso T, Yamamoto M, Kawabe T et al.   Follow-up results of brain metastasis patients undergoing repeat Gamma Knife radiosurgery. J Neurosurg . 2016; 125( suppl 1): 2– 10. Google Scholar PubMed  8. McKay WH, McTyre ER, Okoukoni C et al.   Repeat stereotactic radiosurgery as salvage therapy for locally recurrent brain metastases previously treated with radiosurgery. J Neurosurg . 2017; 127( 1): 148– 156. Google Scholar CrossRef Search ADS PubMed  9. Miller JA, Bennett EE, Xiao R et al.   Association between radiation necrosis and tumor biology after stereotactic radiosurgery for brain metastasis. Int J Radiat Oncol Biol Phys . 2016; 96( 5): 1060– 1069. Google Scholar CrossRef Search ADS PubMed  10. Kohutek ZA, Yamada Y, Chan TA et al.   Long-term risk of radionecrosis and imaging changes after stereotactic radiosurgery for brain metastases. J Neurooncol . 2015; 125( 1): 149– 156. Google Scholar CrossRef Search ADS PubMed  11. Kickingereder P, Dorn F, Blau T et al.   Differentiation of local tumor recurrence from radiation-induced changes after stereotactic radiosurgery for treatment of brain metastasis: case report and review of the literature. Radiat Oncol . 2013; 8( 1): 52. Google Scholar CrossRef Search ADS PubMed  12. Cicone F, Minniti G, Romano A et al.   Accuracy of F-DOPA PET and perfusion-MRI for differentiating radionecrotic from progressive brain metastases after radiosurgery. Eur J Nucl Med Mol Imaging . 2015; 42( 1): 103– 111. Google Scholar CrossRef Search ADS PubMed  13. Rao MS, Hargreaves EL, Khan AJ, Haffty BG, Danish SF. Magnetic resonance-guided laser ablation improves local control for postradiosurgery recurrence and/or radiation necrosis. Neurosurgery . 2014; 74( 6): 658– 667. Google Scholar CrossRef Search ADS PubMed  14. Carpentier A, McNichols RJ, Stafford RJ et al.   Laser thermal therapy: real-time MRI-guided and computer-controlled procedures for metastatic brain tumors. Lasers Surg Med . 2011; 43( 10): 943– 950. Google Scholar CrossRef Search ADS PubMed  15. Carpentier A, McNichols RJ, Stafford RJ et al.   Real-time magnetic resonance-guided laser thermal therapy for focal metastatic brain tumors. Neurosurgery . 2008; 63( 1 suppl 1): ONS21– ONS28. Google Scholar PubMed  16. Hawasli AH, Bagade S, Shimony JS, Miller-Thomas M, Leuthardt EC. Magnetic resonance imaging-guided focused laser interstitial thermal therapy for intracranial lesions: single-institution series. Neurosurgery . 2013; 73( 6): 1007– 1017. Google Scholar CrossRef Search ADS PubMed  17. Rahmathulla G, Recinos PF, Valerio JE, Chao S, Barnett GH. Laser interstitial thermal therapy for focal cerebral radiation necrosis: a case report and literature review. Stereotact Funct Neurosurg . 2012; 90( 3): 192– 200. Google Scholar CrossRef Search ADS PubMed  18. Torres-Reveron J, Tomasiewicz HC, Shetty A, Amankulor NM, Chiang VL. Stereotactic laser induced thermotherapy (LITT): a novel treatment for brain lesions regrowing after radiosurgery. J Neurooncol . 2013; 113( 3): 495– 503. Google Scholar CrossRef Search ADS PubMed  19. Fabiano AJ, Alberico RA. Laser-interstitial thermal therapy for refractory cerebral edema from post-radiosurgery metastasis. World Neurosurg . 2014; 81( 3-4): 652.e1– 652.e4. Google Scholar CrossRef Search ADS   20. Ascher PW, Justich E, Schrottner O. Interstitial thermotherapy of central brain tumors with the Nd:YAG laser under real-time monitoring by MRI. J Clin Laser Med Surg . 1991; 9( 1): 79– 83. Google Scholar PubMed  21. Smith CJ, Myers CS, Chapple KM, Smith KA. Long-term follow-up of 25 cases of biopsy-proven radiation necrosis or post-radiation treatment effect treated with magnetic resonance-guided laser interstitial thermal therapy. Neurosurgery . 2016; 79( suppl 1): S59– S72. Google Scholar CrossRef Search ADS PubMed  22. Torcuator RG, Hulou MM, Chavakula V, Jolesz FA, Golby AJ. Intraoperative real-time MRI-guided stereotactic biopsy followed by laser thermal ablation for progressive brain metastases after radiosurgery. J Clin Neurosci . 2016; 24: 68– 73. Google Scholar CrossRef Search ADS PubMed  23. Jethwa PR, Barrese JC, Gowda A, Shetty A, Danish SF. Magnetic resonance thermometry-guided laser-induced thermal therapy for intracranial neoplasms: initial experience. Neurosurgery . 2012; 71( 1 Suppl Operative): 133– 144. Google Scholar PubMed  24. Patel P, Patel NV, Danish SF. Intracranial MR-guided laser-induced thermal therapy: Single-center experience with the Visualase thermal therapy system. J Neurosurg . 2016; 125( 4): 853– 860. Google Scholar CrossRef Search ADS PubMed  25. Pruitt R, Gamble A, Black K, Schulder M, Mehta AD. Complication avoidance in laser interstitial thermal therapy: Lessons learned. J Neurosurg . 2017; 126( 4): 1238– 1245. Google Scholar CrossRef Search ADS PubMed  26. Patel NV, Jethwa PR, Barrese JC, Hargreaves EL, Danish SF. Volumetric trends associated with MRI-guided laser-induced thermal therapy (LITT) for intracranial tumors. Lasers Surg Med . 2013; 45( 6): 362– 369. Google Scholar CrossRef Search ADS PubMed  27. Kano H, Kondziolka D, Zorro O, Lobato-Polo J, Flickinger JC, Lunsford LD. The results of resection after stereotactic radiosurgery for brain metastases. J Neurosurg . 2009; 111( 4): 825– 831. Google Scholar CrossRef Search ADS PubMed  28. Truong MT, St Clair EG, Donahue BR et al.   Results of surgical resection for progression of brain metastases previously treated by gamma knife radiosurgery. Neurosurgery . 2006; 59( 1): 86– 97. Google Scholar CrossRef Search ADS PubMed  29. Vecil GG, Suki D, Maldaun MV, Lang FF, Sawaya R. Resection of brain metastases previously treated with stereotactic radiosurgery. J Neurosurg . 2005; 102( 2): 209– 215. Google Scholar CrossRef Search ADS PubMed  COMMENT The authors tackle a difficult clinical situation in this article – what to do with the patient presenting after maximum radiation for metastatic brain tumors with progressive enhancing lesions. Given the uncertainty of whether the progressive enhancement represents increasing tumor burden, radiation change, or a combination, the authors term these lesions “progressive enhancing inflammatory reaction”. They present a case series of 59 patients undergoing 74 laser ablations. Of that patients meeting inclusion criteria, local control was achieved in 83%. In this series, biopsies were not performed either before or after the ablation, leaving the diagnosis undetermined. Although new motor weakness was encountered in 9 patients, the majority of these improved with a rate of permanent new neurologic deficit of 3.4%. The clinical conundrum that these authors address is one that will confront any neurosurgeon treating brain metastases. In patients who have already undergone maximal safe radiation, treatment options are limited. A main underlying question is whether or not the etiology of the progressive enhancement needs to be established prior to definitive treatment. While some individuals believe that a tissue diagnosis must be obtained prior to treatment, others favor a single surgery for treatment +/- biopsy, if that treatment can be carried out with minimal risk. In our practice, we favor the second approach. Subjecting patients to 2 surgeries and 2 instances of general anesthetic is likely to carry a higher risk profile compared to the low morbidity of LITT procedures. Additionally, pathologic diagnosis following biopsy may be subject to sampling bias and may not provide an accurate diagnosis in mixed lesions. We believe that in the absence of a clear diagnosis, biopsy, to guide the decision of post-ablation chemotherapy/radiation, in combination with laser ablation to treat the progressive changes is a reasonable treatment paradigm. Certainly, continued discussion on this subject is warranted and may be aided by the careful study of pretreatment physiologic and adjunctive imaging to provide diagnostic certainty regarding the underlying etiology of the inflammatory changes. Angela M. Richardson Ricardo J. Komotar Miami, Florida Copyright © 2018 by the Congress of Neurological Surgeons This article is published and distributed under the terms of the Oxford University Press, Standard Journals Publication Model (https://academic.oup.com/journals/pages/about_us/legal/notices) http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Neurosurgery Oxford University Press

Magnetic Resonance-Guided Laser-Induced Thermal Therapy for the Treatment of Progressive Enhancing Inflammatory Reactions Following Stereotactic Radiosurgery, or PEIRs, for Metastatic Brain Disease

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Congress of Neurological Surgeons
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Copyright © 2018 by the Congress of Neurological Surgeons
ISSN
0148-396X
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1524-4040
D.O.I.
10.1093/neuros/nyy220
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Abstract

Abstract BACKGROUND In patients who have previously undergone maximum radiation for metastatic brain tumors, a progressive enhancing inflammatory reaction (PEIR) that represents either tumor recurrence or radiation necrosis, or a combination of both, can occur. Magnetic resonance-guided laser-induced thermal therapy (LITT) offers a minimally invasive treatment option for this problem. OBJECTIVE To report our single-center experience using LITT to treat PEIRs after radiosurgery for brain metastases. METHODS Patients with progressive, enhancing reactions at the site of prior radiosurgery for metastatic brain tumors and who had a Karnofsky performance status of ≥70 were eligible for LITT. The primary endpoint was local control. Secondary end points included dexamethasone use and procedure-related complications. RESULTS Between 2010 and 2017, 59 patients who underwent 74 LITT procedures for 74 PEIRs met inclusion criteria. The mean pre-LITT PEIR size measured 3.4 ± 0.4 cm3. At a median follow-up of 44.6 wk post-LITT, the local control rate was 83.1%. Most patients were weaned off steroids post-LITT. Patients experiencing a post-LITT complication were more likely to remain on steroids indefinitely. The rate of new permanent neurological deficit was 3.4%. CONCLUSION LITT is an effective treatment for local control of PEIRs after radiosurgery for metastatic brain disease. When possible, we recommend offering LITT once PEIRs are identified and prior to the initiation of high-dose steroids for symptom relief. Brain metastases, Laser ablation, Laser-induced thermal therapy, MRgLITT, Radiosurgery failure ABBREVIATIONS ABBREVIATIONS LITT laser-induced thermal therapy MRgLITT magnetic resonance-guided laser-induced thermal therapy MRI magnetic resonance imaging PEIR progressive enhancing inflammatory reaction RN radiation necrosis SRS stereotactic radiosurgery WBRT whole-brain radiation therapy Brain metastasis is the most common tumor of the brain, with around 200 000 new diagnoses per year. Treatment of newly diagnosed brain metastases has shifted to stereotactic radiosurgery (SRS) with or without whole-brain radiation therapy (WBRT). Recurrence is not uncommon with reported rates of 5.4% to 19.7%.1-8 Radiation necrosis (RN) is a potential complication following SRS, occurring in 6.7-25.8% of patients.1,6,9,10 Distinguishing between tumor recurrence and RN can be challenging. Radiographic modalities such as magnetic resonance spectroscopy, perfusion-weighted magnetic resonance imaging (MRI) and PET offer diagnostic tools to help identify recurrence vs RN; however, results are often inconclusive.11,12 Similarly, biopsy of the lesion can also provide equivocal results, revealing both tumor cells and RN. One of the clinical dilemmas that remains is the belief that if the progressive enhancement represents RN that it will ultimately stabilize without the need for treatment. However, RN can become irreversibly progressive, and predicting which patients will demonstrate progression is not possible. Because it is often difficult to distinguish between pure RN and recurrent metastasis, we have termed this finding progressive enhancing inflammatory reactions, or PEIRs. This is purely a radiographic diagnosis based and termed progressive on the basis of increasing enhancement over 2 consecutive MR scans spaced 6 to 8 wk apart. Patients who are not candidates for surgery and cannot tolerate medical management of infield progression at the site of prior SRS are therefore left without viable options for further treatment. We have previously reported the utility of magnetic resonance-guided laser-induced thermal therapy (MRgLITT) in treating recurrent, enhancing lesions following SRS for metastatic brain disease.13 Other groups have similarly reported data on the use of LITT for infield recurrence and RN.14-22 Due to the difficulty in differentiating between infield recurrence and RN following SRS, and considering LITT has demonstrated reasonable control across both pathologies, we argue against the need for extensive diagnostic workup in order to identify the exact histology of PEIRs following SRS. In our patient population, we consider PEIRs as a single entity without differentiating between RN and tumor progression. In this study, we present our experience with LITT in patients with metastatic brain disease who present with PEIRs at the sites of prior SRS who did not undergo a biopsy as part of their diagnostic workup. This study is a continuation of a previously published smaller series.13 METHODS Patient Selection The study was conducted with the approval of our institutional review board and represents a retrospective cohort study that used data from a prospectively accumulated database. Between November 2010 and May 2017, patients who presented to our institution for intracranial PEIRs were evaluated by a multidisciplinary board consisting of neurosurgeons, neuroradiologists, neurooncologists, and neuropathologists. Informed consent was obtained. Specifically, the following criteria were used to identify recurrence or continued progression: radiologist interpretation of the lesion, new enhancement that progressed over 2 consecutive scans by at least 25% in 2 out of 3 dimensions, or PEIRs that required an intervention for symptom control. Patients were deemed poor candidates for additional radiation therapy because of a history of maximal irradiation. All patients had prior SRS to the target PEIR. Patients were required to have a Karnofsky performance status of ≥70, have extracranial disease under reasonable control as evidenced by 2 consecutive stable PET scans, and have a life expectancy of at least 3 mo. Both asymptomatic and symptomatic patients were eligible for LITT if clear evidence of radiological progression as described above existed. Patients with multiple brain metastases were included based on the following criteria: 3 or fewer dominant PEIRs that would be the target of laser ablation, no radiographic progression of disease elsewhere in the brain, and a target PEIR that was <4 cm in linear dimension, in addition to the criteria listed above. Patients who were concurrently receiving other forms of treatment for RN, such as pentoxifylline, vitamin E, and/or bevacizumab, were excluded. Operative Technique and Procedure The laser thermal ablation technique performed at our institution has been previously described.23 Briefly, laser applicators (Visualase®, Medtronic Inc, Dublin, Ireland) were placed stereotactically with the use of a frameless technique in the operating room. Patients were then transported to MRI where real-time thermal ablation was performed on a 1.5-T MR scanner. Laser ablation was performed until maximal ablation coverage of the PEIR was achieved. Biopsies before or after the procedure were not performed. MRI Scans Preoperative PEIRs were measured using OsiriX software (Pixmeo SARL, Bernex, Switzerland) from an MRI obtained the day prior to or the day of LITT. All patients underwent clinical and radiological follow-up with serial MRIs at 24 h after the procedure, a second MRI at 4 to 8 wk later, and thereafter, serial MRIs of the brain at an interval of 4 to 12 wk until death or local recurrence of the treated PEIR. Only those patients with at least 8 wk of follow-up and were compliant with the above-mentioned schedule were considered suitable for data collection and study analysis. End Points The primary end point was local control of the ablated PEIR. Local control was defined as the lack of progression following LITT (ie, LITT failure). Specifically, the following criteria were used to identify recurrence or continued progression: new enhancement that progressed over 2 consecutive scans by at least 25% in 2 out of 3 dimensions, or PEIRs that required an intervention for symptom control. Secondary end points included procedure-related complications and dexamethasone use following the procedure. Statistical Design Prism 7 software was used to complete the statistical data analyses. Continuous data are reported as means with standard error of the means. Categorical data are reported as frequencies and percentage. Statistical significance was defined as P < .05. Continuous data were analyzed using nonparametric Wilcoxon rank-sum tests. Comparisons between complications, pre-LITT, and post-LITT steroid use were analyzed using chi-squared and Fisher's exact tests, and odds ratios (OR) are reported with the 95% confidence interval (CI). RESULTS Patient Characteristics Between November 2010 and May 2017, a total of 59 patients with 74 PEIRs underwent 74 LITT procedures. Fourteen patients with a total of 15 PEIRs were excluded from the study. The 13 patients lost to follow-up were from outside our hospital system, and we were unable to obtain complete details of their postoperative course. One patient underwent withdrawal of care and hospice 1 mo following surgery. These 14 patients (15 PEIRs) were thus excluded from data analysis. This yielded 45 patients, ages 35 to 90 yr of age, with 59 PEIRs who underwent 59 LITT procedures for inclusion in data analysis (Figure 1). Median time between SRS and LITT was 71.9 wk (range 10-290 wk). Patient demographics and procedure details are summarized in Table 1. FIGURE 1. View largeDownload slide Patient inclusion flow diagram. FIGURE 1. View largeDownload slide Patient inclusion flow diagram. TABLE 1. Patient Demographics and Laser Ablation Characteristics   n  Age (yr)  SRS to LITT Interval (wk)  Pre-LITT Lesion Size (cm3)  Depth to Target (mm)  No. of Ablations  Ablation Time (s)  All Lesions  59  63.1 ± 1.4  73.5 ± 8.3  3.4 ± 0.4  78.0 ± 2.2  2.9 ± 0.1  304.0 ± 23.2  1° Histology     NSCLC  31  66.2 ± 2.0  71.2 ± 9.9  2.8 ± 0.4  77.8 ± 2.6  2.9 ± 0.2  310.7 ± 30.1   Breast  17  59.3 ± 2.3  99.8 ± 20.5  3.6 ± 0.8  77.9 ± 5.7  2.9 ± 0.3  306 ± 50.0   Colon  2  67.0 ± 3.0  37.0 ± 8.0  5.6 ± 1.6  81.1 ± 8.9  3.0 ± 0  229.5 ± 52.5   RCC  2  63.0 ± 0  19 ± 0  2.4 ± 1.3  76.5 ± 16.5  2.0 ± 1.0  298 ± 73.0   Melanoma  3  67.7 ± 5.2  48.3 ± 29.35  4.5 ± 2.6  74.0 ± 9.5  3.0 ± 0.6  251.3 ± 117.5   Testicular  2  40.5 ± 5.5  72 ± 0.0  6.0 ± 2.0  84.3 ± 5.7  4 ± 1.0  450 ± 214   Cervical  1  53  46.1  4.6  66  2  150   SCLC  1  67  35.4  3.1  95  3  285  LITT Failure     No  49  63.0 ± 1.6  76.9 ± 9.6  3.2 ± 0.4  76.6 ± 2.4  2.9 ± 0.2  301.9 ± 23.3   Yes  10  63.4 ± 3.8  53.2 ± 12.6  4.0 ± 0.9  84.9 ± 5.7  2.8 ± 0.4  319.8 ± 80.0    n  Age (yr)  SRS to LITT Interval (wk)  Pre-LITT Lesion Size (cm3)  Depth to Target (mm)  No. of Ablations  Ablation Time (s)  All Lesions  59  63.1 ± 1.4  73.5 ± 8.3  3.4 ± 0.4  78.0 ± 2.2  2.9 ± 0.1  304.0 ± 23.2  1° Histology     NSCLC  31  66.2 ± 2.0  71.2 ± 9.9  2.8 ± 0.4  77.8 ± 2.6  2.9 ± 0.2  310.7 ± 30.1   Breast  17  59.3 ± 2.3  99.8 ± 20.5  3.6 ± 0.8  77.9 ± 5.7  2.9 ± 0.3  306 ± 50.0   Colon  2  67.0 ± 3.0  37.0 ± 8.0  5.6 ± 1.6  81.1 ± 8.9  3.0 ± 0  229.5 ± 52.5   RCC  2  63.0 ± 0  19 ± 0  2.4 ± 1.3  76.5 ± 16.5  2.0 ± 1.0  298 ± 73.0   Melanoma  3  67.7 ± 5.2  48.3 ± 29.35  4.5 ± 2.6  74.0 ± 9.5  3.0 ± 0.6  251.3 ± 117.5   Testicular  2  40.5 ± 5.5  72 ± 0.0  6.0 ± 2.0  84.3 ± 5.7  4 ± 1.0  450 ± 214   Cervical  1  53  46.1  4.6  66  2  150   SCLC  1  67  35.4  3.1  95  3  285  LITT Failure     No  49  63.0 ± 1.6  76.9 ± 9.6  3.2 ± 0.4  76.6 ± 2.4  2.9 ± 0.2  301.9 ± 23.3   Yes  10  63.4 ± 3.8  53.2 ± 12.6  4.0 ± 0.9  84.9 ± 5.7  2.8 ± 0.4  319.8 ± 80.0  LITT: laser-induced thermal therapy; NSCLC: non–small-cell lung cancer; RCC: renal cell carcinoma; SCLC: small-cell lung cancer; SRS: stereotactic radiosurgery; wk: weeks; yr: years. Means reported with standard error of the means. View Large TABLE 1. Patient Demographics and Laser Ablation Characteristics   n  Age (yr)  SRS to LITT Interval (wk)  Pre-LITT Lesion Size (cm3)  Depth to Target (mm)  No. of Ablations  Ablation Time (s)  All Lesions  59  63.1 ± 1.4  73.5 ± 8.3  3.4 ± 0.4  78.0 ± 2.2  2.9 ± 0.1  304.0 ± 23.2  1° Histology     NSCLC  31  66.2 ± 2.0  71.2 ± 9.9  2.8 ± 0.4  77.8 ± 2.6  2.9 ± 0.2  310.7 ± 30.1   Breast  17  59.3 ± 2.3  99.8 ± 20.5  3.6 ± 0.8  77.9 ± 5.7  2.9 ± 0.3  306 ± 50.0   Colon  2  67.0 ± 3.0  37.0 ± 8.0  5.6 ± 1.6  81.1 ± 8.9  3.0 ± 0  229.5 ± 52.5   RCC  2  63.0 ± 0  19 ± 0  2.4 ± 1.3  76.5 ± 16.5  2.0 ± 1.0  298 ± 73.0   Melanoma  3  67.7 ± 5.2  48.3 ± 29.35  4.5 ± 2.6  74.0 ± 9.5  3.0 ± 0.6  251.3 ± 117.5   Testicular  2  40.5 ± 5.5  72 ± 0.0  6.0 ± 2.0  84.3 ± 5.7  4 ± 1.0  450 ± 214   Cervical  1  53  46.1  4.6  66  2  150   SCLC  1  67  35.4  3.1  95  3  285  LITT Failure     No  49  63.0 ± 1.6  76.9 ± 9.6  3.2 ± 0.4  76.6 ± 2.4  2.9 ± 0.2  301.9 ± 23.3   Yes  10  63.4 ± 3.8  53.2 ± 12.6  4.0 ± 0.9  84.9 ± 5.7  2.8 ± 0.4  319.8 ± 80.0    n  Age (yr)  SRS to LITT Interval (wk)  Pre-LITT Lesion Size (cm3)  Depth to Target (mm)  No. of Ablations  Ablation Time (s)  All Lesions  59  63.1 ± 1.4  73.5 ± 8.3  3.4 ± 0.4  78.0 ± 2.2  2.9 ± 0.1  304.0 ± 23.2  1° Histology     NSCLC  31  66.2 ± 2.0  71.2 ± 9.9  2.8 ± 0.4  77.8 ± 2.6  2.9 ± 0.2  310.7 ± 30.1   Breast  17  59.3 ± 2.3  99.8 ± 20.5  3.6 ± 0.8  77.9 ± 5.7  2.9 ± 0.3  306 ± 50.0   Colon  2  67.0 ± 3.0  37.0 ± 8.0  5.6 ± 1.6  81.1 ± 8.9  3.0 ± 0  229.5 ± 52.5   RCC  2  63.0 ± 0  19 ± 0  2.4 ± 1.3  76.5 ± 16.5  2.0 ± 1.0  298 ± 73.0   Melanoma  3  67.7 ± 5.2  48.3 ± 29.35  4.5 ± 2.6  74.0 ± 9.5  3.0 ± 0.6  251.3 ± 117.5   Testicular  2  40.5 ± 5.5  72 ± 0.0  6.0 ± 2.0  84.3 ± 5.7  4 ± 1.0  450 ± 214   Cervical  1  53  46.1  4.6  66  2  150   SCLC  1  67  35.4  3.1  95  3  285  LITT Failure     No  49  63.0 ± 1.6  76.9 ± 9.6  3.2 ± 0.4  76.6 ± 2.4  2.9 ± 0.2  301.9 ± 23.3   Yes  10  63.4 ± 3.8  53.2 ± 12.6  4.0 ± 0.9  84.9 ± 5.7  2.8 ± 0.4  319.8 ± 80.0  LITT: laser-induced thermal therapy; NSCLC: non–small-cell lung cancer; RCC: renal cell carcinoma; SCLC: small-cell lung cancer; SRS: stereotactic radiosurgery; wk: weeks; yr: years. Means reported with standard error of the means. View Large Magnetic resonance-guided laser-induced thermal therapy Fifty-nine LITT procedures were performed for 59 PEIRs (Figure 1). The mean pre-procedure volume measured 3.4 ± 0.4 cm3 (range 0.24-10.8 cm3, median 2.9 cm3). One PEIR was treated with 2 catheters; otherwise, all other PEIRs were treated with a single catheter. On average, the number of ablations per treatment was 2.9 (range 1-6, median 3), depth to target was 78.0 mm (range 7.5-124.3 mm, median 75 mm), ablation dose was 11.3 watts (range 8.3-15 watts, median 11.3 watts), and total ablation time was 304.9 s (range 39-965 s, median 270 s; Table 1). Radiological Local Control Median follow-up was 44.6 wk (range 8-251.1 wk). MRI surveillance of the 59 treated PEIRs identified 10 with recurrence, resulting in a local control rate of 83.1% (Figure 2). LITT failure occurred at a median 18.8 wk post-LITT (range 4.6-111.1 wk). Six PEIRs recurred or demonstrated continued progression within 6 mo of the LITT procedure, 3 recurred between 6 and 8 mo, while the last case was found to have delayed recurrence at 2.1 yr. Five failures were treated with craniotomy for surgical resection, followed by SRS in 1 patient, 3 failures were treated with a repeat LITT procedure, and 2 patients elected not to pursue further intervention. Patient age, tumor size, and ablation characteristics were similar between patients who failed LITT and those who did not show recurrence or continued progression (Table 1). FIGURE 2. View largeDownload slide Local control flow diagram. FIGURE 2. View largeDownload slide Local control flow diagram. Periprocedural Monitoring and Complications All laser catheters were adequately placed as confirmed by MRI and no case required repositioning of the catheter. There was a total of 53 hospital admissions for the 59 LITT procedures. The median length of stay after the procedure was 1 d. Thirteen patients experienced 16 complications, yielding a complication rate of 25.0% (Table 2). The most common postoperative complication was new or increased motor weakness, which was encountered in 9 patients. No patients suffered stroke, infection, or hemorrhage requiring open intervention. There were no procedure-related mortalities. Of the 13 patients with new or worsened neurological deficits following LITT, 7 (53.8%) had complete resolution at last follow-up, 4 (30.1%) had partial resolution at last follow-up, and 2 (15.4%) had persistence of the new deficit at last follow-up, resulting in a rate of permanent new neurological deficit following 59 LITT procedures of 3.4%. Patients who suffered procedure-related complications had a significantly longer mean post-LITT hospital length of stay compared to patients who did not suffer complications (3.0 ± 0.6 d vs 1.7 ± 0.2 d, respectively; P < .5). Patients who experienced complications were more likely to be on dexamethasone prior to the procedure and to be continued on dexamethasone indefinitely post-LITT than patients who did not experience complications (OR 4.0 95% CI 1.0-13.6, P = .04 and OR 5.6 95% CI 1.2-20.9, P = .03, respectively). TABLE 2. Periprocedural Complications Lesion  Lesion Location  Pre-LITT Lesion Size (cm3)  New Neurological Deficit Following LITT  Degree of Resolution at Last Follow-up  Pre-LITT Steroid Dose  Post-LITT Steroid Course  6  Right middle cerebellar peduncle  2.68  Right facial nerve palsy (House-Brackmann IV)  Persistent  None  2-wk taper to off  7  Left frontal lobe  1.51  Expressive aphasia  Complete  6 mg every 6 h  4 mg twice a day until death  13  Right frontal lobe  2.17  Increased left arm weakness, increased seizure frequency  Complete  2 mg twice a day  6-mo taper to off  16  Right frontal lobe  4.4  Left hemiparesis  Partial  4 mg twice a week  4 mg twice a week until death  18  Right frontal lobe  3.88  Left hemiparesis  Partial  None  4-wk taper to off  22  Right parietal lobe  6.28  Left arm weakness  Partial  None  2-wk taper to off  29  Left occipital lobe  4.9  Right eye visual hallucinations  Complete  None  1-wk taper to off  31  Left pons  3.51  Left hemiparesis, slurred speech  Partial  None  6 mg every 6 hours at last follow-up  32  Left frontal lobe  7.88  Expressive aphasia  Complete  4 mg twice a day  6-wk taper to off  34  Right cerebellum  3.21  Right arm weakness  Persistent  1 mg twice a day  1 mg twice a day at last follow-up  39  Left frontal lobe  7.45  Expressive aphasia, right hemiparesis  Complete  4 mg twice a day  8-wk taper to off  47  L parietal lobe  0.51  Right arm weakness  Complete  4 mg twice a day  1 wk taper to off  53  L parietal lobe  3.54  Right arm weakness  Complete  None  1 wk taper to off  Lesion  Lesion Location  Pre-LITT Lesion Size (cm3)  New Neurological Deficit Following LITT  Degree of Resolution at Last Follow-up  Pre-LITT Steroid Dose  Post-LITT Steroid Course  6  Right middle cerebellar peduncle  2.68  Right facial nerve palsy (House-Brackmann IV)  Persistent  None  2-wk taper to off  7  Left frontal lobe  1.51  Expressive aphasia  Complete  6 mg every 6 h  4 mg twice a day until death  13  Right frontal lobe  2.17  Increased left arm weakness, increased seizure frequency  Complete  2 mg twice a day  6-mo taper to off  16  Right frontal lobe  4.4  Left hemiparesis  Partial  4 mg twice a week  4 mg twice a week until death  18  Right frontal lobe  3.88  Left hemiparesis  Partial  None  4-wk taper to off  22  Right parietal lobe  6.28  Left arm weakness  Partial  None  2-wk taper to off  29  Left occipital lobe  4.9  Right eye visual hallucinations  Complete  None  1-wk taper to off  31  Left pons  3.51  Left hemiparesis, slurred speech  Partial  None  6 mg every 6 hours at last follow-up  32  Left frontal lobe  7.88  Expressive aphasia  Complete  4 mg twice a day  6-wk taper to off  34  Right cerebellum  3.21  Right arm weakness  Persistent  1 mg twice a day  1 mg twice a day at last follow-up  39  Left frontal lobe  7.45  Expressive aphasia, right hemiparesis  Complete  4 mg twice a day  8-wk taper to off  47  L parietal lobe  0.51  Right arm weakness  Complete  4 mg twice a day  1 wk taper to off  53  L parietal lobe  3.54  Right arm weakness  Complete  None  1 wk taper to off  LITT: laser-induced thermal therapy. View Large TABLE 2. Periprocedural Complications Lesion  Lesion Location  Pre-LITT Lesion Size (cm3)  New Neurological Deficit Following LITT  Degree of Resolution at Last Follow-up  Pre-LITT Steroid Dose  Post-LITT Steroid Course  6  Right middle cerebellar peduncle  2.68  Right facial nerve palsy (House-Brackmann IV)  Persistent  None  2-wk taper to off  7  Left frontal lobe  1.51  Expressive aphasia  Complete  6 mg every 6 h  4 mg twice a day until death  13  Right frontal lobe  2.17  Increased left arm weakness, increased seizure frequency  Complete  2 mg twice a day  6-mo taper to off  16  Right frontal lobe  4.4  Left hemiparesis  Partial  4 mg twice a week  4 mg twice a week until death  18  Right frontal lobe  3.88  Left hemiparesis  Partial  None  4-wk taper to off  22  Right parietal lobe  6.28  Left arm weakness  Partial  None  2-wk taper to off  29  Left occipital lobe  4.9  Right eye visual hallucinations  Complete  None  1-wk taper to off  31  Left pons  3.51  Left hemiparesis, slurred speech  Partial  None  6 mg every 6 hours at last follow-up  32  Left frontal lobe  7.88  Expressive aphasia  Complete  4 mg twice a day  6-wk taper to off  34  Right cerebellum  3.21  Right arm weakness  Persistent  1 mg twice a day  1 mg twice a day at last follow-up  39  Left frontal lobe  7.45  Expressive aphasia, right hemiparesis  Complete  4 mg twice a day  8-wk taper to off  47  L parietal lobe  0.51  Right arm weakness  Complete  4 mg twice a day  1 wk taper to off  53  L parietal lobe  3.54  Right arm weakness  Complete  None  1 wk taper to off  Lesion  Lesion Location  Pre-LITT Lesion Size (cm3)  New Neurological Deficit Following LITT  Degree of Resolution at Last Follow-up  Pre-LITT Steroid Dose  Post-LITT Steroid Course  6  Right middle cerebellar peduncle  2.68  Right facial nerve palsy (House-Brackmann IV)  Persistent  None  2-wk taper to off  7  Left frontal lobe  1.51  Expressive aphasia  Complete  6 mg every 6 h  4 mg twice a day until death  13  Right frontal lobe  2.17  Increased left arm weakness, increased seizure frequency  Complete  2 mg twice a day  6-mo taper to off  16  Right frontal lobe  4.4  Left hemiparesis  Partial  4 mg twice a week  4 mg twice a week until death  18  Right frontal lobe  3.88  Left hemiparesis  Partial  None  4-wk taper to off  22  Right parietal lobe  6.28  Left arm weakness  Partial  None  2-wk taper to off  29  Left occipital lobe  4.9  Right eye visual hallucinations  Complete  None  1-wk taper to off  31  Left pons  3.51  Left hemiparesis, slurred speech  Partial  None  6 mg every 6 hours at last follow-up  32  Left frontal lobe  7.88  Expressive aphasia  Complete  4 mg twice a day  6-wk taper to off  34  Right cerebellum  3.21  Right arm weakness  Persistent  1 mg twice a day  1 mg twice a day at last follow-up  39  Left frontal lobe  7.45  Expressive aphasia, right hemiparesis  Complete  4 mg twice a day  8-wk taper to off  47  L parietal lobe  0.51  Right arm weakness  Complete  4 mg twice a day  1 wk taper to off  53  L parietal lobe  3.54  Right arm weakness  Complete  None  1 wk taper to off  LITT: laser-induced thermal therapy. View Large There was no correlation between tumor size and resulting complications. Steroid Use Of the 53 patient admissions, 16 patients were taking dexamethasone prior to surgery. Postoperatively, all except for 3 patients were started on dexamethasone tapers. The majority of patients were prescribed a 1- to 2-wk taper. In summary, 4 (25%) of 16 patients on pre-LITT dexamethasone were continued on steroids at death or last follow-up compared to 5 (13.5%) of 37 patients not on pre-LITT dexamethasone continued on steroids at death or last follow-up (Table 3). This difference trended toward but did not reach statistical significance. Additionally, 25% of patients on steroids preoperatively remained on steroids indefinitely. TABLE 3. Effects of Procedure-Related Complications and Steroid Use   n  Age (yr)  Pre-LITT Lesion Size (cm3)  Post-LITT LOS (d)  Patients on Pre-LITT Steroids  Patients on Post-LITT Steroids  Patients With Complications  All patients  53  63.1 ± 0.1  3.4 ± 0.4  2.0 ± 0.2  29.6  16.6%  25.0%  Complication     No  40  61.2 ± 1.6  3.3 ± 0.4  1.7 ± 0.2a  22.50%a  10.0%b  –   Yes  13  67.4 ± 3.0  3.7 ± 0.5  3.0 ± 0.6a  53.6%a  38.5%b  –  Pre-LITT Steroids     No  37  62.8 ± 1.8  3.5 ± 0.4  1.7 ± 0.3  –  13.5%  18.8%   Yes  16  63.8 ± 2.5  3.1 ± 0.6  2.7 ± 0.6  –  25.0%  37.5%  Post-LITT Steroids     No  44  63.1 ± 1.6  3.1 ± 0.4  2.0 ± 0.3  27.2%  –  20.45%   Yes  9  63.2 ± 3.6  4.3 ± 0.9  1.9 ± 0.3  44.4%  –  44.4%    n  Age (yr)  Pre-LITT Lesion Size (cm3)  Post-LITT LOS (d)  Patients on Pre-LITT Steroids  Patients on Post-LITT Steroids  Patients With Complications  All patients  53  63.1 ± 0.1  3.4 ± 0.4  2.0 ± 0.2  29.6  16.6%  25.0%  Complication     No  40  61.2 ± 1.6  3.3 ± 0.4  1.7 ± 0.2a  22.50%a  10.0%b  –   Yes  13  67.4 ± 3.0  3.7 ± 0.5  3.0 ± 0.6a  53.6%a  38.5%b  –  Pre-LITT Steroids     No  37  62.8 ± 1.8  3.5 ± 0.4  1.7 ± 0.3  –  13.5%  18.8%   Yes  16  63.8 ± 2.5  3.1 ± 0.6  2.7 ± 0.6  –  25.0%  37.5%  Post-LITT Steroids     No  44  63.1 ± 1.6  3.1 ± 0.4  2.0 ± 0.3  27.2%  –  20.45%   Yes  9  63.2 ± 3.6  4.3 ± 0.9  1.9 ± 0.3  44.4%  –  44.4%  LITT: laser-induced thermal therapy; LOS: length of stay; wk: weeks; yr: years; n: hospital admissions for LITT procedure. aDifference reached statistical significance, OR 4.0 95% CI 1.0-13.6, P = .04. bDifference reached statistical significance, OR 5.6, 95% CI 1.2-20.9, P = .03. Means reported with standard error of the means. View Large TABLE 3. Effects of Procedure-Related Complications and Steroid Use   n  Age (yr)  Pre-LITT Lesion Size (cm3)  Post-LITT LOS (d)  Patients on Pre-LITT Steroids  Patients on Post-LITT Steroids  Patients With Complications  All patients  53  63.1 ± 0.1  3.4 ± 0.4  2.0 ± 0.2  29.6  16.6%  25.0%  Complication     No  40  61.2 ± 1.6  3.3 ± 0.4  1.7 ± 0.2a  22.50%a  10.0%b  –   Yes  13  67.4 ± 3.0  3.7 ± 0.5  3.0 ± 0.6a  53.6%a  38.5%b  –  Pre-LITT Steroids     No  37  62.8 ± 1.8  3.5 ± 0.4  1.7 ± 0.3  –  13.5%  18.8%   Yes  16  63.8 ± 2.5  3.1 ± 0.6  2.7 ± 0.6  –  25.0%  37.5%  Post-LITT Steroids     No  44  63.1 ± 1.6  3.1 ± 0.4  2.0 ± 0.3  27.2%  –  20.45%   Yes  9  63.2 ± 3.6  4.3 ± 0.9  1.9 ± 0.3  44.4%  –  44.4%    n  Age (yr)  Pre-LITT Lesion Size (cm3)  Post-LITT LOS (d)  Patients on Pre-LITT Steroids  Patients on Post-LITT Steroids  Patients With Complications  All patients  53  63.1 ± 0.1  3.4 ± 0.4  2.0 ± 0.2  29.6  16.6%  25.0%  Complication     No  40  61.2 ± 1.6  3.3 ± 0.4  1.7 ± 0.2a  22.50%a  10.0%b  –   Yes  13  67.4 ± 3.0  3.7 ± 0.5  3.0 ± 0.6a  53.6%a  38.5%b  –  Pre-LITT Steroids     No  37  62.8 ± 1.8  3.5 ± 0.4  1.7 ± 0.3  –  13.5%  18.8%   Yes  16  63.8 ± 2.5  3.1 ± 0.6  2.7 ± 0.6  –  25.0%  37.5%  Post-LITT Steroids     No  44  63.1 ± 1.6  3.1 ± 0.4  2.0 ± 0.3  27.2%  –  20.45%   Yes  9  63.2 ± 3.6  4.3 ± 0.9  1.9 ± 0.3  44.4%  –  44.4%  LITT: laser-induced thermal therapy; LOS: length of stay; wk: weeks; yr: years; n: hospital admissions for LITT procedure. aDifference reached statistical significance, OR 4.0 95% CI 1.0-13.6, P = .04. bDifference reached statistical significance, OR 5.6, 95% CI 1.2-20.9, P = .03. Means reported with standard error of the means. View Large DISCUSSION LITT continues to gain popularity as a salvage treatment option for PEIRs after radiation for brain metastasis. In this study, we report our institution's experience with this technology in a cohort of patients with metastatic brain disease who were radiographically diagnosed with tumor recurrence and/or RN inside the radiation field of treatment and who were treated without a biopsy. We placed these patients into a single diagnostic entity that we termed PEIRs, to help reflect that the treatment strategy can be effective even without separating them into 2 distinct categories. At a median follow-up of 44.6 wk, we achieved a local control rate of 83.1%. This study represents the largest series to date of patients undergoing LITT for recurrence after treatment for brain metastasis. Several other studies have reported on LITT for progressive enhancement following SRS for metastatic brain disease, ranging from 1 to 7 patients with median follow-up ranging from 7 to 52 wk, achieving local control rates of 14% to 100%.13,14,16-19,21,22 One of the benefits of using LITT in this population may be the ability to eliminate the need to differentiate between a recurrent metastatic tumor and RN. Some groups, as is our practice, do not perform biopsy prior to LITT.15,17 In our practice, results of the biopsy would not change the treatment plan, and are only performed if the information will help guide systemic therapy. Other groups do perform a biopsy prior to LITT, though they proceeded with LITT immediately following the biopsy, suggesting that they, too, do not alter their treatment plans based upon the biopsy results.17,18,21 We undoubtedly spend immense resources and time attempting to understand the underlying physiology with the idea that one process is always progressive (recurrent tumor), while the other (RN) is usually not. Both processes, however, can demonstrate progression and lead to significant symptoms and neurological deficits. We have shown that the use of this technology, even in the absence of tissue confirmation via biopsy, yields a reasonable local control rate in patients who have failed primary treatment of brain metastases. This leads us to believe that while LITT can control a recurrent tumor, it can also halt the progression of RN. Two relatively large series reporting on complications associated with LITT identified complication rates of 26.5% and 22.4%.24,25 Our complication rate falls within this range. The risks of LITT can be broadly placed into 2 categories: (1) related to laser insertion and (2) related to thermal ablation.24 In this study, we did not encounter any symptomatic complications related to laser insertion. Risks related to thermal ablation include damage to nearby healthy brain tissue, incomplete ablation, and ablation-induced hemorrhage and cerebral edema. A volumetric analysis of 16 lesions treated with LITT demonstrated on postoperative MRI within 1-h of LITT that ablated lesions enlarged in size on average 281% due to tissue damage and resultant edema.26 Similarly, we previously reported a mean 278% increase in lesion size on MRI 24 h following LITT with reduction back to pretreatment size over the months following the procedure.13 We hypothesize that ablated PEIRs adjacent to eloquent cortex can cause new neurological symptoms due to postablation edema, with resolution of symptoms as they decrease in size during the follow-up period. The majority of our patients with new post-LITT neurological symptoms had complete or partial resolution during follow-up. Literature review of 243 patients reported a permanent deficit rate following LITT of 5.8%25 slightly higher than our rate of permanent neurological deficit of 3.4%. LITT represents one treatment option for recurrent brain metastases or RN following SRS; however, other options exist, including repeat SRS if one is convinced that the underlying physiology represents pure tumor recurrence. One such study examining repeat SRS to recurrent lesions identified a local control rate of 79%, matching the local control rate achieved in our patient population. Importantly, they found 24% of cases developed symptomatic RN and that the volume receiving a cumulative dose of 40 Gy over the 2 SRS treatments was predictive of RN development.8 Repeat SRS to previously irradiated recurrent lesions offers a treatment option for patients who are not surgical candidates or for lesions that are not surgically accessible. However, confirmation of recurrent tumor (vs RN) is required, which can be challenging, and repeat SRS comes with the risk of developing RN, which the abovementioned studies demonstrate is not an insignificant risk, and potentially at a much higher rate than the peri-procedural risk from MRgLITT. Our patients were deemed not eligible for additional SRS by our multidisciplinary board due to having received previous SRS and concerns for neurotoxicity. Another option for recurrent PEIRs following SRS is surgical resection. Three studies examined surgical resection for recurrence of metastases previously treated with SRS with or without WBRT. These studies reported local control rates of 69%, 74%, and 79% and procedure-related complication rates of 9%, 20%, and 22%.27-29 Our local control rate (83.1%) exceeds the best reported of the 3 studies, though our complication rate (25%) is slightly higher. The complication rate of surgical resection in these studies may be lower due to the ability to safely access the lesions with normal surgical corridors. On the other hand, MRgLITT offers a treatment option in these “unresectable locations.” We are performing LITT for more complicated targets, both morphometrically and in regard to location relative to eloquent cortex, which may also contribute to a higher complication rate, and so a comparison to the risk profile from open surgery may not be appropriate. We feel a key to the success of LITT is early intervention once follow-up imaging demonstrates new, progressive enhancement at the sites of previously treated metastases. Based on our study findings and clinical experience, we believe LITT should be offered prior to the PEIRs becoming symptomatic and requiring high-dose dexamethasone. We found that patients entering the procedure on dexamethasone were more likely to be continued on steroids indefinitely in the postoperative period compared to patients who entered the procedure not already on dexamethasone. Additionally, patients already on dexamethasone prior to the procedure were more likely to experience a post-LITT complication. The additive effects of patients’ baseline cerebral edema requiring steroid treatment and new post-ablation edema likely account for the increased complication rate. However, LITT did show a significant effect on the ability to wean patients off steroids following the procedure in that 29.6% of all patients entered the procedure on dexamethasone compared to 16.6% who were continued on dexamethasone indefinitely in the post-LITT period. Limitations This study has a few limitations. Fifteen (20.3%) of the 74 treated lesions were lost to or had inadequate follow-up at the time of data analysis which may contribute to selection bias. Additionally, while we have reported local control with a moderate follow-up period, we do not have data on quality of life measures. As LITT continues to emerge as a minimally invasive treatment option for intracranial lesions, it will be important to know its effect on quality of life. Future studies should include such data. Although this present study represents the largest series examining LITT for PEIRs after radiosurgery for brain metastases, with the longest follow-up to date, larger studies with longer follow-up are needed. CONCLUSION This is the largest single institution series to report on the utility of MRgLITT for the treatment of PEIRs after radiosurgery for brain metastasis. MRgLITT potentially offers an effective salvage therapy without the need to histologically differentiate between tumor recurrence and RN. We recommend offering MRgLITT early once progression is determined. Complications are more likely encountered following treatment of patients already requiring high-dose dexamethasone, particularly within eloquent regions. Further follow-up in a larger patient population is needed to better define the long-term outcomes following LITT. Disclosures Dr Danish receives an honorarium from Medtronic. The other authors have no personal, financial, or institutional interest in any of the drugs, materials, or devices described in this article. REFERENCES 1. Minniti G, Clarke E, Lanzetta G et al.   Stereotactic radiosurgery for brain metastases: analysis of outcome and risk of brain radionecrosis. Radiat Oncol . 2011; 6( 1): 48. Google Scholar CrossRef Search ADS PubMed  2. Baschnagel AM, Meyer KD, Chen PY et al.   Tumor volume as a predictor of survival and local control in patients with brain metastases treated with Gamma Knife surgery. J Neurosurg . 2013; 119( 5): 1139– 1144. Google Scholar CrossRef Search ADS PubMed  3. 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Koiso T, Yamamoto M, Kawabe T et al.   Follow-up results of brain metastasis patients undergoing repeat Gamma Knife radiosurgery. J Neurosurg . 2016; 125( suppl 1): 2– 10. Google Scholar PubMed  8. McKay WH, McTyre ER, Okoukoni C et al.   Repeat stereotactic radiosurgery as salvage therapy for locally recurrent brain metastases previously treated with radiosurgery. J Neurosurg . 2017; 127( 1): 148– 156. Google Scholar CrossRef Search ADS PubMed  9. Miller JA, Bennett EE, Xiao R et al.   Association between radiation necrosis and tumor biology after stereotactic radiosurgery for brain metastasis. Int J Radiat Oncol Biol Phys . 2016; 96( 5): 1060– 1069. Google Scholar CrossRef Search ADS PubMed  10. Kohutek ZA, Yamada Y, Chan TA et al.   Long-term risk of radionecrosis and imaging changes after stereotactic radiosurgery for brain metastases. J Neurooncol . 2015; 125( 1): 149– 156. Google Scholar CrossRef Search ADS PubMed  11. Kickingereder P, Dorn F, Blau T et al.   Differentiation of local tumor recurrence from radiation-induced changes after stereotactic radiosurgery for treatment of brain metastasis: case report and review of the literature. Radiat Oncol . 2013; 8( 1): 52. Google Scholar CrossRef Search ADS PubMed  12. Cicone F, Minniti G, Romano A et al.   Accuracy of F-DOPA PET and perfusion-MRI for differentiating radionecrotic from progressive brain metastases after radiosurgery. Eur J Nucl Med Mol Imaging . 2015; 42( 1): 103– 111. Google Scholar CrossRef Search ADS PubMed  13. Rao MS, Hargreaves EL, Khan AJ, Haffty BG, Danish SF. Magnetic resonance-guided laser ablation improves local control for postradiosurgery recurrence and/or radiation necrosis. Neurosurgery . 2014; 74( 6): 658– 667. Google Scholar CrossRef Search ADS PubMed  14. Carpentier A, McNichols RJ, Stafford RJ et al.   Laser thermal therapy: real-time MRI-guided and computer-controlled procedures for metastatic brain tumors. Lasers Surg Med . 2011; 43( 10): 943– 950. Google Scholar CrossRef Search ADS PubMed  15. Carpentier A, McNichols RJ, Stafford RJ et al.   Real-time magnetic resonance-guided laser thermal therapy for focal metastatic brain tumors. Neurosurgery . 2008; 63( 1 suppl 1): ONS21– ONS28. Google Scholar PubMed  16. Hawasli AH, Bagade S, Shimony JS, Miller-Thomas M, Leuthardt EC. Magnetic resonance imaging-guided focused laser interstitial thermal therapy for intracranial lesions: single-institution series. Neurosurgery . 2013; 73( 6): 1007– 1017. Google Scholar CrossRef Search ADS PubMed  17. Rahmathulla G, Recinos PF, Valerio JE, Chao S, Barnett GH. Laser interstitial thermal therapy for focal cerebral radiation necrosis: a case report and literature review. Stereotact Funct Neurosurg . 2012; 90( 3): 192– 200. Google Scholar CrossRef Search ADS PubMed  18. Torres-Reveron J, Tomasiewicz HC, Shetty A, Amankulor NM, Chiang VL. Stereotactic laser induced thermotherapy (LITT): a novel treatment for brain lesions regrowing after radiosurgery. J Neurooncol . 2013; 113( 3): 495– 503. Google Scholar CrossRef Search ADS PubMed  19. Fabiano AJ, Alberico RA. Laser-interstitial thermal therapy for refractory cerebral edema from post-radiosurgery metastasis. World Neurosurg . 2014; 81( 3-4): 652.e1– 652.e4. Google Scholar CrossRef Search ADS   20. Ascher PW, Justich E, Schrottner O. Interstitial thermotherapy of central brain tumors with the Nd:YAG laser under real-time monitoring by MRI. J Clin Laser Med Surg . 1991; 9( 1): 79– 83. Google Scholar PubMed  21. Smith CJ, Myers CS, Chapple KM, Smith KA. Long-term follow-up of 25 cases of biopsy-proven radiation necrosis or post-radiation treatment effect treated with magnetic resonance-guided laser interstitial thermal therapy. Neurosurgery . 2016; 79( suppl 1): S59– S72. Google Scholar CrossRef Search ADS PubMed  22. Torcuator RG, Hulou MM, Chavakula V, Jolesz FA, Golby AJ. Intraoperative real-time MRI-guided stereotactic biopsy followed by laser thermal ablation for progressive brain metastases after radiosurgery. J Clin Neurosci . 2016; 24: 68– 73. Google Scholar CrossRef Search ADS PubMed  23. Jethwa PR, Barrese JC, Gowda A, Shetty A, Danish SF. Magnetic resonance thermometry-guided laser-induced thermal therapy for intracranial neoplasms: initial experience. Neurosurgery . 2012; 71( 1 Suppl Operative): 133– 144. Google Scholar PubMed  24. Patel P, Patel NV, Danish SF. Intracranial MR-guided laser-induced thermal therapy: Single-center experience with the Visualase thermal therapy system. J Neurosurg . 2016; 125( 4): 853– 860. Google Scholar CrossRef Search ADS PubMed  25. Pruitt R, Gamble A, Black K, Schulder M, Mehta AD. Complication avoidance in laser interstitial thermal therapy: Lessons learned. J Neurosurg . 2017; 126( 4): 1238– 1245. Google Scholar CrossRef Search ADS PubMed  26. Patel NV, Jethwa PR, Barrese JC, Hargreaves EL, Danish SF. Volumetric trends associated with MRI-guided laser-induced thermal therapy (LITT) for intracranial tumors. Lasers Surg Med . 2013; 45( 6): 362– 369. Google Scholar CrossRef Search ADS PubMed  27. Kano H, Kondziolka D, Zorro O, Lobato-Polo J, Flickinger JC, Lunsford LD. The results of resection after stereotactic radiosurgery for brain metastases. J Neurosurg . 2009; 111( 4): 825– 831. Google Scholar CrossRef Search ADS PubMed  28. Truong MT, St Clair EG, Donahue BR et al.   Results of surgical resection for progression of brain metastases previously treated by gamma knife radiosurgery. Neurosurgery . 2006; 59( 1): 86– 97. Google Scholar CrossRef Search ADS PubMed  29. Vecil GG, Suki D, Maldaun MV, Lang FF, Sawaya R. Resection of brain metastases previously treated with stereotactic radiosurgery. J Neurosurg . 2005; 102( 2): 209– 215. Google Scholar CrossRef Search ADS PubMed  COMMENT The authors tackle a difficult clinical situation in this article – what to do with the patient presenting after maximum radiation for metastatic brain tumors with progressive enhancing lesions. Given the uncertainty of whether the progressive enhancement represents increasing tumor burden, radiation change, or a combination, the authors term these lesions “progressive enhancing inflammatory reaction”. They present a case series of 59 patients undergoing 74 laser ablations. Of that patients meeting inclusion criteria, local control was achieved in 83%. In this series, biopsies were not performed either before or after the ablation, leaving the diagnosis undetermined. Although new motor weakness was encountered in 9 patients, the majority of these improved with a rate of permanent new neurologic deficit of 3.4%. The clinical conundrum that these authors address is one that will confront any neurosurgeon treating brain metastases. In patients who have already undergone maximal safe radiation, treatment options are limited. A main underlying question is whether or not the etiology of the progressive enhancement needs to be established prior to definitive treatment. While some individuals believe that a tissue diagnosis must be obtained prior to treatment, others favor a single surgery for treatment +/- biopsy, if that treatment can be carried out with minimal risk. In our practice, we favor the second approach. Subjecting patients to 2 surgeries and 2 instances of general anesthetic is likely to carry a higher risk profile compared to the low morbidity of LITT procedures. Additionally, pathologic diagnosis following biopsy may be subject to sampling bias and may not provide an accurate diagnosis in mixed lesions. We believe that in the absence of a clear diagnosis, biopsy, to guide the decision of post-ablation chemotherapy/radiation, in combination with laser ablation to treat the progressive changes is a reasonable treatment paradigm. Certainly, continued discussion on this subject is warranted and may be aided by the careful study of pretreatment physiologic and adjunctive imaging to provide diagnostic certainty regarding the underlying etiology of the inflammatory changes. Angela M. Richardson Ricardo J. Komotar Miami, Florida Copyright © 2018 by the Congress of Neurological Surgeons This article is published and distributed under the terms of the Oxford University Press, Standard Journals Publication Model (https://academic.oup.com/journals/pages/about_us/legal/notices)

Journal

NeurosurgeryOxford University Press

Published: May 31, 2018

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