Laser Interstitial Thermal Therapy to the Posterior Fossa: Challenges and Nuances

Journal Pre-proof Laser Interstitial Thermal Therapy to the Posterior Fossa: Challenges and Nuances Jeffrey I. Traylor, BS, Rajan Patel, BS, Ahmed Habib, MD, Matthew Muir, BS, Dhiego Chaves de Almeida Bastos, MD, Ganesh Rao, MD, Sujit S. Prabhu, MD PII:

S1878-8750(19)32410-6

DOI:

https://doi.org/10.1016/j.wneu.2019.08.242

Reference:

WNEU 13279

To appear in:

World Neurosurgery

Received Date: 10 May 2019 Revised Date:

29 August 2019

Accepted Date: 30 August 2019

Please cite this article as: Traylor JI, Patel R, Habib A, Muir M, de Almeida Bastos DC, Rao G, Prabhu SS, Laser Interstitial Thermal Therapy to the Posterior Fossa: Challenges and Nuances, World Neurosurgery (2019), doi: https://doi.org/10.1016/j.wneu.2019.08.242. This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. © 2019 Elsevier Inc. All rights reserved.

Laser Interstitial Thermal Therapy to the Posterior Fossa: Challenges and Nuances Jeffrey I. Traylor, BS1†, Rajan Patel, BS1†, Ahmed Habib, MD1, Matthew Muir, BS1, Dhiego Chaves de Almeida Bastos, MD1, Ganesh Rao, MD1, Sujit S. Prabhu, MD1* †

JT and RP contributed equally to this work

1

Department of Neurosurgery, The University of Texas M.D. Anderson Cancer Center, Houston,

Texas (USA)

*

CORRESPONDENCE

Sujit S. Prabhu, MD, FRCS 1515 Holcombe Boulevard Room FC7.2000, Unit 442 Houston, TX 77030-4009 Email: [email protected]

KEYWORDS: Laser Interstitial Thermal Therapy; Brain Metastases; Radiation Necrosis; Posterior Fossa; Deep-Seated Tumor

RUNNING TITLE: LITT to the Posterior Fossa

Traylor 1 1

ABSTRACT

2

Objective: Posterior fossa tumors are rare in adults and pose a challenge to treat due to the bony

3

contour of the posterior fossa, complex anatomical structures including deep venous sinuses, and

4

the proximity of the fourth ventricle and brain stem. We describe our experience with LITT for

5

the management of brain metastases and radiation necrosis of the posterior fossa.

6

Methods: We retrospectively analyzed 13 patients with metastases and radiation necrosis of the

7

posterior fossa managed with LITT.

8

Results: Thirteen patients with histopathologically-confirmed radiation necrosis (n = 5) and

9

metastases (n = 8) of the posterior fossa underwent LITT. The median preoperative tumor and

10

postoperative ablation cavity volume was 4.66 cm3 and 6.29 cm3, respectively. The median

11

volume of the ablation cavity decreased to 2.90 cm3 at 9-month follow-up. The median volume

12

of peritumoral edema was 12.25 cm3 which fell to a median 5.77 cm3 at one-month follow-up.

13

Median progression-free survival was 7 months (range 3 – 14 months) from LITT. The mean

14

overall survival (OS) was 40 months (range 2 – 49 months). There were no intraoperative

15

complications. One patient experienced palsy of the seventh and eighth cranial nerves on follow-

16

up, attributable to LITT.

17

Conclusion: Lesions of the posterior fossa are challenging to treat given their proximity to the

18

dura and venous sinuses. We demonstrate that LITT ablation may be a safe and feasible option

19

for metastases and radiation necrosis of the posterior fossa. Larger studies are needed to confirm

20

the efficacy of this approach.

21 22 23 24 25 26 27 28 29 30 31

Traylor 2 1 2

INTRODUCTION Tumors of the posterior fossa in adults are most commonly caused by extracranial

3

metastases.1 Up to 20% of patients with brain metastases present with posterior fossa tumors,

4

usually considered a marker of poor prognosis.2-6 Tumors in this region can be challenging to

5

treat because of the complex anatomy of the posterior fossa and adjacent critical structures, such

6

as the brainstem and cranial nerves. The inherent challenges related to the location, coupled with

7

higher rates of complications when comparing to supratentorial lesions, makes surgical

8

management of this patient population challenging.7 Stereotactic radiosurgery (SRS) is another

9

option to treat posterior fossa lesions, particularly those in deep-seated loci, without significant

10

edema.8 Although SRS has been shown to improve local control in these cases, radiation delivery

11

for lesions adjacent to cerebrospinal fluid (CSF) outflow tracts can precipitate hydrocephalus due

12

to the mass effect from post-radiation tissue swelling.9 Additionally, the use of SRS and surgical

13

resection in this patient population has shown appreciable rates of recurrence and poses a risk for

14

the development radiation necrosis with studies reporting rates ranging from 5-11% at 6-month

15

follow-up.10,11 Recurrent tumors and radiation necrosis of the posterior fossa especially following

16

surgical resection or radiation pose significant challenges to management. Therefore, there is a

17

need for alternative local treatment options to reduce tumor burden and minimize complications.

18

Laser interstitial thermal therapy (LITT) has emerged as a minimally invasive technique

19

for the treatment of primary brain tumors, metastases, and radiation necrosis.12-14 Specifically,

20

LITT has shown efficacy in the management of deep-seated lesions less amenable to resection by

21

conventional surgical techniques.15 The advent of magnetic resonance (MR) thermography for

22

real-time observation of the extent of tissue ablation as well as stereotactic guidance of the

23

delivery probe has made LITT a precise and potentially safe treatment for brain tumors and

24

radiation necrosis alike.16 Although some studies have shown LITT to be particularly efficacious

25

for deep-seated lesions, there is little evidence to support the use of LITT in patients with brain

26

metastases of the posterior fossa, specifically.17-19 Herein, we describe our experience and the

27

challenges of using LITT for the management of posterior fossa lesions in a cohort of patients

28

with brain metastases and radiation necrosis.

29 30 31

MATERIALS & METHODS

Traylor 3 1

Study Design, Setting, and Participants

2

This study was performed under the auspices of the Institutional Review Board (IRB)-

3

approved protocol of our institution in compliance with institutional regulations with regard to

4

the study of human subjects. A retrospective search of the neurosurgery department database

5

from January 2014 to January 2018, identified thirteen patients treated with LITT for posterior

6

fossa metastases and radiation necrosis. A retrospective chart review was performed to collect

7

demographical, clinical, radiological, and pathological information. One patient (case 12) was

8

selected for illustration of some of the challenges of LITT in the posterior fossa due to the

9

precarious location of this tumor adjacent to the transverse venous sinus and tentorium cerebelli.

10 11 12

Operative Technique All procedures were performed in an intraoperative MRI suite with a Siemens Espree

13

1.5T magnet (Siemens, Berlin, Germany). A preoperative MR scan was attained using the

14

intraoperative MRI machine to plan the trajectory of the ablation probe using Brainlab iPlan

15

software (Brainlab, Munich, Germany). A cannulated bolt was then inserted in the patient’s skull

16

under imaging guidance along the planned trajectory using the VarioGuide system (Brainlab,

17

Munich, Germany) followed by insertion of the pre-measured delivery probe. LITT procedures

18

were performed by the senior authors with the Neuroblate (Monteris, Winnipeg, Canada) system.

19

The details regarding our ablation technique have been described elsewhere.20 The approach to

20

ablation of lesions in the posterior fossa is different, however. Foremost, a larger incision is

21

made (1 cm) for insertion of the cannulated bolt than is required for supratentorial lesions (3 – 4

22

mm) in order to allow for adequate retraction of the posterior cervical musculature before

23

drilling. Additionally, the contour of the posterior fossa provides little anchoring bone for

24

insertion of the cannulated bolt. Thus, the larger incision allows for easier perpendicular

25

insertion of the bolt in the skull along the planned trajectory of the probe.

26 27 28

Study Variables The following variables were collected from patient medical records: age, gender,

29

primary tumor histology, date of LITT procedure, pre-LITT and post-LITT medical treatment

30

(chemotherapy and radiation therapy), tumor volume pre-LITT, ablation volume immediately

31

after LITT, post-LITT tumor volume on every follow up MRI scan (usually every 2-3 months),

Traylor 4 1

local recurrence, and complications. Overall survival (OS) was defined as the time between

2

LITT procedure and date of death for deceased patients or date of last follow-up if currently alive

3

at the end of follow-up. Progression-free survival (PFS) was defined as the time between LITT

4

procedure and date of the first post-LITT local recurrence or date of last follow-up MR image

5

(MRI) for patients who did not develop recurrence at last follow up. Recurrence was defined by

6

two independent neuroradiologists using the Response Assessment in Neuro-Oncology Brain

7

Metastases (RANO-BM) working group criteria.21

8 9 10

Follow-up, MR Imaging, and Volumetric Analysis All patients underwent MR imaging of the brain prior to their procedure and follow up

11

imaging at regular intervals after treatment (usually every 2–3 months). Imaging sequences

12

included T1-weighted pre- and post-contrast (T1C+), and fluid-attenuated inversion recovery

13

(FLAIR) MR images. The MRIs were exported to the iPlan workstation (Brainlab, Munich,

14

Germany) from the electronic medical record (EMR). Using a T1C+ MRI pre-LITT,

15

immediately post-LITT, and at every follow-up, manual tumor segmentation was completed by a

16

neuroradiologist creating a tridimensional volumetric measure. Similarly, manual segmentation

17

of the edema was completed by a neuroradiologist creating a tridimensional volumetric measure

18

using FLAIR imaging. On the preoperative scan, the tumor margin was the enhancing lesion. On

19

the post-treatment scans, the margin was the ablation cavity. Single volume measurements of

20

each lesion and associated edema were calculated and verified by the senior author. Five time

21

periods, (1) pre-LITT MRI scan (2) post-LITT MRI scan (3) 0–30 days (4) 30–60 days (5) 60–90

22

days, were used to categorize the tumor and edema volumes for both the T1-weighted post-

23

contrast images and the FLAIR images following LITT. The diagnosis of radiation necrosis was

24

made by a neuroradiologist and neurosurgeon based on follow-up imaging using our institution’s

25

advanced brain tumor imaging (ABTI) protocol.

26 27 28

Statistical Analysis and Data Synthesis Continuous variables were summarized with medians and ranges, while categorical

29

variables were summarized with frequencies and percentages. Summary statistics were

30

calculated for all variables. A Kaplan–Meier method was used to estimate PFS and OS; survival

31

curves were compared by using a log-rank (Mantel-Cox) test. A Cox proportional hazards model

Traylor 5 1

with 95% confidence intervals (CI) was used to evaluate the difference in PFS between those

2

patients who received post-LITT chemotherapy and those who did not. A p-value < 0.05 was

3

considered significant for all analyses. Analyses were performed using the statistical software

4

SPSS V.24 (IBM Corp., Armonk, New York). Graphs were constructed with the ggplot2

5

(https://CRAN.R-project.org/web/packages/ggplot2/index.html) and ggfortify (https://CRAN.R-

6

project.org/package=ggfortify) packages in R.22,23

7 8 9

RESULTS Patient and lesion characteristics are summarized in Table 1. Thirteen patients with a

10

median age of 58 years (range 31 – 79 years) received LITT to the posterior fossa targeting eight

11

recurrent metastases (n = 4 breast, n = 1 renal cell carcinoma, n =1 colon cancer, n = 1 small cell

12

lung cancer [SCLC] and n = 1 non-small cell lung cancer [NSCLC]) and 5 cases of radiation

13

necrosis. Repeat LITT ablation of the lesion following recurrence was performed in two patients

14

(cases 12 and 13). Of the 5 cases of radiation necrosis, all patients had previous metastases of the

15

posterior fossa (n = 3 breast, n = 1 NSCLC, n = 1 adenocarcinoma of the lung) and were treated

16

with SRS. Of the 13 lesions, 61.5% (n = 8) were dura-based. Patients had a median preoperative

17

Karnofsky performance status (KPS) score of 90 (range 70 – 100) and a median postoperative

18

KPS score of 80 (range 0 – 100) at 3-month follow-up. Median time to discharge postoperatively

19

was 2 days (range 0 – 5 days). Eight patients received chemotherapy (n = 4 targeted therapy, n =

20

2 systemic, n = 2 combined systemic/targeted therapy) and all patients received radiotherapy

21

prior to LITT (n = 11 SRS, n = 1 whole brain radiation therapy [WBRT], n =1 SRS and WBRT).

22

Of note, administration of adjuvant chemotherapy is determined on a case-by-case basis by a

23

multidisciplinary team of medical oncologists, radiation oncologists, and neurosurgeons based on

24

prognosis, status of systemic disease, and primary tumor histology. The median preoperative

25

tumor volume was 4.66 cm3 (range 0.33 – 8.81 cm3) and median one day postoperative ablation

26

volume was 6.29 cm3 (3.0 – 13.40 cm3). The median percent tumor coverage with LITT therapy

27

was 96.2% (range 77.52% – 100%) with a median non-ablated volume of 0.18 cm3 (range 0 –

28

1.03 cm3). The median volume of the ablation cavity at 9-month follow-up was decreased to 2.9

29

cm3 (n = 3, range 1.95 – 4.82 cm3) (Figure 1). Peritumoral edema volume was calculated to be

30

12.25 cm3 (range 0.74 – 41.76 cm3). After a postoperative follow-up of one-month, this median

31

edema volume decreased to 5.77 cm3 (range 2.03 – 24.60 cm3) which fell to 0.94 cm3 (range 0 –

Traylor 6 1

2.87 cm3) at 9-month follow-up (Figure 2). Of the 13 patients in the cohort, 76.9% (n = 10) were

2

alive at last follow-up. For these three patients, cause of death information was not available in

3

the EMR. The Kaplan-Meier estimate of mean overall survival was 40 months (range 2 – 49

4

months). Local recurrence was observed in 69.2 % (n = 9) of the cohort. Median progression free

5

survival (PFS) was 7 months (range 3 – 14 months) from LITT (Figure 3). Median PFS for

6

patients receiving chemotherapy after LITT (n = 2) and patients not receiving chemotherapy

7

after LITT (n = 4) was 13.5 months and 5.0 months, respectively. This relationship was found to

8

be statistically significant with univariate Cox regression analysis (p = 0.02, hazard ratio = 0.07,

9

confidence interval: 0.007 – 0.649) and a log-rank test (p = 0.003). Dura-based lesions were

10

observed to have a similar time to recurrence to non-dura-based lesions (log-rank p = 0.3). No

11

intraoperative complications were observed. During the course of follow-up, one complication

12

was observed; a patient with radiation necrosis following SRS for non-small cell carcinoma of

13

the lung developed permanent, unilateral, seventh and eighth cranial nerve (CN) palsy thought to

14

be due to the proximity of the cranial nerves to the tumor. Leptomeningeal disease was observed

15

in 15.4% of the cohort (n = 2) by 12-month follow-up.

16 17

Case Illustration

18

Case 12

19

A 58-year-old woman with a history of suboccipital craniotomy for metastatic breast

20

carcinoma presented to the neurosurgery clinic after progression of the lesion was discovered on

21

follow-up imaging. She was originally diagnosed with invasive ductal carcinoma of the breast 12

22

years prior to presentation. After a posterior fossa metastasis was discovered four years later, she

23

underwent a subtotal resection followed by multiple rounds of stereotactic radiosurgery and

24

insertion of an Ommaya reservoir. At current presentation the patient had no complaints with a

25

normal neurologic exam. Imaging at that time revealed interval progression of a right

26

superolateral cerebellar metastasis adjacent to the transverse venous sinus and tentorium

27

cerebelli with concern for both a parenchymal and leptomeningeal component (Figure 4A and

28

4B). Additional surveillance imaging indicated no extracranial disease. Due to the proximity of

29

the venous sinus and tentorium cerebelli, the authors did not think a gross total resection of the

30

progressive parenchymal lesion was possible. Instead, we believed ablation of the entire

31

enhancing margin was more feasible with a single trajectory and would reduce tumor burden

Traylor 7 1

while minimizing potential complications. Although leptomeningeal disease is a contraindication

2

to LITT procedure, the leptomeningeal component was noted to be bulky on imaging and

3

cytopathologic analysis of CSF from the Ommaya reservoir did not identify malignant cells,

4

indicating stable disease. After patient consent was obtained, a single trajectory was mapped in

5

Brainlab in the operating room with care taken to avoid violating both the mastoid sinus and

6

transverse and sigmoid sinuses traversing the tumor margin. Additionally, the trajectory must

7

provide for a well-anchored cannulated bolt, ideally perpendicular to the plane of the skull.

8

Alignment and insertion of the LITT probe along this plotted trajectory using stereotactic

9

navigation in the Monteris Neuroblate software suite revealed a subvolume of the tumor by the

10

treatment radius of the ablation probe (Figure 5). Although the lesion was targeted by the

11

thermal damage radius, the adjacent sinus limited the extent of ablation. The patient tolerated the

12

procedure without complication and was discharged on postoperative day one at neurologic

13

baseline. The subsequent follow-up course was unremarkable, although imaging one-month

14

postoperatively revealed a stable ablation cavity (Figure 4C) with some residual tumor at the

15

superolateral cavity margin corresponding to an under-treated tumor subvolume (Figure 4D).

16

These findings were stable on repeat imaging over the following months. However, one year

17

from lesion ablation, a mild increase in size of the residual tumor in the same location (Figure

18

4E) coupled with increased signature from the region on Ktrans MR perfusion imaging (Figure

19

4F) warranted surgical intervention. Consent was then obtained for repeat LITT ablation of the

20

lesion to establish local control using a similar, single trajectory. Again, the patient tolerated the

21

procedure without complication and was discharged on the first postoperative day. One-month

22

follow-up imaging revealed a stable ablation cavity with no residual tumor on T1C+ imaging

23

(Figure 4G) and no signature in the region on Ktrans MR perfusion imaging (Figure 4H). At her

24

most recent follow-up she was neurologically intact with no complaints. Of note, the lesion was

25

particularly challenging to treat due to the proximity of the transverse sinus which complicated

26

trajectory planning. Ultimately, a post-auricular approach was selected that provided an adequate

27

angle for anchoring of the cannulated bolt that provided direct access to the lesion without

28

violating the adjacent sigmoid or transverse sinuses. Although the subvolume was thought to be

29

adequately ablated, the authors attempted to minimize ablation of the portion of the lesion

30

abutting the transverse sinus.

31

Traylor 8 1

DISCUSSION

2

Altogether, the findings of this study suggest that LITT may be an effective therapy for

3

the management of brain metastases and radiation necrosis in the posterior fossa. Specifically,

4

the OS of the patients in this cohort were comparable to standard resection with a significantly

5

lower intraoperative complication rate. No intraoperative morbidity or mortality was experienced

6

in any of the patients in the cohort. Although there is limited penetration of the blood-brain

7

barrier (BBB) by systemically delivered chemotherapeutic agents, our statistical analysis

8

revealed a significant association with patients receiving adjuvant chemotherapy (targeted and

9

systemic) following LITT and a longer time to local progression on Cox univariate analysis, a

10

relationship confirmed by a larger cohort study at our institution from which our series of

11

patients was extracted (currently in press). It is possible that this is secondary to hyperthermic

12

disruption of the BBB by LITT, similar to the mechanism described in 2016 by Leuthardt et al.

13

that may enhance the delivery of chemotherapeutic agents to the central nervous system.24 This

14

finding suggests that the use of chemotherapy in conjunction with LITT may be a useful

15

therapeutic option for the treatment of these lesions. Though the association was statistically

16

significant, our sample size is small and additional well-powered studies are needed before

17

treatment recommendations can be established.

18

Our experience also illustrates many of the challenges with applying LITT to this

19

precarious anatomical region. The proximity of the dural venous sinuses, the brain stem, and

20

fourth ventricle requires careful trajectory planning to provide adequate ablation coverage. Thus,

21

some lesions were not amenable to complete ablation in our series. Notably, the metastasis from

22

our case illustration (case 12) was bordered by the transverse venous sinus laterally, and the

23

tentorium cerebelli superiorly, preventing adequate coverage of the entire tumor volume by the

24

LITT thermal damage threshold lines. This untreated subvolume of the tumor was observed to

25

recur, requiring additional operative intervention. Although LITT provides a minimally invasive

26

technique for reduction of tumor burden in patients with deep-seated intracranial metastases, the

27

anatomic constraints of the posterior fossa may make adequate laser ablation difficult to achieve.

28

We thus recommend a careful assessment of the achievable extent of ablation, particularly by

29

evaluating feasible trajectories and proximity to critical neuroanatomical structures, associated

30

perioperative risks, and potential benefits when considering LITT for this particular patient

31

population.

Traylor 9 1

Although surgical resection has been established for posterior fossa lesions in pediatric

2

patients and for adults with larger lesions causing significant mass effect or hydrocephalus, there

3

is a paucity of evidence for any particular management approach for general infratentorial

4

metastatic disease.25,26 Complication rates for surgical resection in these patients based on

5

current evidence is approximately 26%.7,27 Despite the relatively high rates of complications,

6

surgical management with or without adjuvant radiotherapy is generally pursued for larger

7

lesions with severe mass effect or hydrocephalus.7,28,29 For smaller lesions, with little or no mass

8

effect, SRS is a viable option with proven efficacy in local control with local recurrence rates of

9

7.8% for posterior fossa brain metastases following SRS.11,30 Nonetheless, its use is not devoid

10

of complications, as in cases of radiation necrosis, and larger lesions ≥ 2.5 cm in diameter are

11

less likely to respond to SRS, though improved efficacy with novel techniques are emerging 31-33.

12

In 2014 Eliyas et al. presented the first case where LITT was used to treat lesions of the

13

posterior fossa in adults, paving the way for additional research on the topic.34 Later, Chan et al.

14

described the management of posterior fossa radiation necrosis following radiotherapy for

15

anaplastic astrocytoma.17 Dadey and colleagues described the results of the first case series for

16

patients receiving LITT for epilepsy and brain tumors in the posterior fossa and mesiotemporal

17

regions.18 Finally, Borghei-Razavi, et al. reported on the results of the largest and most recent

18

study to date on LITT for posterior fossa lesions in eight patients with either brain metastases,

19

radiation necrosis, or primary malignancy.19

20

Our study adds to the growing, albeit limited, evidence supporting LITT for posterior

21

fossa lesions, specifically recurrent cerebral metastases. This is the largest study to date and is

22

the first to quantify the OS and PFS of these patients and the role of systemic chemotherapy

23

following ablation. Although the numbers are limited, there seems to be a survival benefit in

24

patients treated with LITT especially those with no other viable surgical options. Further,

25

patients with both brain metastases and suspected radiation necrosis of the posterior fossa

26

responded well to ablation therapy, indicating that LITT may be an appropriate option for

27

management of both disease processes, which has been previously shown.35 This is particularly

28

important as the imaging findings of both disease processes are ambiguous and tissue biopsy is

29

required to confirm the diagnosis. In light of this data, it is the authors’ experience that patients

30

with radiation necrosis treated with LITT show lower rates of local recurrence which has been

31

shown in the literature.14 The hospital stay was minimal in all patients and they were able to

Traylor 10 1

resume adjuvant treatments soon after LITT. In this cohort, we observed local recurrence after

2

the first treatment in seven cases. In these patients, the tumor recurrence was either adjacent to

3

the dura or the major venous sinuses further underscoring the challenges with using LITT in the

4

posterior fossa.36 However, in these recurrences repeat LITT is always a salvage option and buys

5

additional valuable time for patients.

6 7

Limitations The primarily limitation of our study was the small sample size and the retrospective

8 9

nature of data collection. Although our results show LITT to be safe and effective, the benefits of

10

LITT should be validated in larger studies. The significance of post-LITT chemotherapy in

11

prolonging time to local progression seen in our cohort may be confounded by the fact that many

12

patients were not treated with aggressive systemic chemotherapy. Thus, additional studies

13

examining this relationship in particular are needed before meaningful conclusions can be

14

established.

15 16

CONCLUSION Lesions of the posterior fossa are challenging because of their proximity to the dura,

17 18

venous sinuses and deep structures in the posterior fossa. Careful planning of the ablation probe

19

trajectory can overcome some of these challenges. We have demonstrated that LITT is a

20

potentially safe and effective approach to treating these complex lesions that are otherwise

21

difficult to manage with minimal morbidity. We have also shown a modest survival advantage in

22

this cohort of patients suggesting that careful patient selection may help in optimizing outcomes.

23 24 25 26 27 28 29 30 31 32 33 34

REFERENCES 1. 2.

3.

Shih RY, Smirniotopoulos JG. Posterior Fossa Tumors in Adult Patients. Neuroimaging Clinics of North America. 2016;26(4):493-510. https://doi.org/10.1016/j.nic.2016.06.003 Ghia A, Tome WA, Thomas S, et al. Distribution of brain metastases in relation to the hippocampus: implications for neurocognitive functional preservation. International journal of radiation oncology, biology, physics. 2007;68(4):971-977. 10.1016/j.ijrobp.2007.02.016 Cho KH, Hall WA, Gerbi BJ, Higgins PD, Bohen M, Clark HB. Patient selection criteria for the treatment of brain metastases with stereotactic radiosurgery. Journal of neurooncology. 1998;40(1):73-86. Published 1999/01/05.

Traylor 11 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44

4.

5. 6.

7.

8.

9.

10. 11.

12.

13.

14.

15.

16.

17.

18.

Wronski M, Arbit E, Burt M, Galicich JH. Survival after surgical treatment of brain metastases from lung cancer: a follow-up study of 231 patients treated between 1976 and 1991. Journal of neurosurgery. 1995;83(4):605-616. 10.3171/jns.1995.83.4.0605 Wronski M, Arbit E. Resection of brain metastases from colorectal carcinoma in 73 patients. Cancer. 1999;85(8):1677-1685. Published 1999/05/01. Wronski M, Arbit E. Surgical treatment of brain metastases from melanoma: a retrospective study of 91 patients. Journal of neurosurgery. 2000;93(1):9-18. 10.3171/jns.2000.93.1.0009 Sunderland GJ, Jenkinson MD, Zakaria R. Surgical management of posterior fossa metastases. Journal of neuro-oncology. 2016;130(3):535-542. 10.1007/s11060-016-22542 Javalkar V, Cardenas R, Ampil F, Ahmed O, Shi R, Nanda A. The Louisiana State University experience in the management of single small cerebellar metastasis. Neurosurgery. 2010;67(6):1515-1522. 10.1227/NEU.0b013e3181fa239e Lippitz B, Lindquist C, Paddick I, Peterson D, O'Neill K, Beaney R. Stereotactic radiosurgery in the treatment of brain metastases: the current evidence. Cancer treatment reviews. 2014;40(1):48-59. 10.1016/j.ctrv.2013.05.002 Zhang Y, Chang EL. Resection cavity radiosurgery for intracranial metastases: a review of the literature. Journal of radiosurgery and SBRT. 2014;3(2):91-102. Churilla TM, Chowdhury IH, Handorf E, et al. Comparison of Local Control of Brain Metastases With Stereotactic Radiosurgery vs Surgical Resection: A Secondary Analysis of a Randomized Clinical Trial. JAMA oncology. 2018. 10.1001/jamaoncol.2018.4610 Mohammadi AM, Hawasli AH, Rodriguez A, et al. The role of laser interstitial thermal therapy in enhancing progression-free survival of difficult-to-access high-grade gliomas: a multicenter study. Cancer medicine. 2014;3(4):971-979. 10.1002/cam4.266 Beechar VB, Prabhu SS, Bastos D, et al. Volumetric response of progressing post-SRS lesions treated with laser interstitial thermal therapy. Journal of neuro-oncology. 2018;137(1):57-65. 10.1007/s11060-017-2694-3 Ahluwalia M, Barnett GH, Deng D, et al. Laser ablation after stereotactic radiosurgery: a multicenter prospective study in patients with metastatic brain tumors and radiation necrosis. Journal of neurosurgery. 2018:1-8. 10.3171/2017.11.Jns171273 Silva D, Sharma M, Barnett GH. Laser Ablation vs Open Resection for Deep-Seated Tumors: Evidence for Laser Ablation. Neurosurgery. 2016;63 Suppl 1:15-26. 10.1227/neu.0000000000001289 De Poorter J. Noninvasive MRI thermometry with the proton resonance frequency method: study of susceptibility effects. Magnetic resonance in medicine. 1995;34(3):359367. Published 1995/09/01. Chan AY, Tran DK, Gill AS, Hsu FP, Vadera S. Stereotactic robot-assisted MRI-guided laser thermal ablation of radiation necrosis in the posterior cranial fossa: technical note. Neurosurgical focus. 2016;41(4):E5. 10.3171/2016.4.Focus1622 Dadey DY, Kamath AA, Smyth MD, Chicoine MR, Leuthardt EC, Kim AH. Utilizing personalized stereotactic frames for laser interstitial thermal ablation of posterior fossa and mesiotemporal brain lesions: a single-institution series. Neurosurgical focus. 2016;41(4):E4. 10.3171/2016.7.Focus16207

Traylor 12 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46

19.

20.

21.

22. 23. 24.

25.

26.

27.

28. 29.

30.

31.

32.

33.

34.

Borghei-Razavi H, Koech H, Sharma M, et al. Laser Interstitial Thermal Therapy for Posterior Fossa Lesions: An Initial Experience. World Neurosurgery. 2018;117:e146e153. 10.1016/j.wneu.2018.05.217 Thomas JG, Rao G, Kew Y, Prabhu SS. Laser interstitial thermal therapy for newly diagnosed and recurrent glioblastoma. Neurosurgical focus. 2016;41(4):E12. 10.3171/2016.7.Focus16234 Lin NU, Lee EQ, Aoyama H, et al. Response assessment criteria for brain metastases: proposal from the RANO group. The Lancet Oncology. 2015;16(6):e270-278. 10.1016/s1470-2045(15)70057-4 Tang Y, Horikoshi M, Li WJR. ggfortify: unified interface to visualize statistical result of popular R packages. 2016;8(2):474-485. Wickham H. ggplot2: elegant graphics for data analysis. Springer; 2016. URL: https://CRAN.R-project.org/package=ggplot2. Leuthardt EC, Duan C, Kim MJ, et al. Hyperthermic Laser Ablation of Recurrent Glioblastoma Leads to Temporary Disruption of the Peritumoral Blood Brain Barrier. PloS one. 2016;11(2):e0148613. 10.1371/journal.pone.0148613 Dorner L, Fritsch MJ, Stark AM, Mehdorn HM. Posterior fossa tumors in children: how long does it take to establish the diagnosis? Child's nervous system : ChNS : official journal of the International Society for Pediatric Neurosurgery. 2007;23(8):887-890. 10.1007/s00381-007-0323-8 Schoch B, Konczak J, Dimitrova A, Gizewski ER, Wieland R, Timmann D. Impact of surgery and adjuvant therapy on balance function in children and adolescents with cerebellar tumors. Neuropediatrics. 2006;37(6):350-358. 10.1055/s-2007-964904 Hadanny A, Rozovski U, Nossek E, et al. Craniectomy Versus Craniotomy for Posterior Fossa Metastases: Complication Profile. World Neurosurgery. 2016;89:193-198. https://doi.org/10.1016/j.wneu.2016.01.076 Lesser GJ. Chemotherapy of cerebral metastases from solid tumors. Neurosurgery clinics of North America. 1996;7(3):527-536. Published 1996/07/01. Kanner AA, Suh JH, Siomin VE, Lee SY, Barnett GH, Vogelbaum MA. Posterior fossa metastases: aggressive treatment improves survival. Stereotactic and functional neurosurgery. 2003;81(1-4):18-23. 10.1159/000075099 Badiyan SN, Regine WF, Mehta M. Stereotactic Radiosurgery for Treatment of Brain Metastases. Journal of Oncology Practice. 2016;12(8):703-712. 10.1200/JOP.2016.012922 Shiau CY, Sneed PK, Shu HK, et al. Radiosurgery for brain metastases: relationship of dose and pattern of enhancement to local control. International journal of radiation oncology, biology, physics. 1997;37(2):375-383. Published 1997/01/15. Mahajan A, Ahmed S, McAleer MF, et al. Post-operative stereotactic radiosurgery versus observation for completely resected brain metastases: a single-centre, randomised, controlled, phase 3 trial. The Lancet Oncology. 2017;18(8):1040-1048. 10.1016/s14702045(17)30414-x Dohm A, McTyre ER, Okoukoni C, et al. Staged Stereotactic Radiosurgery for Large Brain Metastases: Local Control and Clinical Outcomes of a One-Two Punch Technique. Neurosurgery. 2018;83(1):114-121. 10.1093/neuros/nyx355 Eliyas JK, Bailes J, Merrell R, O'Leary S. NT-15: STEREOTACTIC LASER THERMAL ABLATION OF RECURRENT POSTERIOR FOSSA METASTATIC

Traylor 13 1 2 3 4 5 6 7 8 9 10 11

35.

36.

LESION: DESCRIPTION OF NEW TECHNOLOGY FOR INFRATENTORIAL TUMORS REFRACTORY TO CONVENTIONAL THERAPIES. Neuro-oncology. 2014;16(Suppl 5):v162-v162. 10.1093/neuonc/nou265.14 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; discussion 667. 10.1227/neu.0000000000000332 Salehi A, Kamath AA, Leuthardt EC, Kim AH. Management of Intracranial Metastatic Disease With Laser Interstitial Thermal Therapy. Front Oncol. 2018;8:499. 10.3389/fonc.2018.00499

12

TABLES

13

Table 1: Patient and lesion characteristics following LITT.

14

Table 2: Previous reports of LITT to the posterior fossa.

15 16

FIGURES

17

Figure 1: Individual resection cavity/lesion volume over time per patient.

18

Figure 2: Individual edema volume over time per patient.

19

Figure 3: Kaplan-Meier curve of progression-free survival for the entire cohort (n = 13).

20

Figure 4: MR images detailing the course of a patient (case 12) who received LITT twice for a

21

metastatic lesion adjacent to the right transverse venous sinus and tentorium cerebelli. A coronal

22

T1C+ (A) and axial Ktrans MR perfusion image (B) delineate the tumor pre-LITT. A coronal

23

T1C+ taken at one-month follow-up (C) demonstrates the LITT ablation cavity while the axial

24

Ktrans MR perfusion image shows a marginal residual signature laterally, adjacent to the venous

25

sinus (D). A repeat coronal T1C+ taken one year later shows some increased contras

26

enhancement on the superior margins of the ablation cavity (E) while a Ktrans MR perfusion

27

image shows increased signature in the same region consistent with tumor recurrence. Figures G

28

and H represent T1C+ and Ktrans MR perfusion imaging, respectively, following repeat ablation

29

of the recurrent tumor. The red arrows indicate the pre-treatment and residual tumor volumes,

30

respectively.

31

Figure 5: Screenshots of the Monteris Neuroblate software intraoperatively for a metastatic

32

lesion adjacent to the transverse venous sinus. Probe alignment is planned with a three-plane

33

view of the lesion (axial, coronal, sagittal) (top). Insertion of the probe is subsequently

34

performed based on the trajectory delineated in Brainlab (bottom). The blue line circumscribes

Traylor 14 1

the thermal damage threshold (TDT) line radius for LITT ablation while the pink line outlines

2

the tumor. The volume of tumor (pink) not covered by the superimposed TDT lines (blue) is

3

delineated by the red arrows.

Table 1. Patient and lesion characteristics following LITT

Tumor Vol. (cm3) 6.72 8.11

Cavity Vol. Post-Op (cm3) 11.6 8.10

Cavity Vol. 1month (cm3) N/A 5.09

Cavity Vol. 3month (cm3) N/A 4.39

Cavity Vol. 6month (cm3) N/A 2.63

Cavity Vol. 9-month (cm3) N/A 3.76

Cavity Vol. 12month (cm3) N/A N/A

Alive at Last Follow-up? (Y/N)

Patient 1 2

Gender F F

Age 69 51

Histology Breast RN

Previous Treatment to Lesion* SRS SRS

3

F

63

Breast

SRS

1.30

3.77

2.03

N/A

1.65

N/A

N/A

None

N Y Y

4

F

57

Breast

SRS

1.45

6.10

4.17

2.03

2.16

2.04

4.79

None

Y

5

F

57

RN

1.61

3.48

4.42

0.84

0.28

N/A

N/A

None

Y

6

F

31

RN

SRS WBRT + SRS

8.81

13.40

16.97

14.33

6.53

4.82

N/A

None

7

F

60

RN

SRS

3.29

3.40

2.83

2.33

9.076

N/A

N/A

Complications None None

CN 7 & 8 palsy None None

Y Y

N SRS 4.66 10.56 9.55 11.12 11.12 N/A N/A N WBRT 6.81 7.81 N/A 6.44 N/A N/A N/A Resection Y 10 F 56 Colon 7.52 8.34 6.97 9.81 14.55 N/A N/A None + SRS Y 11 F 36 RCC SRS 0.33 6.29 10.55 3.93 N/A N/A N/A None Resection Y 12 F 58 Breast 5.16 3.90 3.68 3.05 2.36 1.95 1.43 None + SRS Resection Y 13 F 68 RN 4.48 3.00 1.06 N/A N/A N/A N/A None + SRS N/A = data not available; M = male; F = female; SRS; stereotactic radiosurgery; WBRT = whole brain radiotherapy; CN = cranial nerve; RN = radiation necrosis; NSCLC = non-small cell lung cancer; SCLC = small cell lung cancer; RCC = renal cell carcinoma *All patients received systemic chemotherapy for primary malignancy prior to LITT 8 9

F M

69 79

NSCLC SCLC

Table 2. Previous reports of LITT to the posterior fossa. No. of Lesions Year Author Patients Treated 2014 Eliyas et al.34 1 Met. 17 2016 Chan et al. 1 RN 2016 Dadey et al.18 5 EF + BG

Complications

None None None Wound infection, Borghei2018 8 RN + Met. hydrocephalus, Razavi et al.19 CN 6 palsy 2019 Traylor et al*. 13 RN + Met CN 7 & 8 palsy RN: radiation necrosis, EF: epileptogenic foci, BG: brainstem ganglionoma, Met: metastasis(es), CN: cranial nerve *Current series

Progression−Free Survival +

Local Recurrence (%)

100.0%

75.0%

+

50.0%

+

25.0%

+ 0

10

20

Time (months)

30

DISCLOSURE The authors have no conflicts of interest, financial or otherwise, to disclose.

ABBREVIATIONS SRS: stereotactic radiosurgery CSF: cerebrospinal fluid LITT: laser interstitial thermal therpay MR: magnetic resonance IRB: institutional review board OS: overall survival PFS: progression-free survival MRI: magnetic resonance image RANO-BM: Response Assessment in Neuro-Oncology Brain Metastases T1C+: T1-weighted post-contrast FLAIR: fluid-attenuated inversion recovery ABTI: advanced brain tumor imaging EMR: electronic medical record CI: confidence interval SCLC: small cell lung cancer NSCLC: non-small cell lung cancer KPS: Karnofsky performance status WBRT: whole brain radiotherapy BBB: blood brain barrier