The role of micrometastasis in high-risk skin cancers.

The propensity to metastasize is the most important prognostic indicator for solid cancers. New insights into the mechanisms of early carcinogenesis have revealed micrometastases are generated far earlier than previously thought. Evidence supports a synergistic relationship between vascular and lymphatic seeding which can occur before there is clinical evidence of a primary tumour. Early vascular seeding prepares distal sites for colonisation while regional lymphatics are co-opted to promote facilitative cancer cell mutations. In response, the host mounts a global inflammatory and immunomodulatory response towards these cells supporting the concept that cancer is a systemic disease. Cancer staging systems should be refined to better reflect cancer cell loads in various tissue compartments while clinical perspectives should be broadened to encompass this view when approaching high-risk cancers. Measured adjunctive therapies implemented earlier for low-volume, in-transit cancer offers the prospect of preventing advanced disease and the need for heroic therapeutic interventions. This review seeks to re-appraise how we view the metastatic process for solid cancers. It will explore in-transit metastasis in the context of high-risk skin cancer and how it dictates disease progression. It will also discuss how these implications will influence our current staging systems and its consequences on management.

Understanding the Tumor Microenvironment in Melanoma Patients with In-Transit Metastases and Its Impacts on Immune Checkpoint Immunotherapy Responses.

Melanoma is the leading cause of global skin cancer-related death and currently ranks as the third most commonly diagnosed cancer in Australia. Melanoma patients with in-transit metastases (ITM), a type of locoregional metastasis located close to the primary tumor site, exhibit a high likelihood of further disease progression and poor survival outcomes. Immunotherapies, particularly immune checkpoint inhibitors (ICI), have demonstrated remarkable efficacy in ITM patients with reduced occurrence of further metastases and prolonged survival. The major challenge of immunotherapeutic efficacy lies in the limited understanding of melanoma and ITM biology, hindering our ability to identify patients who likely respond to ICIs effectively. In this review, we provided an overview of melanoma and ITM disease. We outlined the key ICI therapies and the critical immune features associated with therapy response or resistance. Lastly, we dissected the underlying biological components, including the cellular compositions and their communication networks within the tumor compartment, to enhance our understanding of the interactions between immunotherapy and melanoma, providing insights for future investigation and the development of drug targets and predictive biomarkers.

Successful management of in-transit cutaneous squamous cell carcinoma with anti-PD-1 immunotherapy.

This report describes the case of a 70-year-old man with metastatic squamous cell carcinoma (SCC) of the right lower leg. Soon after definitive surgical management of the primary and nodal metastases with curative intent, he relapsed, developing aggressive in-transit metastatic disease and recurrent nodal disease. The patient was treated with systemic immunotherapy alone, which not only prompted the progressive nodal metastases to regress, but also resulted in a complete response of the in-transit disease. This situation is previously undescribed in the medical literature.

Management of In-Transit Metastases.

PURPOSE OF REVIEW: The purpose of this study is to discuss the current knowledge and future perspectives regarding the treatment options for in-transit metastases (ITM), along with the optimal algorithms for patients presenting with this adverse manifestation of melanoma. RECENT FINDINGS: In addition to procedures historically accepted for the management of ITM, encompassing surgery and regional techniques, novel medications in the form of immune checkpoint inhibitors (ICI) and targeted therapies now represent standard options, allowing for the possibility of combined approaches, with an expanding role of systemic therapies. Melanoma in-transit metastases consist of intralymphatic neoplastic implants distributed between the primary site and the regional nodal basin, within the subepidermal and dermal lymphatics. Distinct risk factors may influence the development of ITM, and the clinical presentation can be highly heterogeneous, enhancing the complexity of the management of ITM. Surgical resection, when feasible, continues to represent a standard approach for patients with curative intent. Patients with extensive or unresectable disease may also benefit from regional approaches that include isolated limb perfusion or infusion, electrochemotherapy, and a wide variety of intralesional therapies. Over the past decade, regimens with ICI and BRAF/MEK inhibitors dramatically expanded the benefit of systemic treatments for patients with melanoma, both in the adjuvant setting and for those with advanced disease, and the combination of these modalities with regional treatments, as well as neoadjuvant approaches, may represent the future for the treatment of patients with ITM.

An analysis of clinical effectiveness of electrochemotherapy in the treatment of advanced metastatic malignant melanoma performed in the eastern part of Central Europe: a single-centre experience.

Introduction: Patients with cutaneous malignant melanoma (MM), in case of non-resectability of the lesions, have only a limited pool of the available treatment options. In recent years especially electrochemotherapy (ECT) has become an increasingly important therapy in locoregionally advanced MM. Aim: In this study an analysis of the ECT treatment of locoregionally advanced malignant melanoma was presented. Material and methods: Six ECT cycles in 5 patients were performed in the Wroclaw Comprehensive Cancer Centre. Treatment response, long-term observation, technical data downloaded from electroporator and photographs taken before and after the ECT were assessed in the analysis. Results: In total, 200 nodules in 5 patients were treated with ECT in palliative intent. After 5 out of 6 ECT cycles, the particular clinical response has been observed. Four patients with primary unresectable lesions underwent 11 surgeries of the cutaneous metastases. In long-term follow-up in 2 patients, of whom one died 19 months after the ECT, the disease progressed and in another two, no recurrence was observed. Conclusions: ECT is an encouraging therapy for patients in whom the recurrent cutaneous melanoma cannot be treated with other methods, however, access to this method in eastern part of Central Europe is limited. The presented study seems to confirm the usefulness of this palliative approach in a specific group of patients suffering from cutaneous MM.

BRAF status as a predictive factor for response in isolated limb perfusion.

BACKGROUND: Isolated limb perfusion (ILP) is a treatment option for unresectable in-transit melanoma metastases of the extremities. Approximately two-thirds of the patients have a complete response, and known predictive factors mainly regard tumor burden. In an attempt to identify subgroups with higher response rates, we retrospectively analyzed the predictive value of the BRAF V600E/K mutation for response at our institution. METHODS: Between January 2012 and December 2017, 98 consecutive patients underwent first-time ILP with melphalan for melanoma in-transit metastases and were included in the study. Data was retrieved from our prospectively kept database. Tumor burden was assessed preoperatively as number of lesions and largest tumor diameter. BRAF status was determined according to clinical routine. Response rates were classified according to WHO criteria. RESULTS: Of the 98 patients included in the analysis, 32 patients had a BRAF V600E/K mutation (33%) and 66 patients were BRAF wild type (wt). There was no difference in age, sex or tumor burden between the groups. Comparing response between BRAF V600E/K mutation and BRAF wt, the overall response rate was 69% vs. 77% (p=.36) and the complete response rate was 47% vs. 52% (p=.67). There was no difference in survival, with a median survival of 47 months. CONCLUSION: In this consecutive series of patients, BRAF V600E/K mutation was not found to be a significant factor for response or survival following ILP.

Electrochemotherapy for the management of cutaneous and subcutaneous metastasis: a series of 39 patients treated with palliative intent.

BACKGROUND AND OBJECTIVES: Electrochemotherapy (ECT) is technique for local control of skin metastasis. This study is primarily aimed at assessing the clinical activity of ECT in a prospective cohort of patients, and evaluating the association between primary tumor histology, number of metastatic lesions and size of tumor deposits and objective response rate. METHODS AND RESULTS: Thirty-nine patients with skin metastases from melanoma and other tumors underwent intravenous bleomycin ECT with palliative intent. No serious adverse events (SAE) or CTC grade 3 or 4 were observed. Overall response rate (ORR) was 66.6%. Response rate significantly correlated at univariate analysis both with the number (< or >10) and the size (< or >2 cm) of metastases. No relationship was observed for the histology of primary tumor. At multivariate analysis the size of the nodules under 2 cm was associated with a positive response and the correlation was statistically significant. CONCLUSIONS: ORR was 66.6% and all patients obtained a subjective clinical benefit from the treatment with minimal side effects. The most suitable patients were the ones with nodules <2 cm.

Isolated limb perfusion for in-transit melanoma metastases: melphalan or TNF-melphalan perfusion?

Indications for treatment of melanoma in-transit metastases (ITMs) confined to the limb with isolated limb perfusion (ILP) are not well defined. This study reports the Groningen regional therapeutic perfusion experience with melphalan (M-ILP) and TNF-melphalan (TM-ILP) for ITMs, and reviews of the melanoma TNF-melphalan ILP literature. Between 1991 and 2012, 60 patients were treated with ILP. Patients with "small" ITMs received M-ILP (10-13 mg melphalan/L limb volume) and patients with "bulky" disease TM-ILP (1-4 mg TNF); 19 M-ILPs and 41 TM-ILPs were performed, 26 Stage IIIB, 31 Stage IIIB and 1 stage IV disease. Overall response after 57 ILPs was 90%; CR 27 (45%), PR 27 (45%), no response 3 (5%); after 9 M-ILPs CR 6 (32%) and 41 TM-ILPs CR 21 (51%, P = 0.124). For younger patients (<65 years) CR was 69% and for elderly patients 29% (P = 0.003). For low volume disease (<5 ITMs) CR was 75% and for high volume disease (≥5 ITMs) 41% (P = 0.038). After median follow-up of 15 months (range, 1-144) there was local recurrence or disease progression in 36 patients (60%). Positive lymph node status was associated with local progression, absence of CR and Stage IIIC disease; these were independent prognostic factors for progression to systemic disease. M-ILP is an effective regional treatment for melanoma ITMs, whereas for bulky disease TM-ILP should be the first choice. In-field progression-free survival after ILP is determined by the biological behavior of the ITMs and the patient's immune system.

[In-transit metastasis in melanoma: Efficacy of topical imiquimod combined with carbon dioxide laser or with electrocautery]. / Métastases en transit du mélanome : efficacité de l'imiquimod topique combiné au laser CO2 ou à l'électrocoagulation.

BACKGROUND: In-transit metastases in cutaneous melanoma are common and difficult to manage. Therapy is mainly palliative. Use of topical imiquimod has been assessed for surface metastases. PATIENTS AND METHODS: We report on four patients with cutaneous melanoma metastases treated with topical imiquimod associated with carbon dioxide laser in the first two patients and with electrocoagulation in the two others. For two patients, we noted complete regression of the lesions after 15 and 18 months. For the two others, treatment was stopped after 9 to 10 months because of progression of subcutaneous metastasis and distant metastasis. DISCUSSION: Topical imiquimod is an alternative treatment used in superficial in-transit metastasis of melanoma. Its use as a monotherapy is sometimes ineffective. We elected to use combined pre-treatment with carbon dioxide laser or electrocoagulation in order to potentiate the action of imiquimod. This simple and inexpensive therapeutic strategy constitutes a palliative treatment that can allow prolonged local control of cutaneous metastasis.

The Long-Term Results of Electrochemotherapy in the Treatment of Patients with Locoregionally Advanced, Unresectable Melanoma.

Background/Objectives: Despite observing progress in recent years in the treatment of patients with advanced melanoma, the optimal management of locoregional recurrence has not been determined. Various methods are used to treat this group of patients. One of these methods is electrochemotherapy. The present study presents the distant results in treating patients with the locoregional recurrence of melanoma, using the technique of electrochemotherapy. Methods: This study includes a retrospective analysis of 88 patients' data with locoregional melanoma recurrence, treated with electrochemotherapy (ECT) between 2010 and 2023, in two reference centers. Results: Approximately 80% of patients responded to the ECT treatment, achieving partial or complete remission. In a multivariate analysis, statistically significant longer overall survival was found in the group of patients who achieved complete remission after ECT and were treated with immunotherapy. Discussion: The results may suggest the existence of synergy between ECT and immunotherapy. However, confirmation of this fact requires further prospective studies that will also establish the role of ECT in the combination treatment of patients with locoregional recurrence of melanoma.

The effect of a single dose of nivolumab prior to isolated limb perfusion for patients with in-transit melanoma metastases: An interim analysis of a phase Ib/II randomized double-blind placebo-controlled trial (NivoILP trial).

OBJECTIVE: ILP has shown to achieve high response rates in patients with melanoma ITM. Possibly there is a synergistic mechanism of action of ILP and anti-PD1. The aim of this trial was to investigate the safety and efficacy of adding a single dose of systemic anti-PD1 to isolated limb perfusion (ILP) for patients with melanoma in-transit metastases (ITM). METHODS: In this placebo controlled double-blind phase Ib/II trial, patients with melanoma ITM were randomized 1:1 to either a single systemic dose of nivolumab or placebo one day prior to ILP. The primary endpoint was complete response (CR) rate at three months, and safety in terms of incidence and severity of adverse events (AEs). RESULTS: A total of 20 patients were included. AEs of any grade occurred in 90% of patients in the nivolumab arm and in 80% in the placebo arm within three months after ILP. Grade 3 AEs were reported in 40% and 30% respectively, most commonly related to wound infection, wound dehiscence, or skin necrosis. There were no grade 4 or 5 AEs reported. The CR rate was 75% in the nivolumab arm and 60% in the placebo arm. The 1-year local progression-free rate was 86% in the nivolumab arm and 67% in the placebo arm. The 1-year OS was 100% in both arms. CONCLUSION: For patients with melanoma ITM, the addition of a single systemic dose of nivolumab the day before ILP is considered safe and feasible with promising efficacy. Accrual will continue in a phase 2 trial.

Advances in Intralesional Therapy for Locoregionally Advanced and Metastatic Melanoma: Five Years of Progress.

Locoregionally advanced and metastatic melanoma are complex diagnoses with a variety of available treatment options. Intralesional therapy for melanoma has been under investigation for decades; however, it has advanced precipitously in recent years. In 2015, the Food and Drug Administration (FDA) approved talimogene laherparepvec (T-VEC), the only FDA-approved intralesional therapy for advanced melanoma. There has been significant progress since that time with other oncolytic viruses, toll-like receptor agonists, cytokines, xanthene dyes, and immune checkpoint inhibitors all under investigation as intralesional agents. Further to this, there has been exploration of numerous combinations of intralesional therapies and systemic therapies as various lines of therapy. Several of these combinations have been abandoned due to their lack of efficacy or safety concerns. This manuscript presents the various types of intralesional therapies that have reached phase 2 or later clinical trials in the past 5 years, including their mechanism of action, therapeutic combinations under investigation, and published results. The intention is to provide an overview of the progress that has been made, discuss ongoing trials worth following, and share our opinions on opportunities for further advancement.

In transit metastases in children, adolescents and young adults with localized rhabdomyosarcoma of the distal extremities: Analysis of the EpSSG RMS 2005 study.

In-transit metastases (ITM) are defined as metastatic lymph nodes or deposits occurring between the primary tumor and proximal draining lymph node basin. In extremity rhabdomyosarcoma (RMS), they have rarely been reported. This study evaluates the frequency, staging and survival of patients with ITM in distal extremity RMS. METHODS: Patients with extremity RMS distal to the elbow or knee, enrolled in the EpSSG RMS 2005 trial between 2005 and 2016 were eligible for this study. RESULTS: One hundred and nine distal extremity RMS patients, with a median age of 6.2 years (range 0-21 years) were included. Thirty seven of 109 (34%) had lymph node metastases at diagnosis, 19 of them (51%) had ITM, especially in lower extremity RMS. 18F-FDG-PET/CT detected involved lymph nodes in 47% of patients. In patients not undergoing 18F-FDG-PET/CT lymph node involvement was detected in 22%. The 5-yr EFS of patients with ITM vs proximal lymph nodes vs combined proximal and ITM was 88.9% vs 21.4% vs 20%, respectively (p = 0.01) and 5-yr OS was 100% vs 25.2% vs 15%, respectively (p = 0.003). CONCLUSION: Our study showed that in-transit metastases constituted more than 50% of all lymph node metastases in distal extremity RMS. 18F-FDG-PET/CT improved nodal staging by detecting more regional and in-transit metastases. Popliteal and epitrochlear nodes should be considered as true (distal) regional nodes, instead of in-transit metastases. Biopsy of these nodes is recommended especially in distal extremity RMS of the lower limb. Patients with proximal (axillary or inguinal) lymph node involvement have a worse prognosis.

Tumor Burden and Health-Related Quality of Life in Patients with Melanoma In-Transit Metastases.

BACKGROUND: Few studies have investigated the health-related quality of life (HRQOL) in patients with melanoma in-transit metastases (ITM). The aim was to investigate the association between tumor burden and HRQOL, including disparities pertaining to sex and age, in treatment-naïve patients with ITM. METHODS: Functional Assessment of Cancer Therapy-Melanoma (FACT-M) questionnaire was used to assess HRQOL Pairwise comparisons using t-tests between clinical cutoffs are presented and multiple linear regression analysis showing the unique associations of gender, age, number of tumors, tumor size, presence of lymph node metastases, and tumor localization. RESULTS: A total of 95 patients, 47% females and 53% males (median age 72 years) were included between 2012 and 2021. Women scored significantly lower on emotional well-being (p = 0.038) and lower on FACT-M (p = 0.058). Patients who had ≥10 tumors scored significantly lower on FACT-M (p = 0.015), emotional- and functional well-being (p = 0.04, p = 0.004, respectively), melanoma scale (p = 0.005), and FACT-G (p = 0.027). There was no significant difference in HRQOL depending on age, size of tumors, localization, or presence of lymph node metastases. CONCLUSION: For patients with melanoma ITMs, the female sex and higher tumor burden (i.e., number of tumors) were significantly correlated with lower HRQOL. However, these findings do not fully explain HRQOL for this patient population, and future research should consider the possibility that there are specific questions for patients with ITM where current instruments might fail to measure their discomfort to the full extent.

Results of isolated limb perfusion for metastasized malignant melanoma.

BACKGROUND AND OBJECTIVES: Locoregional metastases are typical biological manifestations of advanced malignant melanomas. Treatment with hyperthermic isolated limb perfusion (HILP) should be considered in affected patients. In the present study, we have analyzed the results of HILPs performed in our department. PATIENTS AND METHODS: Eighty patients with locoregional metastases of the extremities received HILP at the Department of Surgery between January 2007 and December 2016. The mean follow-up was 38 months. RESULTS: The study included 50 men and 30 women (mean age: 63 years). The median time between melanoma diagnosis and HILP was 25 months (range: 1-219 months). HILP was performed in curative (n = 45) and palliative (n = 35) intention. Seventy-five patients received a drug combination of melphalan/dactinomycin and five patients received a drug combination of melphalan/tumor necrosis factor-alpha. Remission rates were determined in 72 of 80 patients (90%) as follows: partial response n = 28, complete response n = 25, no response n = 19. Of the 25 patients with complete response, 13 patients developed a new tumor manifestation during follow-up (locoregional recurrences n = 4; distant metastases n = 3; both n = 6). The median overall survival rate was 33 months. Tumor stage influenced the survival rate significantly (p = 0.001). Patients with complete response showed a significantly better overall survival than patients with partial or no response (p = 0.016). CONCLUSION: HILP is an effective therapeutic option in patients with locoregional metastases. This procedure carries a certain risk of side effects and adverse events but overall results in good response rates. Therefore, HILP should be offered to selected patients based on an individual discussion, considering their health status and oncological prognosis.

Molecular Aspects of the Isolated Limb Infusion Procedure.

For decades, isolated limb infusion (ILI) and hyperthermic isolated limb perfusion (HILP) have been used to treat melanoma in-transit metastases and unresectable sarcoma confined to the limb utilizing the effect of loco-regional high-dose chemotherapy to the isolated limb. Both procedures are able to provide high response rates in patients with numerous or bulky lesions in whom other loco-regional treatments are becoming ineffective. In comparison to systemic therapies, on the other hand, ILI and HILP have the advantage of not being associated with systemic side-effects. Although in principle ILI and HILP are similar procedures, ILI is technically simpler to perform and differs from HILP in that it takes advantage of the hypoxic and acidotic environment that develops in the isolated limb, potentiating anti-tumour activity of the cytotoxic agents melphalan +/- actinomycin-D. Due to its simplicity, ILI can be used in both preclinical and clinical studies to test new cytotoxic regimens and combinations with the aim to overcome tumour resistance. In the future, administration of cytotoxic agents by ILI, in combination with systemic treatments such as BRAF/MEK/KIT inhibitors, immunotherapy (CTLA-4 blockade), and/or programmed death (PD-1) pathway inhibitors, has the potential to improve responses further by inducing increased tumour cell death while limiting the ability of the tumour to suppress the immune response.

Minimal Residual Disease in Melanoma:molecular characterization of in transit cutaneous metastases and Circulating Melanoma Cells recognizes an expression panel potentially related to disease progression.

Isolating circulating melanoma cells (CMCs) represents a powerful method to monitor minimal residual disease. We documented that MCAM/MUC18/CD146 expression is strongly associated with disease progression. ABCB5 is melanoma-stem antigen with self-renewal, proliferation, differentiation, tumorigenicity capabilities. These findings supported us to improve CMC detection, investigating MCAM/MUC18/CD146 and ABCB5 as enrichment targets in MM progression. Moreover, we decided to compare possible molecular diversity of these CMC fractions with metastatic tissue expression, collecting concomitantly cutaneous in transit metastases (CTM). We enriched CMCs from eight melanoma patients staged ≥pT1b AJCC, who developed CTMs at baseline or during follow up. We assessed a gene expression panel comprising ABCB5, the differentiation markers (Tyrosinase, MART1), angiogenic factors (VEGF, bFGF), the cell-cell adhesion molecules (MCAM/MUC18/CD146 5'-portion, Long, and Short isoforms, E-Cadherin, N-Cadherin, VE-Cadherin) and matrix-metallo-proteinases (MMP2 and MMP9) via high-sensitive RT-PCR. Preliminary findings defined three distinct sub-populations: "endothelial" CD45-CD146+CMCs, "stem" CD45-ABCB5+CMCs and a "hybrid- stem-endothelial"- CD45-MCAM+ABCB5+CMCs. The expression panel documented that - almost high expression found in CTMs - like in 73.5% of CMCs resulted positive for at least one transcript at baseline, showing gene-expression variability. Longitudinal monitoring documented shut-down of all gene-expressions in "endothelial"- and "hybrid stem-endothelial"-subsets, whilst persistency or acquisition of MCAM/MUC18/CD146, VE-CADH and MMPs was documented in disease-progression status.Conversely, a drastic expression shut-down was documented when patients achieved clinical remission. The "stem"- CMCs fraction" showed quite lower gene expression frequencies. MCAM/MUC18/CD146 and ABCB5 as melanoma-specific-targets are effective in the selection of highly primitive CMCs and highlights those putative genes associated with disease spreading progression.

Advanced Merkel cell carcinoma of the lower extremity treated with surgery and isolated pelvic and limb perfusion using Melphalan: A case of unexpected long-term survival.

INTRODUCTION: Merkel cell carcinoma (MCC) is a rare, neuroendocrine skin tumor, with high frequency of locoregional recurrence, metastases, and poor prognosis. Locoregional MCC recurrence in the extremities can pose considerable treatment challenges. We report a case of long-term survival in a female patient with recurrent MCC of the leg, treated with surgery and locoregional chemotherapy. PRESENTATION OF CASE: A 73-year-old female with cirrhosis and hepatitis C, developed cutaneous MCC in the left inferior limb. This patient initially received surgical treatment, with subsequent negative sentinel lymph-node biopsy in another center, one-month prior recovery in our department, and arrived with 4 new limb nodules, cranially to the previously treated area, without distant metastases or inguinal lymph node recurrence. This patient was not eligible for immunotherapy due to active hepatitis upon treatment with NS5B inhibitors, or eligible for systemic chemotherapy or radiotherapy due to severe neutropenia and was, therefore, subjected to surgical resection combined with Isolated Pelvic and Limb Perfusion (IPLP) with Melphalan. Histological evaluation confirmed MCC diagnosis and during the following 4 months, she developed further locoregional recurrences with homolateral inguinal lymph node involvement and was subjected to two additional rounds of surgery plus IPLP. DISCUSSION: All procedures were tolerated, systemic toxicities were temporary and subsequent clinical and radiological follow-up, following the last combined treatment, indicated that this patient was still alive and disease-free, at 56 months. CONCLUSION: In this case, surgery combined with locoregional Melphalan chemotherapy was an effective and repeatable treatment for recurrent MMC and resulted in unexpected long-term survival.

MRI-Guided Cryoablation of In-Transit Metastases from Cutaneous Melanoma: A Brief Report on a Preliminary Experience.

This study aims to discuss MRI-guided cryoablation (CA) of in-transit (IT) metastases from melanoma and to retrospectively present our preliminary experience in such a specific field. Three female patients (mean age 55.6 years; range 39-64) were included, and eight IT metastases (mean size 12.4 ± 6.5 mm, range: 5-25) were treated in three different sessions. Technical success was 100%; and mean procedural time 129.3 ± 103 min. (range 42-243). Primary local tumour control was 100% at 1-, 6- and 12-month follow-up; and 87.5% at 18-month follow-up. Two complications were recorded (one minor and one major). MRI-guided CA is a novel therapy, which may be included in the armamentarium of local therapies of IT metastases.