Predictive Value of Perilesional Edema Volume in Melanoma Brain Metastasis Response to Stereotactic Radiosurgery

doi:10.21203/rs.3.rs-4888457/v1

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Research Article

Predictive Value of Perilesional Edema Volume in Melanoma Brain Metastasis Response to Stereotactic Radiosurgery

https://doi.org/10.21203/rs.3.rs-4888457/v1

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Journal Publication

published 11 Sep, 2024

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Background and aim:

Stereotactic radiotherapy (SRT) is an established treatment for melanoma brain metastases (MBM). Recent evidence suggests that perilesional edema volume (PEV) might compromise the delivery and efficacy of radiotherapy to treat BM. This study investigated the association between SRT efficacy and PEV extent in MBM.

Materials and Methods

This retrospective study reviewed medical records from January 2020 to September 2023. Patients with up to 5 measurable MBMs, intracranial disease per RANO/iRANO criteria, and on low-dose corticosteroids were included. MRI scans assessed baseline neuroimaging, with PEV analyzed using 3D Slicer. SRT plans were based on MRI-CT fusion, delivering 18–32.5 Gy in 1–5 fractions. Outcomes included intracranial objective response rate (iORR) and survival measures (L-iPFS and OS). Statistical analysis involved decision tree analysis and multivariable logistic regression, adjusting for clinical and treatment variables.

Results

Seventy-two patients with 101 MBM were analyzed, with a mean age of 68.83 years. The iORR was 61.4%, with Complet Response (CR) in 21.8% and Partial Response (PR) in 39.6% of treated lesions. PEV correlated with KPS, BRAF status, and treatment response. Decision tree analysis identified a PEV cutoff at 0.5 cc, with lower PEVs predicting better responses (AUC = 0.82).Patients with PEV ≥ 0.5 cc had lower response rates (iORR 44.7% vs. 63.8%, p < 0.001). Median OS was 9.4 months, with L-iPFS of 27 months. PEV significantly impacted survival outcomes.

Conclusions

A more extensive PEV was associated with a less favorable outcome to SRT in MBM.

Melanoma brain metastasis

perilesional edema

radio-surgery

stereotactic radiotherapy

immunotherapy

Brain metastases from melanoma represent a significant clinical challenge due to their poor prognosis and the complexities of treatment. Melanoma, known for its aggressive nature, frequently metastasizes to the brain, complicating management and impacting survival outcomes [1]. The incidence of brain metastases in melanoma patients has increased with advances in systemic therapies, highlighting the need for effective local treatment strategies [2]. Despite improvements in targeted therapies and immunotherapies, patients with melanoma brain metastases often face limited treatment options and a diminished quality of life [3]. Radiotherapy (RT), whether used alone or in conjunction with surgery and/or systemic therapy, remains a key treatment strategy for managing BMs [4]. Specifically, stereotactic radiotherapy (SRT) is employed to treat patients with up to four unresected BMs, each with a diameter of 30 mm or less, as well as the surgical cavities of patients who have had one or two BMs removed [4–7]. SRT achieves local control rates ranging from 75–95% [8–10], leads to a better quality of life (QoL) compared to whole brain radiation therapy (WBRT) alone [3–4], and can work in synergy with systemic therapies, including immune checkpoint inhibitors (ICIs) [11–15]. Despite these benefits, the prognosis for BMs treated with SRT remains poor, with median overall survival (OS) being less than one year [16, 17]. To date, only a few predictive factors for response have been identified, such as the Karnofsky performance score (KPS), the number of BMs, presence of extracranial metastases, certain molecular and radiomic characteristics, the dose/volume ratio, and the concurrent use of systemic therapies, among others [18–21].

Perilesional edema volume (PEV) is a significant cause of morbidity in patients with both primary and metastatic brain tumors [22]. It has been associated with cancer cell infiltration [23, 24], hypoxia, and neovascularization [25], all of which are known to hinder the effectiveness of radiation and systemic therapies. Larger PE diameters have been linked to a higher risk of intracranial progression and a reduced likelihood of responding to SRT [26–28] or systemic treatments [29] for BMs originating from NSCLC. However, the role of PEV as a predictive factor for response to SRT in brain metastases from melanoma (MBM) remains unclear.

This study seeks to assess the impact of PEV on intracranial response and its association with survival in patients with MBM treated with SRT in combination with systemic therapy.

Patients selection

This retrospective study was performed at the Radiation Oncology Unit of Azienda Ospedaliera Universitaria Senese in Siena, Italy, covering the period from January 2020 to September 2023. Clinical characteristics, histopathological findings, molecular profiles, and details of systemic treatments were gathered from patient medical records. The inclusion criteria for this study included: (i) patients with up to 5 melanoma brain metastases (MBMs); (ii) measurable intracranial disease according to RANO [30] and iRANO [31] guidelines; (iii) treatment involving stereotactic radiotherapy (SRT); and (iv) administration of a low dose of corticosteroids (less than 2 mg/day of dexamethasone) at the time of the brain MRI prior to SRT. Exclusion criteria involved: (i) any prior treatment for MBMs; (ii) prior surgical removal or whole-brain radiation therapy (WBRT); (iii) diagnosis of meningeal carcinomatosis; and (iv) absence of a baseline brain MRI. The study was conducted following the principles of the Declaration of Helsinki and received ethical approval from the institutional review board of "Le Scotte" Hospital of Siena. Written informed consent was obtained from each participant, and patient confidentiality was maintained by anonymizing all data prior to analysis.

Imaging and Measurements

This study exclusively utilized MRI scans for imaging assessments. Standard MRI sequences included axial T1, T2-weighted, and FLAIR images. Baseline neuroimaging features were independently evaluated by two radiation oncologists and a neuroradiologist before the initiation of local therapy. The MRIs obtained at enrollment were analyzed using 3D Slicer software (https://www.slicer.org). For each MBM, segmentation was performed on contrast-enhanced 3D T1-weighted images to determine the gross tumor (GT) volume (Fig. 1a). The volume of perilesional edema (PEV) was quantified by segmenting FLAIR/T2-weighted images (Fig. 1b). The Fast GrowCut Extension with Laplacian 0 settings was used to create 3D models. Both PE and GT volumes were measured in cubic centimeters (cc). Tumors that exhibited overlapping edema due to proximity to other lesions or were incompatible with 3D Slicer's processing were excluded from the analysis.

SRT and Systemic Treatments

Treatment plans were developed by integrating thin-slice MRI with stereotactic CT scans. The gross tumor volume (GTV) was delineated as the entire visible lesion on the CT/MRI fusion. To account for potential errors in imaging fusion, contouring, setup variations, and patient movement during treatment, a 3 mm isotropic margin was added to the GTV to form the planning target volume (PTV). SRT was administered with a total dose of 18–32.5 Gy delivered over 1 to 5 fractions. The total dose, fractionation schedule, and concomitant systemic therapies were individualized based on discussions in a multidisciplinary tumor board.

Outcome Measures

The primary outcome of interest was the intracranial objective response rate (iORR), defined as the percentage of patients achieving either a complete response (CR) or partial response (PR) according RANO criteria. Brain contrast-enhanced MRI was conducted at baseline, 8 to 10 weeks post-SRT, and subsequently every 4 to 6 months or as clinically indicated. The duration of intracranial response (L-iPFS) was measured from the time of SRT to the occurrence of local intracranial progression. Overall survival (OS) was defined as the period from RT to death from any cause. To ensure the accuracy of response evaluations, they were independently reassessed by both a radiation oncologist and a neuroradiologist.

Statistical Analysis

Continuous variables were summarized using medians and interquartile ranges, while categorical variables were presented as frequencies and percentages. A decision tree analysis was performed to determine the cut-off point for PEV that predicted treatment response. The analysis included: Selection of 'Response' as the dependent variable and 'Edema_Volume' as the independent variable; application of the Classification and Regression Trees (C&RT) method for its interpretability and ability to manage non-linear relationships; setting the maximum tree depth to 1 to establish a single cut-off point, and using the Gini impurity measure for splitting; validation through a 10-fold cross-validation approach; and examination of the resulting decision tree structure and classification rules. Comparisons between patient groups classified by PEV cut-off points were conducted using the Mann-Whitney U-test for continuous variables and the χ2 test for categorical variables. Based on expert input [31], a multivariable logistic regression model was created to evaluate the impact of PEV on treatment response, adjusting for gender, age, gross tumor volume, SRT dose (Gy) per fraction, and type of systemic therapy (none, immune checkpoint inhibitors (ICI), targeted therapy (TT), or a combination of ICI and TT). Adjusted Odds Ratios (aORs) for PR or CR and their 95% confidence intervals were calculated. All statistical analyses were performed using IBM SPSS Statistics (version 20.0), with significance defined as a two-sided p-value < 0.05.

Patients’ Characteristics

Seventy-two patients with confirmed diagnoses of MBM met the inclusion criteria and were eligible for analysis. The mean age was 68.83 years (IQR: 61.0–77.0), with 59.3% being male. At diagnosis, 20 patients had a Karnofsky Performance Status (KPS) < 80, and 72.8% (n = 52) had multiple MBM. A total of 101 MBMs were treated with SRT (Table 1). The mean total prescription dose was 24.57 Gy (range: 14-32.5 Gy), with a median of 27 Gy; 9 Gy per fraction was the most common dose. Seventy-three MBMs (72.3%) received the total dose in 3 fractions, 10 (9.9%) in a single fraction, and 18 (17.8%) in 5 fractions. SRT was performed concurrently with immune checkpoint inhibitors (ICI) in 56.4% (n = 56) of treated MBM, with targeted therapy (TT) in 11.9% (n = 12), and without concurrent systemic treatment in 31.7% (n = 32).

Table 1

Characteristics of Melanoma Brain Metastasis (N = 101) by Perilesional Edema Volume (cm3)
	Total	Perilesion Edema < 0,5 cm ³	Perilesion Edema > 0,5 cm ³	p-value
Patients, N	72
MBM, N	101	45	56
Age, Median (IQR)	69,0 (61,0–77,0)	69,0 (63,0–78,0)	69,5 (60,0–76,0)	0,914
Gender, N(%) Female Male	41 (40,6) 60 (59,4)	26 (58,1) 19 (41,9)	15 (26,3) 41 (73,7)	0,008
BRAF mutational status, N (%) Wild-type Mutated Unknown	46 (45,5) 51 (50,5) 4 (4)	17 (16,8) 25 (24,8) 1 (1)	29 (28,7) 26 (25,7) 3 (3)	0,086
Total RT dose (Gy), Median (IQR)	27,0 (24,0–27,0)	27,0 (24,0–30,0)	27,0 (21,0–30,0)	0,965
N° of RT fractions, N (%) 1 3 5	10 (9,9) 73 (72,3) 18 (17,8)	4 (3,9) 32 (31,7) 2 (1,9)	6 (5,9) 41 (40,6) 16 (15,9)	0,250
Systemic therapy, N (%) None Immunotherapy (IT) Target therapy ± IT	32 (31,7) 57 (56,4) 12 (11,9)	20 (19,8) 19 (18,8) 5 (5)	12 (11,9) 38 (37,6) 7 (6,9)	0,067
Gross tumor volume (cm ³), Median (IQR)	0,7 (0,2–2,3)	0,3 (0,1 − 0,4)	2,0 (0,9 − 3,5)	< 0,001
Treatment Response, N (%) CR PR SD PD	22 (21,8) 40 (39,6) 21 (20,8) 18 (17,8)	20 (19,8) 23 (22,8) 1 (1) 1 (1)	2 (2) 17 (16,8) 20 (19,8) 17 (16,8)	< 0,001
MBM: Melanoma Brain Metastasis; RT: Radiotherapy; CR: Complete Response; PR: Partial Response; SD: Stable Disease; PD: Progression Disease

Treatment Outcomes

Post-SRT, complete response (CR) was observed in 21.8% (n = 22) of treated MBMs, partial response (PR) in 39.6% (n = 40), yielding an intracranial objective response rate (iORR) of 61.4%. Treated lesions had a mean gross tumor (GT) volume of 1.41 cc (median: 0.7 cc) and a mean perilesional edema (PEV) volume of 3.6 cc (median: 1.9 cc). PEV correlated significantly with KPS (p < 0.001), BRAF mutation status (p = 0.022), GT volume (p < 0.001), and treatment response (p < 0.001). iORR was significantly related to PEV (p < 0.001), but not to GT volume (p = 0.093).

Decision Tree Analysis

A decision tree analysis identified a PEV cutoff of 0.5 cc releted to iORR. Patients with PEV ≤ 0.5 cc were more likely to respond to treatment compared to those with volumes > 0.5 cc (sensitivity: 86.7%, specificity: 74.4%, AUC = 0.82 [0.67–0.95]). iORR (CR + PR) was achieved in 95.5% of patients with PE volume ≤ 0.5 cc, compared to 33.9% with PEV > 0.5 cc (p < 0.001).

Patients with higher PEV > 0.5 cc also had larger GT volumes (2.0 cc vs. 0.6 cc, p < 0.001) and a higher GT volumes (84.2% vs. 16.1%, p < 0.001).

Multivariable Analysis

Multivariable analysis (Table 2) showed that a PE volume > 0.5 cc was independently associated with a reduced probability of achieving PR or CR (aOR: 0.06, 95% CI: 0.01–0.51). Higher RT doses per fraction were associated with a higher probability of achieving PR or CR (aOR: 1.40, 95% CI: 1.04–1.88). Gender, age, GT volume, and systemic therapy were not significantly associated with outcomes.

Table 2

Logistic regression model for Objective Response (PR or CR) (N = 101).
Odds Ratio		95% CI	p- value
Perilesional Edema Volume (cm3)
< 0.5 cm3	Ref.
≥ 0.5 cm3	0.06	0.01– 0.51	0.010
Gender
Female	Ref.
Male	2.74	0.62–12.0 3	0.182
Age	0.99	0.95– 1.04	0.756
Gross Tumour Volume (cm3)
< 0.5 cm3	Ref.
≥ 0.5 cm3	0.85	0.08– 8.82	0.895
RT dose (Gy) per fraction	1.40	1.04– 1.88	0.026
Systemic therapy
None	Ref.
Immunotherapy only	1.02	0.21– 4.89	0.976
Targeted therapy and/or immunotherapy	1.93	0.16–23.2 5	0.605
PR: Partial Response; CR: Complete Response; RT: Radiotherapy.

Survival Outcomes

The median overall survival (OS) for the entire cohort was 9.4 months. The median local intracranial progression-free survival (L-iPFS) was 24.7 months, with a 6-month local control rate of 81.0%. Patients with PE volume > 0.5 cc had a higher mortality rate compared to those with PE volume ≤ 0.5 cc (76.3% vs. 48.4%, p = 0.016). Patients with PE volume ≤ 0.5 cc had 90% disease control at 6 months and a median L-iPFS not reached, compared to those with PE volume > 0.5 cc (p = 0.031). Multivariable analysis (Cox regression) showed that L-iPFS was related to PE volume (HR: 1.8, 95% CI: 1.2–2.2, p = 0.001). OS was associated with PE volume (p = 0.042, HR: 1.4, 95% CI: 1.01–1.82) and the presence of extracranial disease (p = 0.005, HR: 4.3, 95% CI: 2.2–5.2).

Herein, we show the relevance of PE as a potential biomarker of intracranial response to SRT in patients with MBM.

PE is a significant cause of morbidity and mortality in patients with CNS malignancy, including metastases [32]. PE is associated with the Blood–Brain Barrier disruption, plasma leakage, and inefficient oxygen delivery ultimately resulting in a hypoxic tumor microenvironment [28]. Hypoxia-mediated radioresistance is induced by multiple mechanisms related to cell survival, acceleration of tumor proliferation and repopulation ability [25]. Hypoxia inducible factors (HIF) play a crucial role in the regulation of genes for cell survival in hypoxic environment, including those involved in glycolysis, angiogenesis, and in the expression of growth factors that promote tumor growth [33]. The tumor hypoxic microenvironment also leads to genomic instability and reduces DNA repair leading to tumor disease progression and radioresistance [34, 35]. Furthermore, tumor hypoxia is strongly associated with the cancer stem cells (CSCs) phenotype, characterized by reduced accumulation of radiation-induced DNA damage, increased capacity of DNA repair pathways in response to damage, and activation of antiapoptotic signaling pathways [35]. In addition, CSCs also express lower levels of reactive oxygen species (ROS) and tend to overexpress ROS scavengers that limit the extent of ROS-dependent damage induced by IR [36]. Consequently, lesions with more extensive PE could acquire greater resistance to the effects of RT.

Our results, indicating that MBM with the best CR and PR response have significantly lower volumes than patients with SD, and above all PD, strongly suggest the negative predictive role of PE. Interestingly, lesions with no PE (< 0.5 cc) are those with iORR and which maintain a long-lasting response (L-iPFS) compared to lesions with PE. In fact, the absence of PE seems to have a high specificity and sensitivity in predictive terms, resulting the only multivariate parameter significant for L-iPFS. Furthermore, the significant association between PE volume and OS suggests an important role of intracranial tumor reduction for survival, which however remains mostly related to the presence of extracranial disease (HR 4.3). Measurement of PE represents a potential simple and accessible tool to predict intracranial response following RT. Furthermore, it could be easily integrated into clinical practice for the identification of high-risk patients suitable for intensified treatment strategies and support the rationale for combining anti-angiogenic agents with RT to reduce peritumoral vasogenic edema and improve outcome.

In clinical and preclinical models, agents that target the VEGF pathway have the potential to normalize tumor vasculature, reduce permeability and edema, increase tissue oxygen levels, enhance the efficacy of RT, chemotherapy or immunotherapy [37, 38]. Normalization of the vasculature facilitates the transport of exogenous agents, enhances DNA damage and cell death through the increase of reactive oxygen species following radiation, activates the immune response to the tumor, promoting maturation and activation of dendritic cells and T-cell infiltration, reduces the use of steroids and facilitates ICIs [39]. In the survival analysis data system, the important prognostic role of PE for survival outcome was confirmed, PE remains significantly associated with iPFS when adjusted for other clinical and pathological variables, in particular, PE remains independently associated with a negative outcome. Thus, it would be useful to explore the addition of PE to establish prognostic assessment models to improve prognostic accuracy for patients with melanoma-related ME. The limitations of this study are the retrospective nature and the small number of patients involved. Furthermore, the heterogeneity of the analyzed population, which includes a substantial number of oncogene-dependent variety of therapies, involving target therapy, make the results difficult to generalize.

Although limited by the small number of patients and the retrospective nature, our study seems to be the first to systematically evaluate the role of PE in response to stereotaxic treatment in melanoma brain metastases, suggesting that PE is a strong predictor of response to RT treatment in melanoma ME. The identification of PE can help to better tailor therapeutic strategies in this context and to identify candidates for treatment intensification strategies, to increase the intracranial response. PE could be a good tool to predict patient survival. It would be useful to investigate the addition of PE to establish prognostic assessment models, further studies are needed to validate these findings. The potential efficacy of anti-angiogenic factors in high-risk patients needs further investigation through phase III controlled trials.

Conflict of Interest

The authors declare that they have no competing interests

Authors contribution statement

FM, GM, PT^:Conceptualization, Methodology. MY: Data curation, PT, FM: Writing Original draft preparation. GM, VB, SA: Visualization, Investigation. GM, GLG, MAM: Supervision.MT, EC, PP: Validation. GR, AC: Reviewing and Editing,

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Predictive Value of Perilesional Edema Volume in Melanoma Brain Metastasis Response to Stereotactic Radiosurgery

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Materials and Methods

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Introduction

Methods

Patients selection

Imaging and Measurements

SRT and Systemic Treatments

Outcome Measures

Statistical Analysis

Results

Patients’ Characteristics

Treatment Outcomes

Decision Tree Analysis

Multivariable Analysis

Survival Outcomes

Discussion

Conclusions

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References

Additional Declarations

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Journal Publication

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