Is there some predictive factors for isolated brain PROgression in patients with CErebral metastatic MElanoma after stereotactic brain radiotherapy ? PROCEME

doi:10.21203/rs.3.rs-4149245/v1

Melanoma is a skin cancer with an excellent prognosis if diagnosed at an early stage. However, it has a high potential for brain metastasis, making the prognosis considerably poorer. In current practice, we observe discordant responses and progression at cerebral and extra-cerebral levels. The aim of this study was to identify predictive factors of isolated brain progression after treatment with stereotactic brain radiotherapy, with or without systemic treatment. Between January 2014 and December 2020, 121 patients treated by stereotactic brain radiotherapy (Cyber Knife) were included. Radiotherapy was associated to systemic treatment in the major of cases (Targeted Therapies, Immunotherapy, or Chemotherapy). In our cohort, 83 patients showed progression after stereotactic brain radiotherapy: 38 in brain only, 45 in brain and at distance. The study showed a double increase in the risk of isolated brain progression in BRAF V600 mutated patients compared with BRAF V600 WT patients. BRAF V600 mutated melanomas seems more at risk of isolated brain escape in our cohort, we therefore need to develop new local therapies for these patients in the future, and clarify the mechanisms of intrinsic and extrinsic resistance.

Biological sciences/Cancer/Skin cancer/Melanoma

Biological sciences/Cancer/Cancer therapy/Cancer immunotherapy

Biological sciences/Cancer/Cancer therapy/Radiotherapy

Biological sciences/Cancer/Cancer therapy/Targeted therapies

Brain metastasis

Metastatic melanoma

BRAF

Immunotherapy

Stereotactic radiotherapy

Isolated brain progression

Melanoma is the most aggressive skin cancer, with around 50,000 deaths worldwide every year [1] , with a high predilection for the development of central nervous system (CNS) metastases [2]. In fact, half to two-thirds of patients develop brain metastases during the course of the disease. Around 25% of patients present brain metastases at the initial diagnosis of metastatic disease [3] and more than two-third of deaths are related to symptomatic brain metastases and neurological deficiency [4,5]. Various independent risk factors for the development of brain metastases have been identified: being male, over 60 years of age, having a mucosal melanoma, or a cutaneous melanoma located on the trunk, head and neck, ulcerated, acral or nodular subtype; a high Breslow index; the invasion of more than 3 lymph node sites or the presence of 2 or more visceral metastatic sites; as well as the presence of a BRAF or NRAS mutation [6–11].

Brain involvement is a major step for the prognosis of affected patients. Development of systemic treatments, with the advent of immunotherapies (IT) and targeted therapies (TT), and in local treatments, with improved neurosurgery and radiotherapy technologies, have significantly altered the prognosis of these patients, with many now enjoying prolonged overall survival.

Cohorts of patients with metastatic melanoma are broadly heterogeneous, with different prognoses depending on the number of affected organs, the size of metastases or total metastatic volume, their reported symptomatology, particularly neurological, and mutation status [4].

In current practice, some patients present a controlled disease, even in complete response (CR) at the extra-cerebral level, after local and systemic treatments, but isolated escape at the cerebral level. Explanations for these dissociated responses and escapes are unknown, but are based on a number of theories, including the role of the blood-brain barrier, the presence of tumor microenvironment and the appearance of secondary resistance to treatment.

The aim of this study is to identify predictive factors of isolated brain progression in metastatic melanoma (MM) with controlled disease at the extra-cerebral level, in order to improve management and discuss whether treatment sequences are more beneficial.

We performed an observational, single-center, retrospective study.

Patients:

We included brain metastatic MM who had been treated with stereotactic radiotherapy in Caen between January 2014 and December 2020. Data have been gathered from 2 centers: Caen University Hospital (for melanoma characteristics and treatment) and Cancer Center (for stereotaxic radiotherapy data). The study was approved by the institutional review board of Comprehensive Cancer Centre and registered with the French Health Data Hub under reference F20220414103808. It was conducted in compliance with the French Research Standard MR-004. Non-opposition was sought in the medical records of each of the patients included.

Main and secondary objectives:

The main objective is to identify predictive factors of isolated cerebral escape after treatment by stereotactic brain radiotherapy (SRT), with Cyber Knife technical plateform, rather than cerebral and extra-cerebral progression. The primary endpoint is the evidence of brain progression after treatment with stereotactic radiotherapy, as assessed on cerebral magnetic resonance imaging (MRI) or cerebral scan (CT-TDM).

Secondary objectives included overall survival (OS), in function of number of brain metastasis and largest brain metastasis at the time of SRT.

Statistical analysis:

Qualitative variables are described using numbers and percentages, quantitative variables using the mean (+/- standard deviation), or the median and range if the normality assumption is not verified. The comparison of variables between patients with isolated cerebral progression and those with cerebral and extra-cerebral progression, and between those who had 1 sequence of radiotherapy versus those who had several, will be carried out using a Student's t test (or non-parametric Wilcoxon Mann Withney test) for quantitative variables, and a Chi2 test (or Fisher's exact test) for qualitative variables. The statistical significance threshold is set at 5% for each statistical test and confidence interval.

An univariable and then multivariable logistic regression model was built to identify predictive factors associated with isolated cerebral progression, with Odds Ratios calculations accompanied by a 95% confidence interval. Odds ratios should be interpreted as follows: an OR > 1 indicates an increased risk of isolated cerebral progression; an OR < 1 indicates an increased risk of associated cerebral and extra-cerebral progression.

Progression-free survival and overall survival were estimated using the Kaplan-Meier method. The log-rank test was used to compare survival times between different groups of patients, and a Cox model was constructed to estimate hazard ratios with 95% confidence intervals. As for retrospective studies, note that some data are missing but have not been imputed in analyses.

Systemic therapies:

Patients included received different treatment plans: simple follow-up after excision of the primary melanoma, adjuvant Interferon, targeted therapy with BRAF inhibitor (BRAFi) alone or anti BRAF + MEK inhibitor (MEKi), immunotherapy with anti PD1 or anti CTLA-4 in monotherapy, or combined. As the recruitment period was spread out from 2014 to 2020, current recommendations concerning the performance of the sentinel lymph node technique, and the modalities of adjuvant treatment with anti PD-1 did not exist.

Stereotactic brain radiotherapy:

The technical plateform used was a cyber knife. Doses and fractions of stereotactic cerebral radiotherapy depend on the size of the lesions. Different schemes are used, with a delivered dose of 20 Gy in one fraction, 24 Gy in 3 fractions of 8 Gy, 30 Gy in 3 fractions of 10 Gy or 36 Gy in 6 fractions of 6 Gy, depending on the location and size of the lesions. Stereotactic radiosurgery (SRS) was used when radiotherapy was performed in a single fraction (e.g., 20 Gy in a single fraction).

Assessment:

Cerebral imaging by CT or RMI and body imaging by CT TDM or PET-TDM were performed every 3 months according to center practices. Tumor response was assessed with Response Assessment in Neuro-Oncology Brain Metastases (RANO BM) [12]. Extra-cerebral tumor response was assessed according to the Response Evaluation Criteria in Solid Tumors (RECIST 1.1) [13]

Patients and treatments

From January 2014 to December 2020, 121 patients were treated by SRT and 84 patients progressed in cerebral, among which 38 (46%) with isolated cerebral progression (group A) and 45 (54%) with cerebral and extra-cerebral progression (group B) (see figure 1). Patient’s characteristics are given in Table 1. Median age at first cerebral radiotherapy was 68 years [18-96] with 61% of men and 89% of WHO 0-1, without difference between groups A and B. BRAFV600 mutation was observed in 43% of patients of group A and 63% in group B (p=0.11).

At the time of initial disease diagnosis, the majority of patients had localized, node-negative melanomas, 66% stages I and II in group A, 63% in group B (according to the AJCC 8th classification 2017 edition), as detailed in table 1.

Apart from initial surgical treatment (surgery of the primary tumor with or without lymph node dissection), 13% of few patients received additional systemic adjuvant therapy after initial diagnosis, without difference between groups.

Prior to SRT indicated as local treatment for metastatic disease of the brain, 50% received systemic therapies to treat their isolated extra-cerebral metastatic disease, including chemotherapy, immunotherapy and targeted therapy, without difference between groups (Table 3). 34% of group A patients and 29% of group B underwent neurosurgery for various reasons (symptomatic disease, histological confirmation).

During brain stereotactic radiotherapy, 80% of patients received associated systemic treatment, mainly immunotherapy (anti PD-1 or anti CTLA-4; not in combination). There was no change in systemic treatment during stereotactic radiotherapy. In addition, 13 patients in each group underwent surgery for one or more brain metastases.

Clinical characteristics of patients are described in Table 1 and treatments in Table 2.

Table 1: Patient’s characteristic

	Group A: Isolated cerebral progression (n=38)		Group B: Cerebral and extracerebral progression (n=45)		Total	p value
Patients and characteristics :	Group A: Isolated cerebral progression (n=38)		Group B: Cerebral and extracerebral progression (n=45)
Age at RTc						0.83
< 75 years (N ; %)	27	(71%)	34	(76%)	61
>or= 75 years (N ; %)	11	(29%)	11	(24%)	22
Gender						0.7
male (N ; %)	22	(58%)	29	(64%)	51
women (N ; %)	16	(42%)	16	(36%)	32
WHO at the time of RTc						0.4
0-1	32	(94%)	35	(85%)	67
2-3	2	(6%)	6	(15%)	8
Missing	4		4		8
Localization of primary melanoma						0.58
Upper / lower limbs	13	(41%)	15	(39%)	28
Head and neck	5	(16%)	7	(18%)	12
trunk	14	(44%)	14	(37%)	28
mucous	0		0		0
Lentiginous Acro	0	(0%)	2	(5%)	2
Missing	6		7		7
AJCC2017 stage at initial diagnosis
IA - IB	7	(21%)	5	(13%)	12	0.84
IIA-IIB-IIC	15	(45%)	19	(50%)	34
IIIIA - IIIIB - IIIC - IIID	4	(12%)	5	(13%)	9
IV	7	(21%)	9	(24%)	16
Missing	5		7
Brelow to diagnosis						0,86
median [min-max]	2.85	[0.98-25]	3.36	[0.9-11]
Mutation status
BRAFV600 mutated	24	(63%)	18	(43%)	42	0.11
Wild BRAFV600	14	(37%)	24	(57%)	38
Missing	0		3		3
Mutated NRAS	24	(86%)	28	(82%)	52	0.99
Wild NRAS	4	(14%)	6	(18%)	10
Missing	10		11		21
Cerebral involvement at diagnosis of metastatic disease						0.99
yes	17	(45%)	19	(42%)	36
no	21	(55%)	26	(58%)	47
Number of brain metastases at diagnosis of brain metastatic disease						0.4
1	6	(35%)	11	(58%)	17
2-3	7	(41%)	5	(26%)	12
> 3	4	(24%)	3	(16%)	7
Number of metastatic sites at the time of RTc						0.43
<3	30	(79%)	31	(69%)	61
>=3	8	(21%)	14	(31%)	22
Number of brain metastases at time of cRT						0.44
0 (adjuvant RTc)	2	(5%)	5	(11%)	7
1	11	(29%)	16	(36%)	27
2-3	13	(34%)	9	(20%)	22
> 3	12	(32%)	15	(33%)	27
Maximum size of brain metastasis at time of RT						0.07
< 1cm	13	(42%)	16	(46%)	29
1-2cm	13	(42%)	9	(26%)	22
2-3cm	4	(13%)	2	(6%)	6
> 3cm	1	(3%)	8	(23%)	9
Missing	7		10		17
LDH at the time of RTc						0.09
< 1,50 N	15	(94%)	8	(62%)	23
>= 1,5 N	1	(6%)	5	(38%)	6
Missing (measured out of time)	22		32		54

Table 2: Details of treatments.

	Group A: Isolated cerebral progression (n =38)		Group B: Cerebral and extracerebral progression (n=45)		Total	P

Systemic adjuvant therapy						0.34
yes	7	(18%)	4	(9%)	11
no	31	(82%)	41	(91%)	72
Systemic treatment in metastatic disease prior to SRT						0.1
yes	23	(61%)	18	(40%)	41
no	15	(39%)	27	(60%)	42
Systemic treatment of metastatic disease prior to SRT (non-exclusive)
IT	10	(26%)	12	(27%)	22	1
TT	13	(34%)	9	(20%)	22	0.23
Chemotherapy	4	(11%)	0	(0%)	4	0.08
Systemic treatment of metastatic disease during SRT						0.88
yes	31	(82%)	35	(78%)	66
no	7	(18%)	10	(22%)	17
Systemic treatment of metastatic disease during SRT (exclusive)						0.35
IT	16	(42%)	25	(56%)	41
TT	12	(32%)	7	(15%)	19
Chemotherapy	3	(8%)	3	(7%)	6
No	7	(18%)	10	(22%)	17
Neurosurgery						0.78
yes	13	(34%)	13	(29%)	26
no	25	(66%)	32	(71%)	57

SRT: Stereotactic Radiotherapy; IT : immunotherapy ; TT : Targeted Therapy

Primary outcome:

Results of logistic regression models to predict isolated brain progression are presented in Table 3.

In univariate analysis, BRAF V600-mutation was associated with a two-fold increased incidence of isolated brain progression, although not significant (OR = 2.29; CI95 [0.94; 5.72], p=0.071). A trend was also observed for LDH, with values ≥ 330 associated with lower incidence of isolated brain progression (OR = 0.11 [0; 0.81], p=0.058). Due to large number of missing data, LDH was not included in multivariable analysis. After adjustment on age, gender, number and size of the larger metastasis, treatment during radiotherapy and number of reached organs, BRAF status was no statistically more associated with higher incidence of isolated brain progression (OR=2.28 [0.51; 11.2], p=0.29).

Post-hoc analysis showed that BRAF V600 WT patients treated with IT had a 4-fold greater risk of multi-site progression (OR: 0.233 IC95% [0.58; 0.847]) than BRAFV600 mutated patients treated with BRAFi + MEKi targeted therapies. There was no difference between BRAF V600 mutated treated with IT or with TC in our cohort.

Table 3: Univariate and multivariable logistic regression analysis predicting isolated brain progression.

	Univariate analysis			Multivariate analysis
	Odds ratio	95% CI	p-value	Odds ratio	95% Confidence Interval	p-value
Age >=75	1.26	[0.47-3.38]	0.64	6.01	[1.35-36.2]	0.029
Gender Male	0.76	[0.31-1.84]	0.54	0.59	[0.17-2.01]	0.4
Reached during RT
<3 organs	1			1
>=3 organs	0.47	[0.17-1.19]	0.12	0.26	[0.05-1.06]	0.06
Size of largest metastasis (18 missing values)
< 1 cm	1			1
1-2 cm	1.78	[0.58-5.59]	0.31	2,17	[0.57-9.06]	0.26
2-3 cm	2.46	[0.41-19.9]	0.34	3,2	[0.41-35.7]	0.29
> 3 cm	0.15	[0-0.99]	0.09	0,09	[0-0.86]	0.06
No. of brain metastases
0	1			NA
1	1.07	[0.24-5.14]	0.93	1
2-3	1.5	[0.32-7.66]	0.61	1.43	[0.31-6.78]	0.65
>3	1.5	[0.35-6.91]	0.58	1.65	[0.34-8.79]	0.54
Ulceration
No	1
Not specified	0.9	[0.29-2.79]	0.85
Yes	1.13	[0.38-3.38]	0.83
Regression
No	1
Not specified	0.63	[0.26-1.53]	0.31
Yes	0.95	[0.04-25.19]	0.97
BRAF
No	1			1
Yes	2.29	[0.94-5.72]	0.07	2.28	[0.51-11.2]	0.29
NRAS
No	1
Yes	0.78	[0.18-3.05]	0.72
WHO
0-1	1
2-3	0.36	[0.05-1.71]	0.24
AJCC
I-II	1
III-IV	0.86	[0.32-2.28]	0.76
Treatment during RT
No	1			1
IT	0.83	[0.29-2.37]	0.73	0.67	[0.14-3.27]	0.62
TC	2.23	[0.65-8.04]	0.21	1.18	[0.13-11.3]	0.88
Location
MS/MI	1
Head and neck	0.82	[0.2-1.82]	0.78
Trunk	1.15	[0.40-3.33]	0.79
Mucous/ALK	0	NA	1
SP	2.31	[0.50-1.27]	0.3
LDH (55 missing values)
<330	1
>=330	0.11	[0-0.81]	0.05

Secondary outcomes:

Overall survival (OS) (N=81 assessable patients)

After a median follow up of 10.1 months [range 0.4; 97.7], 63 (77.8%) death were observed. Median overall survival was 10.7 months [95% CI: 8.4-15.1], with lower risk of death for patients with isolated brain progression (OR=0.58 [0.35-0.97]) see figure 2, log-rank p=0.034. OS also differs according to the number of brain metastasis and the size of the largest metastasis, with worse survival when patients had >3 brain metastasis (p<0.001) or when the largest metastasis is >3cm (p=0.0014).

Overall survival is significantly different according to cerebral and/or extra cerebral status (log-rank p=0.0035, Figure 3). Especially, for patients who progressed, a slight better prognosis was observed for patients with isolated cerebral progression as compared to those with both cerebral and extra-cerebral progression (HR=0.61 [0.37-1.02], p=0.059).

In our study, a trend was observed toward an increased risk of isolated brain relapse in BRAF V600 mutated patients in univariate analysis, none of the tested factor was identified to be an independent associated factor or isolated brain relapse in multivariable analysis.

We report a median OS time from diagnosis of brain metastatic disease of 14.1 months, comparable with Gaudy-Marqueste [14] who reported an OS of 11 months. The population in their study was comparable to our own, since it consisted of patients treated with stereotactic brain radiotherapy, combined with systemic treatment by immunotherapy or targeted therapy. Tetu et al [15] found a median overall survival of 16.8 months, and F.Martins et al. [16] 12 months. Lannier et al. found a median overall survival of 15.9% in patients treated with immunotherapy and stereotactic brain radiotherapy [17]

After an initial metastatic event in the brain treated with stereotactic radiotherapy, unsurprisingly, overall survival was better for non-metastatic patients, both cerebral and extra-cerebral.

Nevertheless, OS seems to be better for cerebral vs. cerebral and extra-cerebral progression, itself having a better OS than isolated extra-cerebral progression as shown on Fig3. This data is surprising, and suggests that after a first episode of brain metastasis, the prognosis would be more influenced by progression at non-cerebral sites. It is no longer linked to brain metastases but to extra cerebral disease control. This observation is interesting because comparable to the work of Milsh et al [18]. It is therefore necessary to find an effective systemic therapy to control the extra-cerebral stage, in order to highlight a clinical benefit to local brain control due to brain SRT. This could lead to a reconsideration of brain involvement as a specific disease, different from that of other noble organs, in terms of management, reduced response to immunotherapy and involvement in OS.

Patients with brain metastasis have an increasingly long life expectancy when using immunotherapy and few studies confirm this data. In fact, NIBIT-M2, a phase III study recruited patients with BRAF wild-type or mutant melanoma, and active, untreated, asymptomatic brain metastases randomized (1:1:1) to fotemustine (F), ipilimumab plus fotemustine (I-F), or ipilimumab plus nivolumab (I-N). Median OS was respectively 8.5 months [4.8–12.2] 8.2 months [2.2–14.3] and 29.2 months [0–65.1] in the F arm, I-F arm and I-N arm suggesting superiority of immunotherapy combination.

Four-year survival rate was significantly higher for I+N (41%) vs. F (10.9%) vs I+F (10.3 [19]. With a hindsight of several years, this study also suggests that the greatest impact on OS is borne by extra-cerebral rather than brain metastatic progression after IT-treated cerebral metastatic progression, as we did in our study.

To date, studies point to a better long-term efficacy of immunotherapy treatment in responder patients, and to investigate the best sequential treatment in BRAF V600 mutated melanoma, SECOMBIT study was carried out in patients with BRAF V600 metastatic melanoma with inactive brain metastases.JAK mutation was associated to a better overall survival [20]. Another area under study is the combination of targeted therapy and immunotherapy as TRICOTEL, a phase II trial which combines BRAFi + MEKi + anti PD-L1 (atezolizumab). Preliminary results show an intracranial progression-free survival of 7.2 months for symptomatic patients. Objective intracranial response was 42% for BRAF V600 mutated patients, and 27% for BRAF V600 wild-type patients, but 50 to 60% of patients in both cohorts experienced grade 3 side effects [21] . At ESMO 2023, Elizabeth Burton presented a phase II study challenging the safety and efficacy of atezolizumab, bevacizumab, and cobimetinib in 20 patients with treatment-refractory melanoma brain metastases (Abstract 1085O). This toxic combination in refractory patients highlights the need for therapies adapted to the complexity of the brain tumor environment.

Various trials are still in progress: SWOG S2000 [22] comparing the efficacy of encorafenib (BRAFi) + binimetinib (MEKi) + nivolumab (anti PD-1) with ipilimumab (anti CTLA-4) + nivolumab in patients with BRAF V600 mutated, brain metastatic melanoma that may be symptomatic.These different studies show that the survival of patients with brain metastasis is still challenging, with long term responders, and that it is essential to compare, on the one hand, drugs associations (targeted therapy, immunotherapy), and on the other hand, their sequence of use and the combination with local treatment to improve OS.

When metastatic melanoma is controlled extra cerebrally, we assume that secondary resistance mechanisms specific to the brain stage are responsible, as discussed above: cerebrospinal fluid proteins and efflux proteins (extrinsic resistance), appearance of secondary mutations (intrinsic resistance). It is needed to demonstrate the appearance of secondary mutations during the course of the disease. Ideally, biopsies should be taken from the organ undergoing progression, in this case the brain, and sequencing analyses performed using Next Generation Sequencing (NGS) [23].

Our study has a number of limitations, such as its retrospective monocentric nature and small sample size, which is a real limitation of our study. The symptomatic or asymptomatic nature of brain metastases, with or without corticosteroid use, was not collected, due to a large number of missing data on this subject. We also have to be cautious with regard to local brain progression since local escapes were judged on imaging, without biopsy, which may be confused with radionecrosis.

To the best of our knowledge, this is the first study to look for predictive factors for isolated cerebral progression after a first brain metastasis, which is a daily concern for oncologists and onco-dermatologists and impacts on the patient's care plan and life expectancy. It has recently been agreed that an asymptomatic cerebral metastatic patient has the same prognosis as a non-metastatic cerebral patient. Our study allows us to go further in the prognostic categorization of cerebral metastatic patients, since we argue that after a first metastatic episode in the cerebral stage, the prognosis and OS goes to the extra-cerebral evolution. Future prospective randomized studies should confirm our assertion.

Currently, the management strategy depends on a number of variables (general condition, number of brain metastases, neurological symptoms, presence of extra-cerebral disease), but it is essential to combine systemic treatment, preferring single or even double immunotherapy, with local treatment by neurosurgery and/or stereotactic radiotherapy.

Patients with isolated brain progression may not be considered as systemic treatment failures, but rather as local failures, with the need to develop new therapies adapted to the brain tumor microenvironment, responsible for secondary resistance to treatment, notably through the appearance of mutations, and to the presence of the blood-brain barrier. This complexity of the brain tumor environment is underlined by the fact that, after the occurrence of a first cerebral metastatic event, OS is more impacted by the subsequent occurrence of extra-cerebral than cerebral metastases.

Data availability

The datasets used and/or analysed during the current study are available from the corresponding author on reasonable request.

Ferlay J, Soerjomataram I, Dikshit R, Eser S, Mathers C, Rebelo M, et al. Cancer incidence and mortality worldwide: Sources, methods and major patterns in GLOBOCAN 2012: Globocan 2012. Int J Cancer 2015;136:E359–86. https://doi.org/10.1002/ijc.29210.
Eichler AF, Loeffler JS. Multidisciplinary management of brain metastases. The Oncologist 2007;12:884–98. https://doi.org/10.1634/theoncologist.12-7-884.
Long GV, Atkinson V, Lo S, Sandhu S, Guminski AD, Brown MP, et al. Combination nivolumab and ipilimumab or nivolumab alone in melanoma brain metastases: a multicentre randomised phase 2 study. Lancet Oncol 2018;19:672–81. https://doi.org/10.1016/S1470-2045(18)30139-6.
Gutzmer R, Vordermark D, Hassel JC, Krex D, Wendl C, Schadendorf D, et al. Melanoma brain metastases - Interdisciplinary management recommendations 2020. Cancer Treat Rev 2020;89:102083. https://doi.org/10.1016/j.ctrv.2020.102083.
Chang EL, Selek U, Hassenbusch SJI, Maor MH, Allen PK, Mahajan A, et al. Outcome Variation among “Radioresistant” Brain Metastases Treated with Stereotactic Radiosurgery. Neurosurgery 2005;56:936. https://doi.org/10.1227/01.NEU.0000158324.20757.AC.
Rishi A, Yu H-HM. Current Treatment of Melanoma Brain Metastasis. Curr Treat Options Oncol 2020;21:45. https://doi.org/10.1007/s11864-020-00733-z.
Peuvrel L, Saint-Jean M, Quéreux G, Brocard A, Khammari A, Knol AC, et al. Incidence and characteristics of melanoma brain metastases developing during treatment with vemurafenib. J Neurooncol 2014;120:147–54. https://doi.org/10.1007/s11060-014-1533-z.
Gumusay O, Coskun U, Akman T, Ekinci AS, Kocar M, Erceleb ÖB, et al. Predictive factors for the development of brain metastases in patients with malignant melanoma: a study by the Anatolian society of medical oncology. J Cancer Res Clin Oncol 2014;140:151–7. https://doi.org/10.1007/s00432-013-1553-7.
Bedikian AY, Wei C, Detry M, Kim KB, Papadopoulos NE, Hwu W-J, et al. Predictive Factors for the Development of Brain Metastasis in Advanced Unresectable Metastatic Melanoma. Am J Clin Oncol 2011;34:603. https://doi.org/10.1097/COC.0b013e3181f9456a.
Sampson JH, Carter JH, Friedman AH, Seigler HF. Demographics, prognosis, and therapy in 702 patients with brain metastases from malignant melanoma. J Neurosurg 1998;88:11–20. https://doi.org/10.3171/jns.1998.88.1.0011.
Breslow A. Thickness, cross-sectional areas and depth of invasion in the prognosis of cutaneous melanoma. Ann Surg 1970;172:902–8.
Lin NU, Lee EQ, Aoyama H, Barani IJ, Barboriak DP, Baumert BG, et al. Response assessment criteria for brain metastases: proposal from the RANO group. Lancet Oncol 2015;16:e270-278. https://doi.org/10.1016/S1470-2045(15)70057-4.
Eisenhauer EA, Therasse P, Bogaerts J, Schwartz LH, Sargent D, Ford R, et al. New response evaluation criteria in solid tumours: Revised RECIST guideline (version 1.1). Eur J Cancer 2009;45:228–47. https://doi.org/10.1016/j.ejca.2008.10.026.
Gaudy-Marqueste C, Dussouil AS, Carron R, Troin L, Malissen N, Loundou A, et al. Survival of melanoma patients treated with targeted therapy and immunotherapy after systematic upfront control of brain metastases by radiosurgery. Eur J Cancer 2017;84:44–54. https://doi.org/10.1016/j.ejca.2017.07.017.
Tétu P, Allayous C, Oriano B, Dalle S, Mortier L, Leccia M-T, et al. Impact of radiotherapy administered simultaneously with systemic treatment in patients with melanoma brain metastases within MelBase, a French multicentric prospective cohort. Eur J Cancer Oxf Engl 1990 2019;112:38–46. https://doi.org/10.1016/j.ejca.2019.02.009.
Martins F, Schiappacasse L, Levivier M, Tuleasca C, Cuendet MA, Aedo-Lopez V, et al. The combination of stereotactic radiosurgery with immune checkpoint inhibition or targeted therapy in melanoma patients with brain metastases: a retrospective study. J Neurooncol 2020;146:181–93. https://doi.org/10.1007/s11060-019-03363-0.
Lanier CM, Hughes R, Ahmed T, LeCompte M, Masters AH, Petty WJ, et al. Immunotherapy is associated with improved survival and decreased neurologic death after SRS for brain metastases from lung and melanoma primaries. Neuro-Oncol Pract 2019;6:402–9. https://doi.org/10.1093/nop/npz004.
Milsch L, Gesierich A, Kreft S, Livingstone E, Zimmer L, Goebeler M, et al. Patterns of disease control and survival in patients with melanoma brain metastases undergoing immune-checkpoint blockade. Eur J Cancer 2018;99:58–65. https://doi.org/10.1016/j.ejca.2018.05.012.
Di Giacomo AM, Chiarion-Sileni V, Del Vecchio M, Ferrucci PF, Guida M, Quaglino P, et al. Primary Analysis and 4-Year Follow-Up of the Phase III NIBIT-M2 Trial in Melanoma Patients With Brain Metastases. Clin Cancer Res Off J Am Assoc Cancer Res 2021;27:4737–45. https://doi.org/10.1158/1078-0432.CCR-21-1046.
Ascierto PA, Mandala M, Ferrucci PF, Guidoboni M, Rutkowski P, Ferraresi V, et al. LBA41 Phase II study SECOMBIT (sequential combo immuno and target therapy study): 4-years OS data and preliminary biomarkers evaluation. Ann Oncol 2022;33:S1408–9. https://doi.org/10.1016/j.annonc.2022.08.040.
Atezolizumab, vemurafenib, and cobimetinib in patients with melanoma with CNS metastases (TRICOTEL): a multicentre, open-label, single-arm, phase 2 study - The Lancet Oncology n.d. https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(22)00452-1/fulltext (accessed September 13, 2022).
Moon J, Najjar YG, Kotecha R, Spektor V, Wu M, Sharon E, et al. A randomized phase 2 trial of encorafenib + binimetinib + nivolumab vs ipilimumab + nivolumab in BRAFV600-mutant melanoma brain metastases: SWOG S2000. J Clin Oncol 2023. https://doi.org/10.1200/JCO.2023.41.16_suppl.TPS9603.
Martínez-Fernández P, Pose P, Dolz-Gaitón R, García A, Trigo-Sánchez I, Rodríguez-Zarco E, et al. Comprehensive NGS Panel Validation for the Identification of Actionable Alterations in Adult Solid Tumors. J Pers Med 2021;11:360. https://doi.org/10.3390/jpm11050360.

No competing interests reported.

SupplementarySR.docx

Is there some predictive factors for isolated brain PROgression in patients with CErebral metastatic MElanoma after stereotactic brain radiotherapy ? PROCEME

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