Is there some predictive factors for isolated brain PROgression in patients with CErebral metastatic MElanoma after treatment with stereotactic brain radiotherapy ? a retrospective, single-center study. PROCEME

Is there some predictive factors for isolated brain PROgression in patients with CErebral metastatic MElanoma after treatment with stereotactic brain radiotherapy ? a retrospective, single-center study. 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PROCEME Manuel CROIX, Justine LEQUESNE, Julien GEFFRELOT, Anne DOMPMARTIN, and 1 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-3958515/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Purpose Melanoma is a skin cancer with an excellent prognosis if diagnosed at an early stage. Melanoma has a high potential for brain metastasis, making the prognosis considerably poorer despite the development of local and systemic treatments. In current practice, we observe discordant responses and progression profiles 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. Methods Between January 2014 and December 2020, 121 patients treated with stereotactic brain radiotherapy in context of melanoma stage IV were included. Radiotherapy was associated to systemic treatment in the major of cases (Targeted Therapies, Immunotherapy, or Chemotherapy). Results 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 (OR = 2.29; CI 95 [0.94; 5.72] p-value 0.071), but not confirmed after adjustment on confounding factors. BRAF V600 WT patients treated with immunotherapy have a 4-fold greater risk of multi-site progression, compared to BRAF V600 mutated treated with targeted therapies (OR: 0.233 IC95% [0.58 ;0.847]). Conclusion 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. Brain metastasis Melanoma BRAF Stereotactic radiotherapy Isolated brain progression Figures Figure 1 Figure 2 Figure 3 Introduction Melanoma is the most aggressive skin cancer, with around 50,000 deaths worldwide every year [1]. Melanoma present a high cerebral tropism [2] since half to two-thirds of patients will develop brain metastases during the course of the disease. Around 25% of patients present with brain metastases at the initial diagnosis of metastatic disease [3] and more than two-third of deaths are related to the presence of brain metastases [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]. Cerebral involvement is a major turning point in the prognosis of affected patients. Developments in systemic treatments, with the advent of immunotherapies (IT) and targeted therapies (TT), and in local treatments, with improved neurosurgery and radiotherapy techniques, 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. In current practice, some patients present with controlled disease even 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. Materials and Methods We performed an observational, single-center, retrospective study. Patients: We included patients with brain metastatic melanomas (MM) 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), rather than cerebral and extra-cerebral progression. The primary endpoint is the evidence of local or distant cerebral 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), 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: 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] Results 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). 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% of patients received systemic therapies to treat their isolated extra-cerebral metastatic disease, including chemotherapy, immunotherapy and targeted therapy, without difference between groups A and B . During cerebral 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 . Table 1 Patient’s characteristics Group A: Isolated cerebral progression (n = 38) Group B: Cerebral and extracerebral progression (n = 45) Total p value Patients and characteristics : Age at RTc 0.83 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 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 3cm 1 (3%) 8 (23%) 9 Missing 7 10 17 LDH at the time of RTc 0.09 = 1,5 N 1 (6%) 5 (38%) 6 Missing (measured out of time) 22 32 54 Primary outcome: Results of logistic regression models to predict isolated cerebral progression are presented in Table 2 . In univariate analysis, BRAF V600 -mutation was associated with a two-fold increased incidence of isolated cerebral 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 cerebral 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 cerebral 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 2 Univariate and multivariable logistic regression analysis predicting isolated cerebral 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 0.47 [0.17–1.19] 0.12 0.26 [0.05–1.06] 0.06 Size of largest metastasis (18 missing values) 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 0.11 [0-0.81] 0.05 Secondary outcomes: Overall survival (OS) (N = 81 assessable patients) After median 10.1 months [range 0.4; 97.7] of follow-up, 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 cerebral progression (OR = 0.58 [0.35–0.97]) see Fig. 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 cerebral metastasis (p 3cm (p = 0.0014). Overall survival is significantly different according to cerebral and/or extra cerebral status (log-rank p = 0.0035, Fig. 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). Discussion In our study, a trend was observed toward an increased risk of isolated cerebral relapse in BRAF V600 mutated patients in univariate analysis, none of the tested factor was identified to be an independent associated factor or isolated cerebral 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 cerebral 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 cerebral 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 Fig. 3 . This data is surprising, and suggests that after a first episode of cerebral 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 cerebral control due to cerebral SRT. This could lead to a reconsideration of cerebral 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 [20]. With a hindsight of several years, this study also suggests that the greatest impact on OS is borne by extra-cerebral rather than cerebral 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 [19]. 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 [24] 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 cerebral 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) [22]. 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 cerebral 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. Conclusion 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 cerebral progression may not be considered as systemic treatment failures, but rather as local failures, with the need to develop new therapies adapted to the cerebral 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 cerebral 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. 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CROIX","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA50lEQVRIiWNgGAWjYNCCAhDB2MDwAUixsROlxQCihXEGSAsz8VoYGJh5wCQBxbrtZ49JfDBgkDdvb26Ttvm1TZ6PmYHxw8cc3FrMzuSlSc4wYDCcc+Zgs3Fu323DNmYGZsmZ2/BoOZBjJs1jwJAgIZHY+Di35zYjUAsbMy8+LeffmEn/gWhpOGzZc9uesJYbQFsYYLYw/LidSISWN8aWPQYShjN4DjYb9jbcTm5jZmzG75fzOYY3flTYyEuwtz+T+PHntu389uaDHz7i0QIFEhCKsQ1MNhBUjwT+kKJ4FIyCUTAKRgoAABZ5SaNyCGrPAAAAAElFTkSuQmCC","orcid":"","institution":"CHU Caen","correspondingAuthor":true,"prefix":"","firstName":"Manuel","middleName":"","lastName":"CROIX","suffix":""},{"id":273529679,"identity":"224178e3-2a9b-440c-9f0b-fd545d3fdea4","order_by":1,"name":"Justine LEQUESNE","email":"","orcid":"","institution":"Centre François Baclesse","correspondingAuthor":false,"prefix":"","firstName":"Justine","middleName":"","lastName":"LEQUESNE","suffix":""},{"id":273529681,"identity":"3758fff7-331d-41f2-a925-27e3f7f00500","order_by":2,"name":"Julien GEFFRELOT","email":"","orcid":"","institution":"Centre François Baclesse","correspondingAuthor":false,"prefix":"","firstName":"Julien","middleName":"","lastName":"GEFFRELOT","suffix":""},{"id":273529682,"identity":"31291bd0-3689-4839-bab4-7ba70cd04e21","order_by":3,"name":"Anne DOMPMARTIN","email":"","orcid":"","institution":"CHU Caen","correspondingAuthor":false,"prefix":"","firstName":"Anne","middleName":"","lastName":"DOMPMARTIN","suffix":""},{"id":273529684,"identity":"91988616-57e7-4b47-9828-db9db4612f19","order_by":4,"name":"Jean Matthieu L’ORPHELIN","email":"","orcid":"","institution":"CHU Caen","correspondingAuthor":false,"prefix":"","firstName":"Jean","middleName":"Matthieu","lastName":"L’ORPHELIN","suffix":""}],"badges":[],"createdAt":"2024-02-15 11:37:19","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-3958515/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-3958515/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":51337463,"identity":"4963bc17-6a83-4857-a769-f22dd1355459","added_by":"auto","created_at":"2024-02-19 20:08:30","extension":"jpg","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":44492,"visible":true,"origin":"","legend":"\u003cp\u003eFlow-chart of the study.\u003c/p\u003e","description":"","filename":"1.jpg","url":"https://assets-eu.researchsquare.com/files/rs-3958515/v1/7a350d3b00e04773f9e9e1f5.jpg"},{"id":51337464,"identity":"f29734e9-10b9-429d-84e0-b0db9c84f3e2","added_by":"auto","created_at":"2024-02-19 20:08:30","extension":"jpg","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":64412,"visible":true,"origin":"","legend":"\u003cp\u003eOverall survival in function of cerebral status\u003c/p\u003e","description":"","filename":"2.jpg","url":"https://assets-eu.researchsquare.com/files/rs-3958515/v1/5758f6e94864cc2b70aa6602.jpg"},{"id":51337465,"identity":"4025add7-ceba-46c4-b051-2adf87f66fc9","added_by":"auto","created_at":"2024-02-19 20:08:30","extension":"jpg","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":59264,"visible":true,"origin":"","legend":"\u003cp\u003eOverall survival according to cerebral and/or extra cerebral status\u003c/p\u003e","description":"","filename":"3.jpg","url":"https://assets-eu.researchsquare.com/files/rs-3958515/v1/fc921884426e09152592a8b4.jpg"},{"id":51926930,"identity":"14e30da5-41d6-4674-9858-3ba0f4e76d0b","added_by":"auto","created_at":"2024-03-04 03:17:10","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":634185,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-3958515/v1/40b51985-6a31-40a9-94e3-218f0bd9747c.pdf"},{"id":51337467,"identity":"95568073-04bc-40e2-8344-a8d1105e6876","added_by":"auto","created_at":"2024-02-19 20:08:30","extension":"docx","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":5374648,"visible":true,"origin":"","legend":"","description":"","filename":"Supplementaryinformation.docx","url":"https://assets-eu.researchsquare.com/files/rs-3958515/v1/2bc39745adff57f6ebd05def.docx"}],"financialInterests":"No competing interests reported.","formattedTitle":"Is there some predictive factors for isolated brain PROgression in patients with CErebral metastatic MElanoma after treatment with stereotactic brain radiotherapy ? a retrospective, single-center study. PROCEME","fulltext":[{"header":"Introduction","content":"\u003cp\u003eMelanoma is the most aggressive skin cancer, with around 50,000 deaths worldwide every year [1]. Melanoma present a high cerebral tropism [2] since half to two-thirds of patients will develop brain metastases during the course of the disease. Around 25% of patients present with brain metastases at the initial diagnosis of metastatic disease [3] and more than two-third of deaths are related to the presence of brain metastases [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 \u003cem\u003eBRAF\u003c/em\u003e or \u003cem\u003eNRAS\u003c/em\u003e mutation [6\u0026ndash;11].\u003c/p\u003e \u003cp\u003eCerebral involvement is a major turning point in the prognosis of affected patients. Developments in systemic treatments, with the advent of immunotherapies (IT) and targeted therapies (TT), and in local treatments, with improved neurosurgery and radiotherapy techniques, have significantly altered the prognosis of these patients, with many now enjoying prolonged overall survival.\u003c/p\u003e \u003cp\u003eCohorts 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.\u003c/p\u003e \u003cp\u003eIn current practice, some patients present with controlled disease even 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.\u003c/p\u003e \u003cp\u003eThe 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.\u003c/p\u003e"},{"header":"Materials and Methods","content":"\u003cp\u003eWe performed an observational, single-center, retrospective study.\u003c/p\u003e \u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003ePatients:\u003c/h2\u003e \u003cp\u003eWe included patients with brain metastatic melanomas (MM) 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.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec4\" class=\"Section2\"\u003e \u003ch2\u003eMain and secondary objectives:\u003c/h2\u003e \u003cp\u003eThe main objective is to identify predictive factors of isolated cerebral escape after treatment by stereotactic brain radiotherapy (SRT), rather than cerebral and extra-cerebral progression. The primary endpoint is the evidence of local or distant cerebral progression after treatment with stereotactic radiotherapy, as assessed on cerebral magnetic resonance imaging (MRI) or cerebral scan (CT-TDM).\u003c/p\u003e \u003cp\u003eSecondary objectives included overall survival (OS), number of brain metastasis and largest brain metastasis at the time of SRT.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec5\" class=\"Section2\"\u003e \u003ch2\u003eStatistical analysis:\u003c/h2\u003e \u003cp\u003eQualitative 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.\u003c/p\u003e \u003cp\u003eAn 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\u0026thinsp;\u0026gt;\u0026thinsp;1 indicates an increased risk of isolated cerebral progression; an OR\u0026thinsp;\u0026lt;\u0026thinsp;1 indicates an increased risk of associated cerebral and extra-cerebral progression.\u003c/p\u003e \u003cp\u003eProgression-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.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec6\" class=\"Section2\"\u003e \u003ch2\u003eSystemic therapies:\u003c/h2\u003e \u003cp\u003ePatients 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\u0026thinsp;+\u0026thinsp;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.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec7\" class=\"Section2\"\u003e \u003ch2\u003eStereotactic brain radiotherapy:\u003c/h2\u003e \u003cp\u003eDoses 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).\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec8\" class=\"Section2\"\u003e \u003ch2\u003eAssessment:\u003c/h2\u003e \u003cp\u003eCerebral 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]\u003c/p\u003e \u003c/div\u003e"},{"header":"Results","content":"\u003cdiv id=\"Sec10\" class=\"Section2\"\u003e\n\u003ch2\u003ePatients and treatments\u003c/h2\u003e\n\u003cp\u003eFrom 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). Patient\u0026rsquo;s characteristics are given in Table\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e1\u003c/span\u003e. Median age at first cerebral radiotherapy was 68 years [18\u0026ndash;96] with 61% of men and 89% of WHO 0\u0026ndash;1, without difference between groups A and B. \u003cem\u003eBRAFV600\u003c/em\u003e mutation was observed in 43% of patients of group A and 63% in group B (p\u0026thinsp;=\u0026thinsp;0.11).\u003c/p\u003e\n\u003cp\u003eAt 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 \u003cspan class=\"InternalRef\"\u003e1\u003c/span\u003e.\u003c/p\u003e\n\u003cp\u003eApart 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.\u003c/p\u003e\n\u003cp\u003ePrior to SRT indicated as local treatment for metastatic disease of the brain, 50% of patients received systemic therapies to treat their isolated extra-cerebral metastatic disease, including chemotherapy, immunotherapy and targeted therapy, without difference between groups A and B .\u003c/p\u003e\n\u003cp\u003eDuring cerebral 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.\u003c/p\u003e\n\u003cp\u003eClinical characteristics of patients are described in Table\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e1\u003c/span\u003e.\u003c/p\u003e\n\u003cdiv class=\"gridtable\"\u003e\n\u003ctable id=\"Tab1\" border=\"1\"\u003e\u003ccaption\u003e\n\u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e\n\u003cdiv class=\"CaptionContent\"\u003e\n\u003cp\u003ePatient\u0026rsquo;s characteristics\u003c/p\u003e\n\u003c/div\u003e\n\u003c/caption\u003e\n\u003cthead\u003e\n\u003ctr\u003e\n\u003cth align=\"left\"\u003e\u0026nbsp;\u003c/th\u003e\n\u003cth colspan=\"2\" rowspan=\"2\" align=\"left\"\u003e\n\u003cp\u003eGroup A: Isolated cerebral progression (n\u0026thinsp;=\u0026thinsp;38)\u003c/p\u003e\n\u003c/th\u003e\n\u003cth colspan=\"2\" rowspan=\"2\" align=\"left\"\u003e\n\u003cp\u003eGroup B:\u003c/p\u003e\n\u003cp\u003eCerebral and extracerebral progression (n\u0026thinsp;=\u0026thinsp;45)\u003c/p\u003e\n\u003c/th\u003e\n\u003cth align=\"left\"\u003e\n\u003cp\u003eTotal\u003c/p\u003e\n\u003c/th\u003e\n\u003cth align=\"left\"\u003e\n\u003cp\u003ep value\u003c/p\u003e\n\u003c/th\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003cth align=\"left\"\u003e\n\u003cp\u003ePatients and characteristics :\u003c/p\u003e\n\u003c/th\u003e\n\u003cth align=\"left\"\u003e\u0026nbsp;\u003c/th\u003e\n\u003cth align=\"left\"\u003e\u0026nbsp;\u003c/th\u003e\n\u003c/tr\u003e\n\u003c/thead\u003e\n\u003ctbody\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u003cstrong\u003eAge at RTc\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.83\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u0026lt;\u0026thinsp;75 years (N ; %)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e27\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e(71%)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e34\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e(76%)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e61\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u0026gt;or =\u0026thinsp;75 years (N ; %)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e11\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e(29%)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e11\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e(24%)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e22\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u003cstrong\u003eGender\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.7\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003emale (N ; %)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e22\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e(58%)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e29\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e(64%)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e51\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003ewomen (N ; %)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e16\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e(42%)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e16\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e(36%)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e32\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u003cstrong\u003eWHO at the time of RTc\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.4\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0\u0026ndash;1\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e32\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e(94%)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e35\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e(85%)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e67\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e2\u0026ndash;3\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e2\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e(6%)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e6\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e(15%)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e8\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u003cem\u003eMissing\u003c/em\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e4\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e4\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e8\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u003cstrong\u003eLocalization of primary melanoma\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.58\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eUpper / lower limbs\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e13\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e(41%)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e15\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e(39%)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e28\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eHead and neck\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e5\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e(16%)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e7\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e(18%)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e12\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003etrunk\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e14\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e(44%)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e14\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e(37%)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e28\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003emucous\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e0\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eLentiginous Acro\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e(0%)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e2\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e(5%)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e2\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u003cem\u003eMissing\u003c/em\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e6\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e7\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e7\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u003cstrong\u003eAJCC2017 stage at initial diagnosis\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eIA - IB\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e7\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e(21%)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e5\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e(13%)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e12\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.84\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eIIA-IIB-IIC\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e15\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e(45%)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e19\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e(50%)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e34\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eIIIIA - IIIIB - IIIC - IIID\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e4\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e(12%)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e5\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e(13%)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e9\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eIV\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e7\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e(21%)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e9\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e(24%)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e16\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u003cem\u003eMissing\u003c/em\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e5\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e7\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u003cstrong\u003eBrelow to diagnosis\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0,86\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003emedian [min-max]\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e2.85\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e[0.98-25]\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e3.36\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e[0.9\u0026ndash;11]\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u003cstrong\u003eMutation status\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eBRAFV600 mutated\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e24\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e(63%)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e18\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e(43%)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e42\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.11\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eWild BRAFV600\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e14\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e(37%)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e24\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e(57%)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e38\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u003cem\u003eMissing\u003c/em\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e3\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e3\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eMutated NRAS\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e24\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e(86%)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e28\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e(82%)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e52\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.99\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eWild NRAS\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e4\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e(14%)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e6\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e(18%)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e10\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u003cem\u003eMissing\u003c/em\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e10\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e11\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e21\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u003cstrong\u003eCerebral involvement at diagnosis of metastatic disease\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.99\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eyes\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e17\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e(45%)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e19\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e(42%)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e36\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eno\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e21\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e(55%)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e26\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e(58%)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e47\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u003cstrong\u003eNumber of brain metastases at diagnosis of brain metastatic disease\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.4\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e1\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e6\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e(35%)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e11\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e(58%)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e17\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e2\u0026ndash;3\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e7\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e(41%)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e5\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e(26%)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e12\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u0026gt;\u0026thinsp;3\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e4\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e(24%)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e3\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e(16%)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e7\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u003cstrong\u003eNumber of metastatic sites at the time of RTc\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.43\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u0026lt;\u0026thinsp;3\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e30\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e(79%)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e31\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e(69%)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e61\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u0026gt;=3\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e8\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e(21%)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e14\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e(31%)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e22\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u003cstrong\u003eNumber of brain metastases at time of cRT\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.44\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0 (adjuvant RTc)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e2\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e(5%)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e5\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e(11%)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e7\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e1\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e11\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e(29%)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e16\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e(36%)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e27\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e2\u0026ndash;3\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e13\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e(34%)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e9\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e(20%)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e22\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u0026gt;\u0026thinsp;3\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e12\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e(32%)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e15\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e(33%)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e27\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u003cstrong\u003eMaximum size of brain metastasis at time of RT\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.07\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u0026lt;\u0026thinsp;1cm\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e13\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e(42%)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e16\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e(46%)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e29\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e1-2cm\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e13\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e(42%)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e9\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e(26%)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e22\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e2-3cm\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e4\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e(13%)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e2\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e(6%)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e6\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u0026gt;\u0026thinsp;3cm\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e1\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e(3%)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e8\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e(23%)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e9\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u003cem\u003eMissing\u003c/em\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e7\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e10\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e17\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u003cstrong\u003eLDH at the time of RTc\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.09\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u0026lt;\u0026thinsp;1,50 N\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e15\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e(94%)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e8\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e(62%)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e23\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u0026gt;= 1,5 N\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e1\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e(6%)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e5\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e(38%)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e6\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u003cem\u003eMissing\u003c/em\u003e (measured out of time)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e22\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e32\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e54\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003c/tr\u003e\n\u003c/tbody\u003e\n\u003c/table\u003e\n\u003c/div\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec11\" class=\"Section2\"\u003e\n\u003ch2\u003ePrimary outcome:\u003c/h2\u003e\n\u003cp\u003eResults of logistic regression models to predict isolated cerebral progression are presented in Table\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e2\u003c/span\u003e.\u003c/p\u003e\n\u003cp\u003eIn univariate analysis, \u003cem\u003eBRAF V600\u003c/em\u003e-mutation was associated with a two-fold increased incidence of isolated cerebral progression, although not significant (OR\u0026thinsp;=\u0026thinsp;2.29; CI95 [0.94; 5.72], p\u0026thinsp;=\u0026thinsp;0.071). A trend was also observed for LDH, with values\u0026thinsp;\u0026ge;\u0026thinsp;330 associated with lower incidence of isolated cerebral progression (OR\u0026thinsp;=\u0026thinsp;0.11 [0; 0.81], p\u0026thinsp;=\u0026thinsp;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 cerebral progression (OR\u0026thinsp;=\u0026thinsp;2.28 [0.51; 11.2], p\u0026thinsp;=\u0026thinsp;0.29).\u003c/p\u003e\n\u003cp\u003ePost-hoc analysis showed that \u003cem\u003eBRAF V600\u003c/em\u003e WT patients treated with IT had a 4-fold greater risk of multi-site progression (OR: 0.233 IC95% [0.58; 0.847]) than \u003cem\u003eBRAFV600\u003c/em\u003e mutated patients treated with BRAFi\u0026thinsp;+\u0026thinsp;MEKi targeted therapies. There was no difference between \u003cem\u003eBRAF V600\u003c/em\u003e mutated treated with IT or with TC in our cohort.\u003c/p\u003e\n\u003cdiv class=\"gridtable\"\u003e\n\u003ctable id=\"Tab2\" border=\"1\"\u003e\u003ccaption\u003e\n\u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e\n\u003cdiv class=\"CaptionContent\"\u003e\n\u003cp\u003eUnivariate and multivariable logistic regression analysis predicting isolated cerebral progression.\u003c/p\u003e\n\u003c/div\u003e\n\u003c/caption\u003e\n\u003cthead\u003e\n\u003ctr\u003e\n\u003cth align=\"left\"\u003e\u0026nbsp;\u003c/th\u003e\n\u003cth colspan=\"3\" align=\"left\"\u003e\n\u003cp\u003eUnivariate analysis\u003c/p\u003e\n\u003c/th\u003e\n\u003cth colspan=\"3\" align=\"left\"\u003e\n\u003cp\u003eMultivariate analysis\u003c/p\u003e\n\u003c/th\u003e\n\u003c/tr\u003e\n\u003c/thead\u003e\n\u003ctbody\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eOdds ratio\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e95% CI\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003ep-value\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eOdds ratio\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e95% Confidence Interval\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003ep-value\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eAge\u0026thinsp;\u0026gt;\u0026thinsp;=\u0026thinsp;75\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e1.26\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e[0.47\u0026ndash;3.38]\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.64\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e6.01\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e[1.35\u0026ndash;36.2]\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.029\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eGender Male\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.76\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e[0.31\u0026ndash;1.84]\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.54\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.59\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e[0.17\u0026ndash;2.01]\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.4\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eReached during RT\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u003cem\u003e\u0026lt;\u0026thinsp;3 organs\u003c/em\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e1\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e1\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u003cem\u003e\u0026gt;=3 organs\u003c/em\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.47\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e[0.17\u0026ndash;1.19]\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.12\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.26\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e[0.05\u0026ndash;1.06]\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.06\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eSize of largest metastasis (18 missing values)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u003cem\u003e\u0026lt;\u0026thinsp;1 cm\u003c/em\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e1\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e1\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u003cem\u003e1\u0026ndash;2 cm\u003c/em\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e1.78\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e[0.58\u0026ndash;5.59]\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.31\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e2,17\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e[0.57\u0026ndash;9.06]\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.26\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u003cem\u003e2\u0026ndash;3 cm\u003c/em\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e2.46\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e[0.41\u0026ndash;19.9]\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.34\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e3,2\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e[0.41\u0026ndash;35.7]\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.29\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u003cem\u003e\u0026gt;\u0026thinsp;3 cm\u003c/em\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.15\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e[0-0.99]\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.09\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0,09\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e[0-0.86]\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.06\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eNo. of brain metastases\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u003cem\u003e0\u003c/em\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e1\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eNA\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u003cem\u003e1\u003c/em\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e1.07\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e[0.24\u0026ndash;5.14]\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.93\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e1\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u003cem\u003e2\u0026ndash;3\u003c/em\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e1.5\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e[0.32\u0026ndash;7.66]\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.61\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e1.43\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e[0.31\u0026ndash;6.78]\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.65\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u003cem\u003e\u0026gt;\u0026thinsp;3\u003c/em\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e1.5\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e[0.35\u0026ndash;6.91]\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.58\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e1.65\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e[0.34\u0026ndash;8.79]\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.54\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eUlceration\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u003cem\u003eNo\u003c/em\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e1\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u003cem\u003eNot specified\u003c/em\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.9\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e[0.29\u0026ndash;2.79]\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.85\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u003cem\u003eYes\u003c/em\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e1.13\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e[0.38\u0026ndash;3.38]\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.83\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eRegression\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u003cem\u003eNo\u003c/em\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e1\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u003cem\u003eNot specified\u003c/em\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.63\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e[0.26\u0026ndash;1.53]\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.31\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u003cem\u003eYes\u003c/em\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.95\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e[0.04\u0026ndash;25.19]\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.97\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eBRAF\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u003cem\u003eNo\u003c/em\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e1\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e1\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u003cem\u003eYes\u003c/em\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e2.29\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e[0.94\u0026ndash;5.72]\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.07\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e2.28\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e[0.51\u0026ndash;11.2]\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.29\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eNRAS\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u003cem\u003eNo\u003c/em\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e1\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u003cem\u003eYes\u003c/em\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.78\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e[0.18\u0026ndash;3.05]\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.72\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eWHO\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u003cem\u003e0\u0026ndash;1\u003c/em\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e1\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u003cem\u003e2\u0026ndash;3\u003c/em\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.36\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e[0.05\u0026ndash;1.71]\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.24\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eAJCC\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u003cem\u003eI-II\u003c/em\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e1\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u003cem\u003eIII-IV\u003c/em\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.86\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e[0.32\u0026ndash;2.28]\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.76\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eTreatment during RT\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u003cem\u003eNo\u003c/em\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e1\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e1\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u003cem\u003eIT\u003c/em\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.83\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e[0.29\u0026ndash;2.37]\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.73\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.67\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e[0.14\u0026ndash;3.27]\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.62\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u003cem\u003eTC\u003c/em\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e2.23\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e[0.65\u0026ndash;8.04]\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.21\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e1.18\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e[0.13\u0026ndash;11.3]\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.88\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eLocation\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u003cem\u003eMS/MI\u003c/em\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e1\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u003cem\u003eHead and neck\u003c/em\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.82\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e[0.2\u0026ndash;1.82]\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.78\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u003cem\u003eTrunk\u003c/em\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e1.15\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e[0.40\u0026ndash;3.33]\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.79\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u003cem\u003eMucous/ALK\u003c/em\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eNA\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e1\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u003cem\u003eSP\u003c/em\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e2.31\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e[0.50\u0026ndash;1.27]\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.3\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eLDH (55 missing values)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u003cem\u003e\u0026lt;\u0026thinsp;330\u003c/em\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e1\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u003cem\u003e\u0026gt;=330\u003c/em\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.11\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e[0-0.81]\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.05\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003c/tr\u003e\n\u003c/tbody\u003e\n\u003c/table\u003e\n\u003c/div\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec12\" class=\"Section2\"\u003e\n\u003ch2\u003eSecondary outcomes:\u003c/h2\u003e\n\u003cp\u003eOverall survival (OS) (N\u0026thinsp;=\u0026thinsp;81 assessable patients)\u003c/p\u003e\n\u003cp\u003eAfter median 10.1 months [range 0.4; 97.7] of follow-up, 63 (77.8%) death were observed. Median overall survival was 10.7 months [95% CI: 8.4\u0026ndash;15.1], with lower risk of death for patients with isolated cerebral progression (OR\u0026thinsp;=\u0026thinsp;0.58 [0.35\u0026ndash;0.97]) see Fig.\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e2\u003c/span\u003e, log-rank p\u0026thinsp;=\u0026thinsp;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\u0026thinsp;\u0026gt;\u0026thinsp;3 cerebral metastasis (p\u0026thinsp;\u0026lt;\u0026thinsp;0.001) or when the largest metastasis is \u0026gt;\u0026thinsp;3cm (p\u0026thinsp;=\u0026thinsp;0.0014).\u003c/p\u003e\n\u003cp\u003eOverall survival is significantly different according to cerebral and/or extra cerebral status (log-rank p\u0026thinsp;=\u0026thinsp;0.0035, Fig.\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e3\u003c/span\u003e). 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\u0026thinsp;=\u0026thinsp;0.61 [0.37\u0026ndash;1.02], p\u0026thinsp;=\u0026thinsp;0.059).\u003c/p\u003e\n\u003c/div\u003e"},{"header":"Discussion","content":"\u003cp\u003eIn our study, a trend was observed toward an increased risk of isolated cerebral relapse in \u003cem\u003eBRAF V600\u003c/em\u003e mutated patients in univariate analysis, none of the tested factor was identified to be an independent associated factor or isolated cerebral relapse in multivariable analysis.\u003c/p\u003e \u003cp\u003eWe 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 cerebral radiotherapy, combined with systemic treatment by immunotherapy or targeted therapy. Tetu \u003cem\u003eet al\u003c/em\u003e [15] found a median overall survival of 16.8 months, and F.Martins \u003cem\u003eet al\u003c/em\u003e. [16] 12 months. Lannier \u003cem\u003eet al.\u003c/em\u003e found a median overall survival of 15.9% in patients treated with immunotherapy and stereotactic cerebral radiotherapy [17]\u003c/p\u003e \u003cp\u003eAfter 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.\u003c/p\u003e \u003cp\u003eNevertheless, 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 Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003e. This data is surprising, and suggests that after a first episode of cerebral 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 cerebral control due to cerebral SRT. This could lead to a reconsideration of cerebral involvement as a specific disease, different from that of other noble organs, in terms of management, reduced response to immunotherapy and involvement in OS.\u003c/p\u003e \u003cp\u003ePatients 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\u0026ndash;12.2] 8.2 months [2.2\u0026ndash;14.3] and 29.2 months [0\u0026ndash;65.1] in the F arm, I-F arm and I-N arm suggesting superiority of immunotherapy combination.\u003c/p\u003e \u003cp\u003eFour-year survival rate was significantly higher for I\u0026thinsp;+\u0026thinsp;N (41%) vs. F (10.9%) vs I\u0026thinsp;+\u0026thinsp;F (10.3 [20]. With a hindsight of several years, this study also suggests that the greatest impact on OS is borne by extra-cerebral rather than cerebral metastatic progression after IT-treated cerebral metastatic progression, as we did in our study.\u003c/p\u003e \u003cp\u003eTo date, studies point to a better long-term efficacy of immunotherapy treatment in responder patients, and to investigate the best sequential treatment in \u003cem\u003eBRAF V600\u003c/em\u003e mutated melanoma, SECOMBIT study was carried out in patients with \u003cem\u003eBRAF V600\u003c/em\u003e metastatic melanoma with inactive brain metastases. JAK mutation was associated to a better overall survival [19]. Another area under study is the combination of targeted therapy and immunotherapy as TRICOTEL, a phase II trial which combines BRAFi\u0026thinsp;+\u0026thinsp;MEKi\u0026thinsp;+\u0026thinsp;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 \u003cem\u003eBRAF V600\u003c/em\u003e mutated patients, and 27% for \u003cem\u003eBRAF V600\u003c/em\u003e 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.\u003c/p\u003e \u003cp\u003eVarious trials are still in progress: SWOG S2000 [24] comparing the efficacy of encorafenib (BRAFi)\u0026thinsp;+\u0026thinsp;binimetinib (MEKi)\u0026thinsp;+\u0026thinsp;nivolumab (anti PD-1) with ipilimumab (anti CTLA-4)\u0026thinsp;+\u0026thinsp;nivolumab in patients with \u003cem\u003eBRAF V600\u003c/em\u003e 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.\u003c/p\u003e \u003cp\u003eWhen metastatic melanoma is controlled extra cerebrally, we assume that secondary resistance mechanisms specific to the cerebral 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) [22].\u003c/p\u003e \u003cp\u003eOur 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.\u003c/p\u003e \u003cp\u003eTo the best of our knowledge, this is the first study to look for predictive factors for isolated cerebral progression after a first cerebral 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.\u003c/p\u003e"},{"header":"Conclusion","content":"\u003cp\u003eCurrently, 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.\u003c/p\u003e \u003cp\u003ePatients with isolated cerebral progression may not be considered as systemic treatment failures, but rather as local failures, with the need to develop new therapies adapted to the cerebral 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 cerebral 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.\u003c/p\u003e"},{"header":"Declarations","content":"\u003ch2\u003eAuthor Contribution\u003c/h2\u003e\u003cp\u003eJMLO founded the research and supervised itMC, JL, JMLO wrote the main original manuscript text and revised manuscriptJL made statistics and all analyses, tables and figuresAD supervised the major corrections in the manuscript and revised manuscriptJG supervised the project, approved manuscript\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eFerlay 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. 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Outcome Variation among \u0026ldquo;Radioresistant\u0026rdquo; Brain Metastases Treated with Stereotactic Radiosurgery. Neurosurgery 2005;56:936. https://doi.org/10.1227/01.NEU.0000158324.20757.AC.\u003c/li\u003e\n\u003cli\u003eRishi 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.\u003c/li\u003e\n\u003cli\u003ePeuvrel L, Saint-Jean M, Qu\u0026eacute;reux 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\u0026ndash;54. https://doi.org/10.1007/s11060-014-1533-z.\u003c/li\u003e\n\u003cli\u003eGumusay O, Coskun U, Akman T, Ekinci AS, Kocar M, Erceleb \u0026Ouml;B, 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\u0026ndash;7. https://doi.org/10.1007/s00432-013-1553-7.\u003c/li\u003e\n\u003cli\u003eBedikian 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.\u003c/li\u003e\n\u003cli\u003eSampson 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\u0026ndash;20. https://doi.org/10.3171/jns.1998.88.1.0011.\u003c/li\u003e\n\u003cli\u003eBreslow A. Thickness, cross-sectional areas and depth of invasion in the prognosis of cutaneous melanoma. Ann Surg 1970;172:902\u0026ndash;8.\u003c/li\u003e\n\u003cli\u003eLin 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.\u003c/li\u003e\n\u003cli\u003eEisenhauer 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\u0026ndash;47. https://doi.org/10.1016/j.ejca.2008.10.026.\u003c/li\u003e\n\u003cli\u003eGaudy-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\u0026ndash;54. https://doi.org/10.1016/j.ejca.2017.07.017.\u003c/li\u003e\n\u003cli\u003eT\u0026eacute;tu 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\u0026ndash;46. https://doi.org/10.1016/j.ejca.2019.02.009.\u003c/li\u003e\n\u003cli\u003eMartins 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\u0026ndash;93. https://doi.org/10.1007/s11060-019-03363-0.\u003c/li\u003e\n\u003cli\u003eLanier 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\u0026ndash;9. https://doi.org/10.1093/nop/npz004.\u003c/li\u003e\n\u003cli\u003eMilsch 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\u0026ndash;65. https://doi.org/10.1016/j.ejca.2018.05.012.\u003c/li\u003e\n\u003cli\u003eAscierto 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\u0026ndash;9. https://doi.org/10.1016/j.annonc.2022.08.040.\u003c/li\u003e\n\u003cli\u003eDi 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\u0026ndash;45. https://doi.org/10.1158/1078-0432.CCR-21-1046.\u003c/li\u003e\n\u003cli\u003eAtezolizumab, 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).\u003c/li\u003e\n\u003cli\u003eMart\u0026iacute;nez-Fern\u0026aacute;ndez P, Pose P, Dolz-Gait\u0026oacute;n R, Garc\u0026iacute;a A, Trigo-S\u0026aacute;nchez I, Rodr\u0026iacute;guez-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.\u003c/li\u003e\n\u003cli\u003eConcurrent intrathecal and intravenous nivolumab in leptomeningeal disease: phase 1 trial interim results | Nature Medicine n.d. https://www.nature.com/articles/s41591-022-02170-x (accessed December 1, 2023).\u003c/li\u003e\n\u003cli\u003eMoon 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.\u003c/li\u003e\n\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"Brain metastasis, Melanoma, BRAF, Stereotactic radiotherapy, Isolated brain progression","lastPublishedDoi":"10.21203/rs.3.rs-3958515/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-3958515/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cb\u003ePurpose\u003c/b\u003e\u003c/p\u003e \u003cp\u003eMelanoma is a skin cancer with an excellent prognosis if diagnosed at an early stage. Melanoma has a high potential for brain metastasis, making the prognosis considerably poorer despite the development of local and systemic treatments. In current practice, we observe discordant responses and progression profiles 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.\u003c/p\u003e\u003cp\u003e\u003cb\u003eMethods\u003c/b\u003e\u003c/p\u003e \u003cp\u003eBetween January 2014 and December 2020, 121 patients treated with stereotactic brain radiotherapy in context of melanoma stage IV were included. Radiotherapy was associated to systemic treatment in the major of cases (Targeted Therapies, Immunotherapy, or Chemotherapy).\u003c/p\u003e\u003cp\u003e\u003cb\u003eResults\u003c/b\u003e\u003c/p\u003e \u003cp\u003eIn 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 \u003cem\u003eBRAF V600\u003c/em\u003e mutated patients compared with \u003cem\u003eBRAF V600\u003c/em\u003e WT patients (OR\u0026thinsp;=\u0026thinsp;2.29; CI 95 [0.94; 5.72] p-value 0.071), but not confirmed after adjustment on confounding factors. \u003cem\u003eBRAF V600\u003c/em\u003e WT patients treated with immunotherapy have a 4-fold greater risk of multi-site progression, compared to \u003cem\u003eBRAF V600\u003c/em\u003e mutated treated with targeted therapies (OR: 0.233 IC95% [0.58 ;0.847]).\u003c/p\u003e\u003cp\u003e\u003cb\u003eConclusion\u003c/b\u003e\u003c/p\u003e \u003cp\u003e \u003cem\u003eBRAF V600\u003c/em\u003e 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.\u003c/p\u003e","manuscriptTitle":"Is there some predictive factors for isolated brain PROgression in patients with CErebral metastatic MElanoma after treatment with stereotactic brain radiotherapy ? a retrospective, single-center study. PROCEME","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2024-02-19 20:08:25","doi":"10.21203/rs.3.rs-3958515/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"f9e4c5ae-cd6f-4949-b55d-37c103370c55","owner":[],"postedDate":"February 19th, 2024","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2024-03-04T03:16:38+00:00","versionOfRecord":[],"versionCreatedAt":"2024-02-19 20:08:25","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-3958515","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-3958515","identity":"rs-3958515","version":["v1"]},"buildId":"qtupq5eGEP_6zYnWcrvyt","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}