[Electrochemotherapy in metastatic melanoma]. / Elektrokemoterápia áttétes melanomában.

INTRODUCTION: In metastatic melanoma, despite the increased survival rates with new innovative therapies, therapeutic response is still quite heterogenous, not always durable. In the case of oligoprogression, several additional therapeutic modalities are available such as electrochemotherapy in the local treatment of cutaneous or subcutaneous metastases. OBJECTIVE: Analysis of our experiences with electrochemotherapy in patients with metastatic melanoma. METHOD AND RESULTS: 23 patients with metastatic melanoma (10 male and 13 female) were treated with electrochemotherapy, between 2016 and 2021 in our Institute. Median age was 74.5 years. The location of metastases varied. 13 of our patients (57%) had metastases on the lower limbs, in 5 cases (22%) metastases were located in the head and neck region, in 4 cases (17%) on the upper limbs, and one (4%) patient received electrochemotherapy for metastases located on the chest. Prior to electrochemotherapy, 7 patients (30%) received chemotherapy, 6 patients (26%) were treated with immunotherapy and 2 patients (9%) received targeted therapy, while electrochemotherapy was first-line treatment for 8 patients (35%). Complete remission was achieved in 12 cases (52%), and partial remission in 6 cases (26%). In 1 case (4%) stable disease was observed, and in 4 patients (35%) progression was detected. We continued the previous systemic therapy which was effective in other localizations after the electrochemotherapy in 8 patients (35%) and in the case of 4 patients (17%) no further systemic therapy was needed. Side effects were observed in 8 patients (35%), 1 had severity of G3. CONCLUSION: Electrochemotherapy in melanoma results in effective local tumor control, improved quality of life, and survival advantage in most of the patients, with tolerable side effects. Orv Hetil. 2023; 164(35): 1381-1386.

Therapeutic and Adverse Effect of Anti-PD1 Immunotherapy in Melanoma: A Retrospective, Single-Institute Study of 222 Patients.

BACKGROUND: The introduction of immuno- and targeted therapeutic modalities meant a breakthrough step in the therapy of melanoma. As a checkpoint inhibitor, the more effective and less toxic anti-PD1 therapy followed an anti-CTLA4 approach. METHODS: From our patient pool, 222 advanced melanoma cases were selected, where anti-PD1 (pembrolizumab, nivolumab) therapy was initiated between March 2015 and December 2020. During our retrospective analysis, the efficacy and safety of the therapy were assessed. RESULTS: The median follow-up was 16 months (interval: 0-64 months), and 150 patients (67.6%) received therapy in the first line, while second and third line therapy was performed among 72 patients (32.4%) for the median of 7.0 months (0-60). In 50 cases, BRAF mutations were detected. Ninety-six patients showed objective response (11.3% CR, 32.0% PR). The median PFS was 10.0 months (0-60), and the median OS was 23.0 months (0-64). Autoimmune side effects were found in 79 patients (35.5%); grade 3 occurred in 6.3% of the cases, while 1 patient died due to fulminant pneumonitis (0.25%). CONCLUSION: Although the range of immunotherapeutic options is getting wider, in the management of melanoma patients, anti-PD1 monotherapy remains an important, effective, and safe method. However, significant correlation was found between the immune-related side effects and therapeutic efficacy.

[BRAF-MEK inhibitor therapy in melanoma]. / BRAF-MEK gátló terápiával elért eredményeink 118, metasztatikus melanómában szenvedo betegnél az Országos Onkológiai Intézetben.

We investigated the efficacy and safety of vemurafenib+cobimetinib (V+C) and dabrafenib+trametinib (D+T) based on real-life data. From 2015 and 2018 we have selected 118 BRAF-mutated metastatic melanoma patients, treated with V+C and D+T in our institute. We retrospectively analyzed the overall response rate (ORR), the progression-free survival (PFS), the overall survival (OS) and the adverse events of the therapies. The median follow-up time was 18 months (3-43) with V+C and 12 months (3-43) with D+T. The median PFS was 8 months in the V+C and 8.5 months in the D+T group. Median OS was 18 months in V+C group and 12 months with D+T. The ORR was revealed to be 82% in D+T group and 76% in V+C group. Each combination displayed a slightly different safety profile. In our retrospective analysis both BRAF-MEK inhibitor combination therapies showed favorable efficacy with a slightly different spectrum of toxicity profile.

Predictive and Prognostic Value of BRAF and NRAS Mutation of 159 Sentinel Lymph Node Cases in Melanoma-A Retrospective Single-Institute Study.

PURPOSE: To assess the prognostic role of sentinel lymph node status (SLN) in melanoma patients, a statistical comparison was performed with the application of already known prognostic factors, mutational occurrence of BRAF and NRAS in the primary tumor, as well as disease outcome. METHODS: Our retrospective single-center study involved 159 melanoma cases, who underwent SLN biopsy. The following clinico-pathological data were collected: age, gender, location of primary tumor, Breslow thickness, ulceration degree, histological subtype, mitosis count, lymphovascular and perineural invasion, presence of tumor-infiltrating lymphocytes, regression signs, mutations of BRAF and NRAS of the primary tumors, and SLN status. RESULTS: From the studied clinico-pathological factors, only Breslow thickness increased the risk of SLN positivity (p = 0.025) by multivariate analysis, while neither BRAF nor NRAS mutation of the primary tumor proved to be a predictor of the SLN status. While the NRAS-mutant subgroup showed the most unfavorable outcome for progression-free and distant metastasis-free survival, their rate of positive SLNs proved to be relatively lower than that of patient groups with BRAF mutation and double-wild-type phenotypes. CONCLUSION: Similarly to the importance of SLN positivity, NRAS mutation of the primary tumor proved to be an independent prognostic factor of progression. Therefore, despite negative SLN, this NRAS-mutant subgroup of patients still requires closer monitoring to detect disease progression.

Biomarkers Associated with Clinical Outcome of Advanced Melanoma Patients Treated with Ipilimumab.

Ipilimumab was the first immunotherapy approved for metastatic melanoma in decades and is currently registered as a second-line treatment. However, new immunotherapies, in combination with ipilimumab, offer even better clinical outcomes for patients compared with single-agent treatments, at the expense of improved toxicity. The aim of this study was to evaluate the feasibility of ipilimumab outside the clinical trials and to identify survival predictors for treatment benefit. Data were collected on 47 advanced melanoma patients treated with ipilimumab between 2010 and 2015 at a single center. Association of clinical characteristics (including primary tumor characteristics), serum lactate dehydrogenase (LDH), erythrocyte sedimentation rate, absolute eosinophil, lymphocyte, and neutrophil count, neutrophil/lymphocyte and eosinophil/lymphocyte ratio with toxicity and clinical outcome were assessed using univariate and multivariate analysis. Median progression-free survival at a median follow-up of 10 months was 2.7 months and median overall survival was 9.8 months. Objective response was observed in 17% of patients and the disease control rate at week 24 was 40%. The 1- and 2-year survival rates documented were 40 and 28%, respectively. Significant association between high LDH level (>1.5× upper limit of normal) and decreased overall survival was demonstrated in uni- and multivariate analysis (hazard ratio [HR]: 3.554, 95% CI: 1.225-10.306, p = 0.019). Neither biomarkers nor clinical outcome were associated with toxicity. Using baseline serum LDH to identify patients most likely to benefit from ipilimumab therapy could serve as a simple and inexpensive biomarker of clinical outcome.

Efficacy of Vemurafenib Treatment in 43 Metastatic Melanoma Patients with BRAF Mutation. Single-Institute Retrospective Analysis, Early Real-Life Survival Data.

BRAF inhibitor vemurafenib achieved improved overall survival over chemotherapy and have been approved by the FDA and EMA for the treatment of BRAF-mutated metastatic melanoma. The aim of our retrospective analysis was to determine the efficacy and safety of vemurafenib therapy for BRAF mutated metastatic melanoma and subsequently to prove the clinical benefit for the studied 43 patients, based on real-life data. From November 2012 to October 2015 we have selected 43 BRAF mutated, metastatic melanoma patients, treated with vemurafenib. The median follow-up time was 15.9 months. We evaluated progression free survival (PFS), overall survival (OS) and toxicities. According to the AJCC staging system 70% of the patients had stage M1c metastasis, including 6 with stable brain metastasis. Objective responses were noted in 51.1%, the disease control rate was achieved in 79% of the patients. Complete responses were attained by 5 patients (11.6%). Median PFS was 6.48 (95% CI:4.8-15.0) months, median OS was 11.47 (95% CI:8.08-NA) months. We found significant association between LDH level and OS in univariate (p = 0.000613) and multivariate analysis (p = 0.0168). The most common adverse events (AEs) included follicular hyperkeratosis, rash, arthralgia and photosensitivity. Grade 3 AEs, such as cutaneous squamous-cell carcinoma, QTcB interval prolongation, rash, arthralgia were reported in 7 patients (17%). We had no Grade 4 side effects. Similar to the previously published data our analysis confirms the improved survival with vemurafenib treatment (11.47 months) in patients with BRAF V600 mutation. Vemurafenib therapy was well tolerated, the AE profile was almost consistent with the previously reported data of randomised clinical trials.

Dabrafenib Therapy in 30 Patients with Melanoma Metastatic to the Brain: a Single-centre Controlled Retrospective Study in Hungary.

Dabrafenib is a potent BRAF inhibitor, which showed intracranial tumor activity. The purpose of our retrospective analysis was to evaluate the efficacy of dabrafenib for patients with melanoma brain metastasis (BM). We studied 30 BRAF mutant melanoma patients with BM, who received dabrafenib after local control of the brain between 2014 and 2017. Eastern Cooperative Oncology Group Performance Status (ECOG) was 0-2. The control arm consisted of 204 melanoma patients from our institutional melanoma database with BM and ECOG 0-2 treated with local therapies and/or chemotherapy, between 2003 and 2015. We found the intracranial disease control rate (DCR) was 83% including four (13%) complete remissions (CR), nine (30%) partial remissions (PR) and twelve (40%) stable diseases (SD) in contrast to five (17%) progressive diseases (PD). With a median follow-up of 14 months, median progression-free survival (PFS) and overall survival (OS) were 5.5 months, and 8.8 months, respectively. If calculated from BM onset, the OS turned to be 11.8 months on the dabrafenib arm, while it was only 6.0 months in the control arm (HR = 0.45, p = 0.0014). Higher risk of progression was observed with increasing ECOG (HR =4.06, p = 0.00027) and if more than 2 extracranial organs were involved (HR = 3.4, p = 0.0077). Elevated lactate dehydrogenase (LDH) was non-significantly associated with worse clinical outcome. Remarkable intracranial activity of dabrafenib in real practice was confirmed by our analysis.

Distance from Primary Tumor Is the Strongest Predictor for Early Onset of Brain Metastases in Melanoma.

BACKGROUND/AIM: The frequency of brain metastasis (BM) is up to 45-50% in patients with advanced melanoma. Our aim was to identify the risk factors for the early occurrence of BM. PATIENTS AND METHODS: A total of 333 patients with BM were identified from our database of 2,972 patients with melanoma between 2003-2015. RESULTS: The median elapsed time to BM (TTBM) was significantly associated with Breslow thickness, ulceration, location, and patient age. Head and neck location was the strongest predictor for early BM development [hazard ratio (HR)=1.81, 95% confidence interval (CI)=1.05-3.12; p=0.031) followed by Breslow thickness >2 mm (HR=1.53, 95% CI=1.04-2.23; p=0.027). Body part-specific median TTBM was 51.5, 43, 38.5, 32, 35, 36.5, 35.5 and 19 months in leg-foot, thigh, abdomen-pelvic, chest-back, lower arm-hand, upper arm-shoulder, face-neck and scalp regions, respectively. CONCLUSION: We suggest brain magnetic resonance imaging follow-up in the high-risk patient group of patients with melanoma in the head and neck region, especially for those with primary melanoma over Breslow 2 mm located in the scalp.

[Psychological aspects of immunotherapies in the treatment of malignant melanoma]. / Immunterápiák pszichológiai vonatkozásai a melanoma komplex és multidiszciplináris kezelésében.

Psychological problems may arise in connection with oncomedical treatments in three ways: 1. acute and/or 2. chronic ways, as well as 3. co-morbid psychiatric diseases that already exist must also be taken into account. Immunotherapies have the most common and also clinically relevant psychological side effects. Fatigue, anhedonia, social isolation, psychomotor slowness is reported during treatment. Anti-CTLA-4 antibody (ipilimumab) immunotherapy can present one of the most modern opportunities for adequate treatment for patients having distant metastasis or unresectable tumour. In relation to immunotherapies, acute psychological side effects (acute stress) emerging during treatments develop in a way that can mostly be linked to environmental factors, e.g. notification of diagnosis, hospitalisation, progression, deterioration in quality of life, imminent dates of control. Crisis is a temporary and threatening condition that endangers psychological balance. In such conditions, enhanced psychological vulnerability must be taken into account and doctors play a key role in the rapid recognition of the condition. Chronic psychological problems, which may arise from the depressogenic effect of the applied treatment or originated from a pre-melanoma psychiatric condition, may exceed the diagnostic and psychotherapeutic competences of a clinical psychologist. Even in case of a well-defined depressogenic biological mechanism such as the activation of the pro-inflammatory cytokine pathway, positive environmental effects can reduce symptoms and thus increase compliance. Side effects can be treated successfully using psychotherapeutic methods and/or psychiatric medicines. The application of routinely used complex psychosocial screening packages can provide the easiest method to identify worsening psychological condition during immunotherapy and give rapid feedback to the oncologist and the patient. Team work is of particular importance in a situation like this as it requires complex, interdisciplinary and high-level professional collaboration. Multidisciplinarity is the basic framework for modern tumour therapy where, under the guidance of oncologists, the work of specialist nurses, social workers, physiotherapists, dieticians and last but not least psychiatrists/psychologists are indispensable and play a significant role.