Health-related quality of life of long-term advanced melanoma survivors treated with anti-CTLA-4 immune checkpoint inhibition compared to matched controls

Background: Checkpoint inhibitors have changed overall survival for patients with advanced melanoma. However, there is a lack of data on health-related quality of life (HRQoL) of long-term advanced melanoma survivors, years after treatment. Therefore, we evaluated HRQoL in long-term advanced melanoma survivors and compared the study outcomes with matched controls without cancer.Material and methods: Ipilimumab-treated advanced melanoma survivors without evidence of disease and without subsequent systemic therapy for a minimum of two years following last administration of ipilimumab were eligible for this study. The European Organization for Research and Treatment of Cancer quality of life questionnaire Core 30 (EORTC QLQ-C30), the Multidimensional Fatigue Inventory (MFI), the Hospital Anxiety and Depression Scale (HADS), and the Functional Assessment of Cancer Therapy-Melanoma questionnaire (FACT-M) were administered. Controls were individually matched for age, gender, and educational status. Outcomes of survivors and controls were compared using generalized estimating equations, and differences were interpreted as clinically relevant according to published guidelines.Results: A total of 89 survivors and 265 controls were analyzed in this study. After a median follow-up of 39 (range, 17-121) months, survivors scored significantly lower on physical (83.7vs. 89.8, difference (diff) = -5.80,p=.005), role (83.5vs.90, diff = -5.97,p=.02), cognitive (83.7vs.91.9, diff = -8.05,p=.001), and social functioning (86.5vs.95.1, diff = -8.49,p= <.001) and had a higher symptom burden of fatigue (23.0vs.15.5, diff = 7.48,p=.004), dyspnea (13.3vs.6.7, diff = 6.47p=.02), diarrhea (7.9vs.4.0, diff = 3.78,p=.04), and financial impact (10.5vs.2.5, diff = 8.07,p=.001) than matched controls. Group differences were indicated as clinically relevant.Discussion: Compared to matched controls, long-term advanced melanoma survivors had overall worse functioning scores, more physical symptoms, and financial difficulties. These data may contribute to the development of appropriate survivorship care.Experimentele farmacotherapi

A subset of cutaneous melanomas contains high expression of genes related to oxidative phosphorylation determined using consensus clustering

Despite new treatment options, prognosis of many melanoma patients remains poor and new treatment strategies are still needed. Stratification in molecular subclasses may aid therapeutic development. Therefore, we performed consensus clustering of 405 RNA microarray profiles obtained from the Gene Expression Omnibus (GEO) and 469 RNA sequencing profiles obtained from The Cancer Genome Atlas (TCGA), all from tumor samples of patients with cutaneous melanoma of any stage. We biologically annotated each cluster based on the enrichment of pre-defined Hallmark gene sets as assessed by Gene Set Enrichment Analysis (GSEA). To evaluate the concordance between both datasets Spearman's rank correlations between the Z-transformed P-values of matched genes as obtained by pair-wise class comparison were calculated. Consensus clustering revealed four molecular clusters in the GEO dataset. These clusters were biologically annotated and labeled 'immune' (27% of samples), 'estrogen response/p53-pathway' (estrogen/p53) (34% of samples), 'cell cycle' (15% of samples) and 'oxidative phosphorylation' (24% of samples). In the TCGA database we also identified four clusters and annotated them 'immune' (36% of samples), 'estrogen/p530 (7% of samples), 'cell cycle' (24% of samples) and 'oxidative phosphorylation' (32% of samples) according to the GSEA results. Spearman's rank correlations were 0.61 for the 'immune', 0.47 for the 'estrogen/p53', 0.60 for the 'cell cycle' and 0.68 for the oxidative phosporylation clusters. These data indicate four robust molecular subclasses in cutaneous melanoma that may guide future research and development of treatment strategies. Inhibition of mitochondrial function is of interest as a potential treatment strategy for tumors in the oxidative phosphorylation cluster

Visual and quantitative evaluation of [(18)F]FES and [(18)F]FDHT PET in patients with metastatic breast cancer: an interobserver variability study

Contains fulltext : 220741.pdf (publisher's version ) (Open Access)PURPOSE: Correct identification of tumour receptor status is important for treatment decisions in breast cancer. [(18)F]FES PET and [(18)F]FDHT PET allow non-invasive assessment of the oestrogen (ER) and androgen receptor (AR) status of individual lesions within a patient. Despite standardised analysis techniques, interobserver variability can significantly affect the interpretation of PET results and thus clinical applicability. The purpose of this study was to determine visual and quantitative interobserver variability of [(18)F]FES PET and [(18)F]FDHT PET interpretation in patients with metastatic breast cancer. METHODS: In this prospective, two-centre study, patients with ER-positive metastatic breast cancer underwent both [(18)F]FES and [(18)F]FDHT PET/CT. In total, 120 lesions were identified in 10 patients with either conventional imaging (bone scan or lesions > 1 cm on high-resolution CT, n = 69) or only with [(18)F]FES and [(18)F]FDHT PET (n = 51). All lesions were scored visually and quantitatively by two independent observers. A visually PET-positive lesion was defined as uptake above background. For quantification, we used standardised uptake values (SUV): SUVmax, SUVpeak and SUVmean. RESULTS: Visual analysis showed an absolute positive and negative interobserver agreement for [(18)F]FES PET of 84% and 83%, respectively (kappa = 0.67, 95% CI 0.48-0.87), and 49% and 74% for [(18)F]FDHT PET, respectively (kappa = 0.23, 95% CI - 0.04-0.49). Intraclass correlation coefficients (ICC) for quantification of SUVmax, SUVpeak and SUVmean were 0.98 (95% CI 0.96-0.98), 0.97 (95% CI 0.96-0.98) and 0.89 (95% CI 0.83-0.92) for [(18)F]FES, and 0.78 (95% CI 0.66-0.85), 0.76 (95% CI 0.63-0.84) and 0.75 (95% CI 0.62-0.84) for [(18)F]FDHT, respectively. CONCLUSION: Visual and quantitative evaluation of [(18)F]FES PET showed high interobserver agreement. These results support the use of [(18)F]FES PET in clinical practice. In contrast, visual agreement for [(18)F]FDHT PET was relatively low due to low tumour-background ratios, but quantitative agreement was good. This underscores the relevance of quantitative analysis of [(18)F]FDHT PET in breast cancer. TRIAL REGISTRATION: ClinicalTrials.gov, NCT01988324. Registered 20 November 2013, https://clinicaltrials.gov/ct2/show/NCT01988324?term=FDHT+PET&draw=1&rank=2

Serum lactate dehydrogenase (LDH) as a prognostic selection criterion for ipilimumab treatment in metastatic melanoma

Experimentele farmacotherapi

First-line BRAF/MEK inhibitors versus anti-PD-1 monotherapy in BRAF(V600)-mutant advanced melanoma patients: a propensity-matched survival analysis

Contains fulltext : 232046.pdf (Publisher’s version ) (Closed access)BACKGROUND: Anti-PD-1 antibodies and BRAF/MEK inhibitors are the two main groups of systemic therapy in the treatment of BRAF(V600)-mutant advanced melanoma. Until now, data are inconclusive on which therapy to use as first-line treatment. The aim of this study was to use propensity score matching to compare first-line anti-PD-1 monotherapy vs. BRAF/MEK inhibitors in advanced BRAF(V600)-mutant melanoma patients. METHODS: We selected patients diagnosed between 2014 and 2017 with advanced melanoma and a known BRAF(V600)-mutation treated with first-line BRAF/MEK inhibitors or anti-PD-1 antibodies, registered in the Dutch Melanoma Treatment Registry. Patients were matched based on their propensity scores using the nearest neighbour and the optimal matching method. RESULTS: Between 2014 and 2017, a total of 330 and 254 advanced melanoma patients received BRAF/MEK inhibitors and anti-PD-1 monotherapy as first-line systemic therapy. In the matched cohort, patients receiving anti-PD-1 antibodies as a first-line treatment had a higher median and 2-year overall survival compared to patients treated with first-line BRAF/MEK inhibitors, 42.3 months (95% CI: 37.3-NE) vs. 19.8 months (95% CI: 16.7-24.3) and 65.4% (95% CI: 58.1-73.6) vs. 41.7% (95% CI: 34.2-51.0). CONCLUSIONS: Our data suggest that in the matched BRAF(V600)-mutant advanced melanoma patients, anti-PD-1 monotherapy is the preferred first-line treatment in patients with relatively favourable patient and tumour characteristics

Serum lactate dehydrogenase (LDH) as a prognostic selection criterion for ipilimumab treatment in metastatic melanoma

Experimentele farmacotherapi

Real-world Outcomes of First-line Anti-PD-1 Therapy for Advanced Melanoma: A Nationwide Population-based Study

Contains fulltext : 225776.pdf (Publisher’s version ) (Closed access)The efficacy of anti-programmed death-1 (PD-1) monotherapy for advanced melanoma has been established, but it is unknown to what extent patients benefit in the real world. In this observational study with nationwide population-based data from the Dutch Melanoma Treatment Registry, we analyzed real-world outcomes of first-line anti-PD-1 monotherapy in advanced melanoma patients diagnosed in 2015 to 2016. Overall survival (OS) was estimated with the Kaplan-Meier method. Competing risks analysis was used to estimate probabilities for second-line treatment, with death as competing risk. With a Cox model, the association of factors with OS was estimated. Patients who received anti-PD-1 monotherapy (n=550) had a median age of 65 years and 502 (95%) patients had an Eastern Cooperative Oncology Group performance status (ECOG PS) of 0-1, 383 (70%) had normal lactate dehydrogenase (LDH), 370 (67%) had stage IV-M1c disease, and in 441 (81%), brain metastases were absent. The median OS was 24 months [95% confidence interval (CI): 20-30 mo]. The median OS of patients normally eligible for phase III trial participation was 31 months (95% CI: 23-not estimable). The BRAF mutation was associated with superior OS. ECOG PS of ≥1, symptomatic brain metastases, and liver metastases were associated with inferior OS and, together with elevated LDH, with death before second-line treatment. Patients with a complete response had a 2-year OS probability from first reported complete response of 92% (95% CI: 86%-99%). Real-world advanced melanoma patients in the Netherlands have benefitted from anti-PD-1 monotherapy. ECOG PS ≥1, symptomatic brain metastasis, liver metastasis, and elevated LDH are important prognostic factors for survival. The additional information that this study provides could help to improve more effective use in the real world