Outcome of melanoma patients with elevated LDH treated with first-line targeted therapy or PD-1-based immune checkpoint inhibition.

BACKGROUND: Elevated lactate dehydrogenase (LDH) is a known predictive and prognostic factor for a poor outcome in patients with metastatic melanoma. It is unclear whether first-line targeted therapy (TT) or immune checkpoint inhibition (ICI) is more beneficial in melanoma patients with elevated LDH because prospective studies in this area are lacking. METHODS: This multicentre retrospective cohort study was conducted at 25 melanoma centres worldwide to analyse progression-free survival (PFS) and overall survival (OS) among melanoma patients with elevated LDH. The role of confounders was addressed by using inverse probability of treatment weighting. RESULTS: Among 173 BRAFV600-mutant patients, PFS at 12 months in the TT group was 22% compared with 52% in the combined anti-PD-1 and anti-CTLA-4 group (HR 0.6, 95% CI 0.4-1.0, p = 0.07) and 18% in the anti-PD-1 monotherapy group (HR 1.8, 95% CI 1.2-2.8, p = 0.003). Twelve months' OS was 48% in the TT group compared with 83% in the combined anti-PD-1 and anti-CTLA-4 group (HR 0.5, 95% CI 0.3-1.0, p = 0.03) and 50% in the anti-PD-1 monotherapy group (HR 1.2, 95% CI 0.8-2.0, p = 0.37). The ORR in the TT group was 63%, compared with 55% and 20% in the combined anti-PD-1 and anti-CTLA-4 and anti-PD-1 monotherapy group, respectively. Among 314 patients receiving ICI first-line, PFS at 12 months was 33% in the anti-PD-1 group versus 38% in the combined anti-PD-1 and anti-CTLA-4 group (HR 0.8, 95% CI 0.6-1.0; p = 0.07). OS at 12 months was 54% in the anti-PD-1 group versus 66% in the combined ICI group (HR 0.7, 95% CI 0.5-1.0; p = 0.03). The ORR was 30% in the anti-PD-1 monotherapy group and 43% in the combined anti-PD-1 and anti-CTLA-4 group. Results from multivariate analysis confirmed the absence of qualitative confounding. CONCLUSIONS: Among BRAF-mutant patients with elevated LDH, combined anti-PD-1 and anti-CTLA-4 blockade seems to be associated with prolonged OS compared with first-line TT. Among patients receiving ICI as a first-line treatment, OS appears to be longer for the combination of anti-PD-1 and anti-CTLA-4 than for anti-PD-1 alone.

Leptomeningeal disease from melanoma-Poor prognosis despite new therapeutic modalities.

OBJECTIVE: The development of leptomeningeal disease (LMD) among melanoma patients is associated with short survival. Unspecific clinical symptoms and imprecise diagnostic criteria often delay diagnosis. Because melanoma patients with LMD have been excluded from most clinical trials, the efficacy of immune checkpoint blockade (ICB) and targeted therapies (TTs) has not been adequately investigated among these patients. METHODS: We performed a retrospective study in two tertiary-referral skin cancer centres to evaluate the clinical characteristics, diagnostics, treatments, and overall survival (OS) of melanoma patients with LMD between June 2011 and March 2019. RESULTS: In total, 52 patients were included. The median age at LMD diagnosis was 58 years. Most patients (n = 30, 58%) were men. The median time from the first diagnosis of unresectable disease to the first diagnosis of LMD was 8.5 months (range 0-91.5 months). Most patients (65%, n = 34) were BRAF V600 mutated. Sixteen patients (31%) presented with LMD only, whereas 36 patients (69%) presented with concomitant brain metastases at LMD diagnosis. Eleven patients (21%) showed no evidence of extracranial disease. Forty-four patients (85%) had clinical symptoms at LMD diagnosis. Forty-two patients (81%) had received at least one prior therapy. Forty patients (77%) received at least one treatment after LMD diagnosis, including TT (n = 17), ICB (n = 13), bevacizumab (n = 1), radiotherapy (n = 3), and intrathecal chemotherapy (n = 1); five patients received both TT and ICB. Twelve patients (23%) received no treatment because of rapid progression of LMD. The median OS for the entire cohort was 2.9 months (95% confidence interval [CI] 1.7-4.1). Among patients receiving systemic therapy, OS was 3.7 months (95% CI 2.4-4.9). CONCLUSIONS: Systemic treatment with TT or ICB seems to improve OS among patients with LMD. However, despite new therapy modalities, the prognosis of LMD remains poor.

Impact of a preceding radiotherapy on the outcome of immune checkpoint inhibition in metastatic melanoma: a multicenter retrospective cohort study of the DeCOG.

BACKGROUND: Immune checkpoint inhibition (ICI) is an essential treatment option in melanoma. Its outcome may be improved by a preceding radiation of metastases. This study aimed to investigate the impact of a preceding radiotherapy on the clinical outcome of ICI treatment. METHODS: This multicenter retrospective cohort study included patients who received anti-cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) or anti-programmed cell death protein 1 (PD-1) ICI with or without preceding radiotherapy for unresectable metastatic melanoma. ICI therapy outcome was measured as best overall response (BOR), progression-free (PFS) and overall survival (OS). Response and survival analyses were adjusted for confounders identified by directed acyclic graphs. Adjusted survival curves were calculated using inverse probability treatment weighting. RESULTS: 835 patients who received ICI (anti-CTLA-4, n=596; anti-PD-1, n=239) at 16 centers were analyzed, whereof 235 received a preceding radiotherapy of metastatic lesions in stage IV disease. The most frequent organ sites irradiated prior to ICI therapy were brain (51.1%), lymph nodes (17.9%) and bone (17.9%). After multivariable adjustment for confounders, no relevant differences in ICI therapy outcome were observed between cohorts with and without preceding radiotherapy. BOR was 8.7% vs 13.0% for anti-CTLA-4 (adjusted relative risk (RR)=1.47; 95% CI=0.81 to 2.65; p=0.20), and 16.5% vs 25.3% for anti-PD-1 (RR=0.93; 95% CI=0.49 to 1.77; p=0.82). Survival probabilities were similar for cohorts with and without preceding radiotherapy, for anti-CTLA-4 (PFS, adjusted HR=1.02, 95% CI=0.86 to 1.25, p=0.74; OS, HR=1.08, 95% CI=0.81 to 1.44, p=0.61) and for anti-PD-1 (PFS, HR=0.84, 95% CI=0.57 to 1.26, p=0.41; OS, HR=0.73, 95% CI=0.43 to 1.25, p=0.26). Patients who received radiation last before ICI (n=137) revealed no better survival than those who had one or more treatment lines between radiation and start of ICI (n=86). In 223 patients with brain metastases, we found no relevant survival differences on ICI with and without preceding radiotherapy. CONCLUSIONS: This study detected no evidence for a relevant favorable impact of a preceding radiotherapy on anti-CTLA-4 or anti-PD-1 ICI treatment outcome in metastatic melanoma.

A Systematic Review of the Effect of Neurofeedback in Cancer Patients.

INTRODUCTION: Neurofeedback (NF) or electroencephalogram (EEG)-Biofeedback is a drug-free form of brain training to directly alter the underlying neural mechanisms of cognition and behavior. It is a technique that measures a subject's EEG signal, processes it in real time, with the goal to enable a behavioral modification by modulating brain activity. The most common application of the NF technology is in epilepsies, migraine, attention-deficit/hyperactivity disorder, autism spectrum disorder, affective disorders, and psychotic disorders. Few studies have investigated the use of NF in context of psychosomatic illnesses. Little is known about the use in cancer patients or postcancer survivors despite the high number of this patient group. OBJECTIVES: We here provide a systematic review of the use and effect of NF on symptoms and burden in cancer patients and long-term cancer survivors. METHODS: In conducting this systematic review, we followed the guidelines of the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) Statement. RESULTS: Our search resulted in only 3 experimental studies, 1 observational study, and 2 case reports. Given the heterogeneity of the intervention systems and protocols, no meta-analysis was conducted. CONCLUSION: Altogether, there is initial evidence that NF is a complementary, drug-free, and noninvasive therapy that has the potential to ameliorate symptoms in this patient group, such as pain, fatigue, depression, and sleep. Further studies are highly needed.

A Skin Cancer Prevention Facial-Aging Mobile App for Secondary Schools in Brazil: Appearance-Focused Interventional Study.

BACKGROUND: The incidence of melanoma is increasing faster than any other major cancer both in Brazil and worldwide. Southeast Brazil has especially high incidences of melanoma, and early detection is low. Exposure to ultraviolet (UV) radiation is a primary risk factor for developing melanoma. Increasing attractiveness is a major motivation among adolescents for tanning. A medical student-delivered intervention that takes advantage of the broad availability of mobile phones and adolescents' interest in their appearance indicated effectiveness in a recent study from Germany. However, the effect in a high-UV index country with a high melanoma prevalence and the capability of medical students to implement such an intervention remain unknown. OBJECTIVE: In this pilot study, our objective was to investigate the preliminary success and implementability of a photoaging intervention to prevent skin cancer in Brazilian adolescents. METHODS: We implemented a free photoaging mobile phone app (Sunface) in 15 secondary school classes in southeast Brazil. Medical students "mirrored" the pupils' altered 3-dimensional (3D) selfies reacting to touch on tablets via a projector in front of their whole grade accompanied by a brief discussion of means of UV protection. An anonymous questionnaire capturing sociodemographic data and risk factors for melanoma measured the perceptions of the intervention on 5-point Likert scales among 356 pupils of both sexes (13-19 years old; median age 16 years) in grades 8 to 12 of 2 secondary schools in Brazil. RESULTS: We measured more than 90% agreement in both items that measured motivation to reduce UV exposure and only 5.6% disagreement: 322 (90.5%) agreed or strongly agreed that their 3D selfie motivated them to avoid using a tanning bed, and 321 (90.2%) that it motivated them to improve their sun protection; 20 pupils (5.6%) disagreed with both items. The perceived effect on motivation was higher in female pupils in both tanning bed avoidance (n=198, 92.6% agreement in females vs n=123, 87.2% agreement in males) and increased use of sun protection (n=197, 92.1% agreement in females vs n=123, 87.2% agreement in males) and independent of age or skin type. All medical students involved filled in a process evaluation revealing that they all perceived the intervention as effective and unproblematic, and that all pupils tried the app in their presence. CONCLUSIONS: The photoaging intervention was effective in changing behavioral predictors for UV protection in Brazilian adolescents. The predictors measured indicated an even higher prospective effectiveness in southeast Brazil than in Germany (>90% agreement in Brazil vs >60% agreement in Germany to both items that measured motivation to reduce UV exposure) in accordance with the theory of planned behavior. Medical students are capable of complete implementation. A randomized controlled trial measuring prospective effects in Brazil is planned as a result of this study.

The safety and efficacy of dabrafenib and trametinib for the treatment of melanoma.

INTRODUCTION: The introduction of BRAF and MEK inhibitors into clinical practice improved the prognosis of metastatic melanoma patients. The combination of BRAF inhibitor dabrafenib with MEK inhibitor trametinib has shown its superiority to single agent therapy and is characterized by a tolerable spectrum of adverse events which shows a decrease in incidence over time on treatment. Areas covered: The current scientific literature on safety and adverse events (AEs) related to BRAF and MEK-inhibition has been investigated with special focus on the large phase 3 studies (COMBI-v, COMBI-d and CoBRIM) as well as recent updates presented at oncology and melanoma meetings. Additionally, published case series/case reports were screened for information on AEs. Expert opinion: Even though almost every patient (98%) under combination therapy with dabrafenib and trametinib experiences at least one adverse event, these are generally mild to moderate, reversible and can be managed with dose reductions or interruptions. However, due to an increased life expectancy, there is a substantial need to prevent and treat also mild adverse events, as they play a central role for the quality of life of patients. Ongoing clinical trials will have to demonstrate the efficacy as well as safety of triple combination with anti-PD-1/anti-PD-L1 antibodies.

Systematization of Oncoplastic Surgery: Selection of Surgical Techniques and Patient-Reported Outcome in a Cohort of 1,035 Patients.

INTRODUCTION: Functional and aesthetic outcome after breast-conserving surgery are vital endpoints for patients with primary breast cancer. A large variety of oncoplastic techniques exist; however, it remains unclear which techniques yield the highest rates of local control at first surgery, omission of reexcision or subsequent mastectomy, and merits the highest degree of patient satisfaction. METHODS: In this retrospective case cohort trial with a customized investigational questionnaire for assessment of patient satisfaction with the surgical result, we analyzed 1,035 patients with primary, unilateral breast cancer and oncoplastic surgery from 2004 to 2009. RESULTS: Analysis of patient reported outcome (PRO) revealed that 88 % of the cohort was satisfied with their aesthetic result using oncoplastic techniques following the concept presented. These results also were achieved in difficult tumor localizations, such as upper inner and lower inner quadrant. Conversion rate from breast-conserving therapy to secondary mastectomy was low at 7.2 % (n = 68/944 patients). The systematization of oncoplastic techniques presented-embedded in a multimodal concept of breast cancer therapy-facilitates tumor control with a few number of uncomplicated techniques adapted to tumor site and size with a median resection of 32 (range 11-793) g. Five-year recurrence rate in our cohort was 4.0 %. CONCLUSIONS: Patient's satisfaction was independent from age, body mass index, resection volume, tumor localization, and type of oncoplastic surgery (p > 0.05). We identified postoperative pain as an important negative impact factor on patient's satisfaction with the aesthetic result (p = 0.0001).